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Sample records for dipeptide amide inhibitors

  1. Synthesis and Evaluation of Coumaroyl Dipeptide Amide as Potential Whitening Agents

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jaeil; Lee, Jaeho [Gwangju Institute of Science and Technology, Gwangju (Korea, Republic of); Lee, Hyesuk; Shin, Kyonghoon; Ryu, Geunseog; Cho, Inshik; Kim, Hanyoung [Central Research Laboratories, Daejeon (Korea, Republic of)

    2013-10-15

    Coumaroyl dipeptide amide, Coumaric acid-LG-NH{sub 2}, was prepared successfully using the solid-phase method, and its efficacy as a skin whitening agent was studied. Coumaric acid-LG-NH{sub 2} was prepared with Rink-amide resin, and 96.354% of purity was obtained. Using MTT assay and LDH release assay, we found that it exhibited very low cytotoxicity. And, we found that Coumaric acid-LG-NH{sub 2} inhibited tyrosinase activity dose-dependently and showed superior tyrosinase inhibitory activity to well-known whitening agent, arbutin. IC{sub 50} value of Coumaric acid-LG-NH{sub 2} was 182.4 μM, and IC{sub 50} value of arbutin was 384.6 μM. Also, in measurement of melanin contents using B16F1 melanoma cell lines, Coumaric acid-LG-NH{sub 2} reduced melanin production induced by α-MSH statistically significant, and showed superior melanin inhibitory activity to p-coumaric acid or arbutin. In addition, Coumaric acid-LG-NH{sub 2} reduced MC1R mRNA expression level. Thus, we concluded that MC1R pathway is the significant pathway of Coumaric acid-LG-NH{sub 2}, and Coumaric acid-LG-NH{sub 2} has great potential to be used as novel whitening agents.

  2. Dipeptide-derived nitriles containing additional electrophilic sites: potentially irreversible inhibitors of cysteine proteases.

    Science.gov (United States)

    Löser, Reik; Gütschow, Michael

    2009-12-01

    Heterocyclic and open-chain dipeptide-derived nitriles have been synthesized, containing an additional electrophilic center enabling the subsequent covalent modification of the thioimidate nitrogen formed in situ at the active site of the enzyme. The inhibitory potential of these nitriles against the cysteine proteases papain and cathepsins L, S, and K was determined. The open-chain dipeptide nitriles 8 and 10 acted as moderate reversible inhibitors, but no evidence for an irreversible inhibition of these enzymes was discernable.

  3. Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors.

    Science.gov (United States)

    Schmitz, Janina; Furtmann, Norbert; Ponert, Moritz; Frizler, Maxim; Löser, Reik; Bartz, Ulrike; Bajorath, Jürgen; Gütschow, Michael

    2015-08-01

    Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex class II. Cathepsin S is the major processing enzyme of the invariant chain, but cathepsin F acts in macrophages as its functional synergist which is as potent as cathepsin S in invariant chain cleavage. Dedicated low-molecular-weight inhibitors for cathepsin F have not yet been developed. An active site mapping with 52 dipeptide nitriles, reacting as covalent-reversible inhibitors, was performed to draw structure-activity relationships for the non-primed binding region of human cathepsin F. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsins F, B, L, K and S. Compounds 10 (N-(4-phenylbenzoyl)-leucylglycine nitrile) and 12 (N-(4-phenylbenzoyl)leucylmethionine nitrile) were found to be potent inhibitors of human cathepsin F, with Ki values nitriles from our study, a 3D activity landscape was generated to visualize structure-activity relationships for this series of cathepsin F inhibitors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state.

    Science.gov (United States)

    Xu, Guoyan G; Zhang, Yan; Mercedes-Camacho, Ana Y; Etzkorn, Felicia A

    2011-11-08

    The mechanism of the cell cycle regulatory peptidyl prolyl isomerase (PPIase), Pin1, was investigated using reduced-amide inhibitors designed to mimic the twisted-amide transition state. Inhibitors, R-pSer-Ψ[CH(2)N]-Pro-2-(indol-3-yl)ethylamine, 1 [R = fluorenylmethoxycarbonyl (Fmoc)] and 2 (R = Ac), of Pin1 were synthesized and bioassayed. Inhibitor 1 had an IC(50) value of 6.3 μM, which is 4.5-fold better for Pin1 than our comparable ground-state analogue, a cis-amide alkene isostere-containing inhibitor. The change of Fmoc to Ac in 2 improved aqueous solubility for structural determination and resulted in an IC(50) value of 12 μM. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 Å resolution. The structure revealed that the reduced amide adopted a conformation similar to the proposed twisted-amide transition state of Pin1, with a trans-pyrrolidine conformation of the prolyl ring. A similar conformation of substrate would be destabilized relative to the planar amide conformation. Three additional reduced amides, with Thr replacing Ser and l- or d-pipecolate (Pip) replacing Pro, were slightly weaker inhibitors of Pin1.

  5. Evaluation of dipeptide nitriles as inhibitors of rhodesain, a major cysteine protease of Trypanosoma brucei.

    Science.gov (United States)

    Schirmeister, Tanja; Schmitz, Janina; Jung, Sascha; Schmenger, Torsten; Krauth-Siegel, R Luise; Gütschow, Michael

    2017-01-01

    A series of dipeptide nitriles known as inhibitors of mammalian cathepsins were evaluated for inhibition of rhodesain, the cathepsin L-like protease of Trypanosoma brucei. Compound 35 consisting of a Leu residue fitting into the S2 pocket and a triarylic moiety consisting of thiophene, a 1,2,4-oxadiazole and a phenyl ring fitting into the S3 pocket, and compound 33 with a 3-bromo-Phe residue (S2) and a biphenyl fragment (S3) were found to inhibit rhodesain in the single-digit nanomolar range. The observed steep structure-activity relationship could be explained by covalent docking simulations. With their high selectivity indices (ca. 200) and the good antitrypanosomal activity (8μM) the compounds represent promising starting points for new rhodesain inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Novel substrates and inhibitors of peptidylglycine alpha-amidating monooxygenase.

    Science.gov (United States)

    Katopodis, A G; May, S W

    1990-05-15

    Peptidylglycine alpha-amidating monooxygenase (PAM, EC 1.14.17.3) catalyzes the formation of alpha-amidated peptides from their glycine-extended precursors, thus playing a key role in the processing of peptide neurohormones. We now report that PAM readily catalyzes three alternate monooxygenase reactions--sulfoxidation, amine N-dealkylation, and O-dealkylation. Thus, (4-nitrobenzyl)thioacetic acid is converted to the analogous sulfoxide, N-(4-nitrobenzyl)glycine is converted to 4-nitrobenzylamine and glyoxylate, and [(4-nitrobenzyl)oxy]acetic acid is converted to 4-nitrobenzyl alcohol and glyoxylate. All these new activities display the characteristics expected for the normal PAM-catalyzed reductive oxygenation pathway and produce an equimolar amount of glyoxylate together with the heteroatom-containing dealkylation products. The ester [(4-methoxybenzoyl)oxy]acetic acid is not a PAM substrate, but is instead a good competitive inhibitor (KI = 0.48 mM). In addition, we report that the olefinic substrate analogues trans-benzoylacrylic acid and 4-phenyl-3-butenoic acid are potent time-dependent inactivators of PAM, with inactivation exhibiting the characteristics expected for mechanism-based inhibition. Monoethyl fumarate is also a time-dependent inactivator of PAM. Finally, we introduce several small non-peptide substrates for PAM by demonstrating that PAM catalyzes the transformation of hippuric acid and several ring-substituted derivatives to the corresponding benzamides and glyoxylic acid, with the most facile substrate of this class being 4-nitrohippuric acid. These compounds are the smallest amide substrates yet reported for PAM, and it is thus apparent that only the minimal structure of an acylglycine is required for PAM-catalyzed oxygenative amidation.

  7. Synthesis and activity study of phosphonamidate dipeptides as potential inhibitors of VanX.

    Science.gov (United States)

    Yang, Ke-Wu; Cheng, Xu; Zhao, Chuan; Liu, Cheng-Cheng; Jia, Chao; Feng, Lei; Xiao, Jian-Min; Zhou, Li-Sheng; Gao, Hui-Zhou; Yang, Xia; Zhai, Le

    2011-12-01

    In an effort to develop inhibitors of VanX, the phosphonamidate analogs of D-Ala-D-Ala dipeptides, N-[(1-aminoethyl) hydroxyphosphinyl]-glycine (1a), -alanine (1b), -valine (1c), -leucine (1d) and -phenylalanine (1e) were synthesized, characterized and evaluated using recombinant VanX. The crystal structure of the intermediate 6d was obtained (Deposition number: CCDC 839134), and structural analysis revealed that it is orthorhombic with a space group P2(1)2(1)2(1), the bond length of P-N is 1.62Å and angle of C-N-P is 123.6°. Phosphonamidate 1(a-e) showed to be inhibitors of VanX with IC(50) values of 0.39, 0.70, 1.12, 2.82, and 4.13mM, respectively, which revealed that the inhibition activities of the phosphonamidates were dependent on the size of R-substituent of them, with the best inhibitor 1a having the smallest substituent. Also, 1a showed antibacterial activity against Staphylococcus aureus (ATCC 25923) with a MIC value of 0.25 μg/ml.

  8. Protein-Templated Formation of an Inhibitor of the Blood Coagulation Factor Xa through a Background-Free Amidation Reaction.

    Science.gov (United States)

    Jaegle, Mike; Steinmetzer, Torsten; Rademann, Jörg

    2017-03-20

    Protein-templated reactions enable the target-guided formation of protein ligands from reactive fragments, ideally with no background reaction. Herein, we investigate the templated formation of amides. A nucleophilic fragment that binds to the coagulation factor Xa was incubated with the protein and thirteen differentially activated dipeptides. The protein induced a non-catalytic templated reaction for the phenyl and trifluoroethyl esters; the latter was shown to be a completely background-free reaction. Starting from two fragments with millimolar affinity, a 29 nm superadditive inhibitor of factor Xa was obtained. The fragment ligation reaction was detected with high sensitivity by an enzyme activity assay and by mass spectrometry. The reaction progress and autoinhibition of the templated reaction by the formed ligation product were determined, and the structure of the protein-inhibitor complex was elucidated.

  9. Clicked Cinnamic/Caffeic Esters and Amides as Radical Scavengers and 5-Lipoxygenase Inhibitors

    OpenAIRE

    Doiron, Jérémie A.; Benoît Métayer; Ryan R. Richard; Dany Desjardins; Boudreau, Luc H.; Natalie A. Levesque; Jacques Jean-François; Samuel J. Poirier; Surette, Marc E.; Mohamed Touaibia

    2014-01-01

    5-Lipoxygenase (5-LO) is the key enzyme responsible for the conversion of arachidonic acid to leukotrienes, a class of lipid mediators implicated in inflammatory disorders. In this paper, we describe the design, synthesis, and preliminary activity studies of novel clicked caffeic esters and amides as radical scavengers and 5-LO inhibitors. From known 5-LO inhibitor 3 as a lead, cinnamic esters 8a–h and amides 9a–h as well as caffeic esters 15a–h and amides 16a–h were synthesized by Cu(I)-cata...

  10. Pain and beyond: fatty acid amides and fatty acid amide hydrolase inhibitors in cardiovascular and metabolic diseases.

    Science.gov (United States)

    Pillarisetti, Sivaram; Alexander, Christopher W; Khanna, Ish

    2009-12-01

    Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of several important endogenous fatty acid amides (FAAs), including anandamide, oleoylethanolamide and palmitoylethanolamide. Because specific FAAs interact with cannabinoid and vanilloid receptors, they are often referred to as 'endocannabinoids' or 'endovanilloids'. Initial interest in this area, therefore, has focused on developing FAAH inhibitors to augment the actions of FAAs and reduce pain. However, recent literature has shown that these FAAs - through interactions with unique receptors (extracellular and intracellular) - can induce a diverse array of effects that include appetite suppression, modulation of lipid and glucose metabolism, vasodilation, cardiac function and inflammation. This review gives an overview of FAAs and diverse FAAH inhibitors and their potential therapeutic utility in pain and non-pain indications.

  11. L-Homoserylaminoethanol, a novel dipeptide alcohol inhibitor of eukaryotic DNA polymerase from a plant cultured cells, Nicotina tabacum L.

    Science.gov (United States)

    Kuriyama, Isoko; Asano, Naoki; Kato, Ikuo; Oshige, Masahiko; Sugino, Akio; Kadota, Yasuhiro; Kuchitsu, Kazuyuki; Yoshida, Hiromi; Sakaguchi, Kengo; Mizushina, Yoshiyuki

    2004-03-01

    We found a novel inhibitor specific to eukaryotic DNA polymerase epsilon(pol epsilon) from plant cultured cells, Nicotina tabacum L. The compound (compound 1) was a dipeptide alcohol, L-homoserylaminoethanol. The 50% inhibition of pol epsilon activity by the compound was 43.6 microg/mL, and it had almost no effect on the activities of the other eukaryotic DNA polymerases such as alpha, beta, gamma and delta, prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human telomerase, human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase, human DNA topoisomerase I and II, T4 polynucleotide kinase and bovine deoxyribonuclease I. Kinetic studies showed that inhibition of pol epsilon by the compound was non-competitive with respect to both template-primer DNA and nucleotide substrate. We succeeded in chemically synthesizing the stereoisomers, L-homoserylaminoethanol and D-homoserylaminoethanol, and found both were effective to the same extent. The IC(50) values of L- and D-homoserylaminoethanols for pol epsilon were 42.0 and 41.5 microg/mL, respectively. This represents the second discovery of a pol epsilon-specific inhibitor, and the first report on a water-soluble peptide-like compound as the inhibitor, which is required in biochemical studies of pol epsilon.

  12. Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH).

    Science.gov (United States)

    Aghazadeh Tabrizi, Mojgan; Baraldi, Pier Giovanni; Ruggiero, Emanuela; Saponaro, Giulia; Baraldi, Stefania; Romagnoli, Romeo; Martinelli, Adriano; Tuccinardi, Tiziano

    2015-06-05

    Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article.

  13. The design, synthesis of amide KARI inhibitors and their biological activities

    Institute of Scientific and Technical Information of China (English)

    Baolei WANG; Yi MA; Yonghong LI; Suhua WANG; Zhengming LI

    2009-01-01

    Ketol-acid reductoisomerase(KARI) is a promising target for the design of herbicides yet there are only few reports on the molecular design of KARI inhibitors. In this paper, based on the reported 0.165 nm high resolution crystal structure of the spinach KARI complex, 279 molecules with low binding energy toward KARI were obtained from an MDL/ACD 3D database search using the program DOCK 4.0. According to the structural information of 279 molecules provided, some amide compounds have been designed and synthesized. The bioassay results show that most of these amides had inhibitory activity to rice KARI at a test concentration of 200 μg/mL. Among which eight amides, compounds 1 and 6 show 57.4% and 48.1% inhibitory activity to KARI. The herbicidal activities of these amides were further investigated on di-cotyledonous rape (Brassica campestris) and mono-cotyledonous bar-nyardgrass (Echinochloa crusgalli). Compounds 1 and 6 were more favorable than others and showed 52.0% and 72.6% inhibitory activity on rape root at 100 μg/mL concentration, respectively. These amides could be further optimized for finding more potent candidates.

  14. Clicked Cinnamic/Caffeic Esters and Amides as Radical Scavengers and 5-Lipoxygenase Inhibitors

    Directory of Open Access Journals (Sweden)

    Jérémie A. Doiron

    2014-01-01

    Full Text Available 5-Lipoxygenase (5-LO is the key enzyme responsible for the conversion of arachidonic acid to leukotrienes, a class of lipid mediators implicated in inflammatory disorders. In this paper, we describe the design, synthesis, and preliminary activity studies of novel clicked caffeic esters and amides as radical scavengers and 5-LO inhibitors. From known 5-LO inhibitor 3 as a lead, cinnamic esters 8a–h and amides 9a–h as well as caffeic esters 15a–h and amides 16a–h were synthesized by Cu(I-catalyzed [1,3]-dipolar cycloaddition with the appropriate azide precursors and terminal alkynes. All caffeic analogs are proved to be good radical scavengers (IC50: 10–20 μM. Esters 15g and 15f possessed excellent 5-LO inhibition activity in HEK293 cells and were equipotent with the known 5-LO inhibitor CAPE and more potent than Zileuton. Several synthesized esters possess activities rivaling Zileuton in stimulated human polymorphonuclear leukocytes.

  15. Amide-based inhibitors of p38alpha MAP kinase. Part 2: design, synthesis and SAR of potent N-pyrimidyl amides.

    Science.gov (United States)

    Tester, Richland; Tan, Xuefei; Luedtke, Gregory R; Nashashibi, Imad; Schinzel, Kurt; Liang, Weiling; Jung, Joon; Dugar, Sundeep; Liclican, Albert; Tabora, Jocelyn; Levy, Daniel E; Do, Steven

    2010-04-15

    Optimization of a tri-substituted N-pyridyl amide led to the discovery of a new class of potent N-pyrimidyl amide based p38alpha MAP kinase inhibitors. Initial SAR studies led to the identification of 5-dihydrofuran as an optimal hydrophobic group. Additional side chain modifications resulted in the introduction of hydrogen bond interactions. Through extensive SAR studies, analogs bearing free amino groups and alternatives to the parent (S)-alpha-methyl benzyl moiety were identified. These compounds exhibited improved cellular activities and maintained balance between p38alpha and CYP3A4 inhibition.

  16. Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.

    Science.gov (United States)

    Lucas, Matthew C; Bhagirath, Niala; Chiao, Eric; Goldstein, David M; Hermann, Johannes C; Hsu, Pei-Yuan; Kirchner, Stephan; Kennedy-Smith, Joshua J; Kuglstatter, Andreas; Lukacs, Christine; Menke, John; Niu, Linghao; Padilla, Fernando; Peng, Ying; Polonchuk, Liudmila; Railkar, Aruna; Slade, Michelle; Soth, Michael; Xu, Daigen; Yadava, Preeti; Yee, Calvin; Zhou, Mingyan; Liao, Cheng

    2014-03-27

    Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.

  17. Novel amide derivatives as inhibitors of histone deacetylase: design, synthesis and SAR

    DEFF Research Database (Denmark)

    Andrianov, V.; Gailite, V.; Lola, D.;

    2009-01-01

    HDAC inhibitors (HDACi), with IC(50) values in the low nanomolar (nM) range against enzyme activity in HeLa cell extracts and sub-microM for their in vitro anti-proliferative effect on cell lines. The introduction of an unsaturated linking group between the terminal aryl ring and the amide moiety...... was the key to obtain good potency. This approach yielded compounds such as (E)-N-[6-(hydroxyamino)-6-oxohexyl]-3-(7-quinolinyl)-2-propenamide (27) (HDAC IC(50) 8 nM) which showed potent in vivo activity in the P388 mouse leukemia syngeneic model (an increased lifespan (ILS) of 111% was obtained...

  18. Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase.

    Science.gov (United States)

    Kim, In-Hae; Park, Yong-Kyu; Nishiwaki, Hisashi; Hammock, Bruce D; Nishi, Kosuke

    2015-11-15

    Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore.

  19. Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies.

    Science.gov (United States)

    Thanigaimalai, Pillaiyar; Konno, Sho; Yamamoto, Takehito; Koiwai, Yuji; Taguchi, Akihiro; Takayama, Kentaro; Yakushiji, Fumika; Akaji, Kenichi; Chen, Shen-En; Naser-Tavakolian, Aurash; Schön, Arne; Freire, Ernesto; Hayashi, Yoshio

    2013-10-01

    We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.

  20. Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: structure-activity relationship study.

    Science.gov (United States)

    Thanigaimalai, Pillaiyar; Konno, Sho; Yamamoto, Takehito; Koiwai, Yuji; Taguchi, Akihiro; Takayama, Kentaro; Yakushiji, Fumika; Akaji, Kenichi; Kiso, Yoshiaki; Kawasaki, Yuko; Chen, Shen-En; Naser-Tavakolian, Aurash; Schön, Arne; Freire, Ernesto; Hayashi, Yoshio

    2013-07-01

    This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CL(pro). In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1' position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  1. Addition of thiols to the double bond of dipeptide C-terminal dehydroalanine as a source of new inhibitors of cathepsin C.

    Science.gov (United States)

    Lenartowicz, Paweł; Makowski, Maciej; Oszywa, Bartosz; Haremza, Kinga; Latajka, Rafał; Pawełczak, Małgorzata; Kafarski, Paweł

    2017-08-01

    Addition of thiols to double bond of glycyl-dehydroalanine and phenyl-dehydroalanine esters provided micromolar inhibitors of cathepsin C. The structure-activity studies indicated that dipeptides containing N-terminal phenylalanine exhibit higher affinity towards the enzyme. A series of C-terminal S-substituted cysteines are responsible for varying interaction with S1 binding pocket of cathepsin C. Depending on diastereomer these compounds most likely act as slowly reacting substrates or competitive inhibitors. This was proved by TLC analysis of the medium in which interaction of methyl (S)-phenylalanyl-(R,S)-(S-adamantyl)cysteinate (7i) with the enzyme was studied. Molecular modeling enabled to establish their mode of binding showed that S2 pocket is long and narrow and accommodates phenyl group of phenylalanine while significantly spacious sites located at the surface of the enzyme (one of them being S1 pocket) bind the adamantyl moiety oriented in different direction for each stereoisomer. Finally replacement of carboxymethyl moiety of methyl (S)-phenylalanyl-(R,S)-(S-phenyl)cysteinate (7c) with nitrile group provided about 650-times more potent inhibitor of cathepsin C indicating that the studied C-terminal S-substituted cysteines are good activity probes for S1 binding pocket of this enzyme. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  2. Design, synthesis and biological evaluation of benzamide and phenyltetrazole derivatives with amide and urea linkers as BCRP inhibitors.

    Science.gov (United States)

    Gujarati, Nehaben A; Zeng, Leli; Gupta, Pranav; Chen, Zhe-Sheng; Korlipara, Vijaya L

    2017-10-15

    Breast cancer resistant protein (BCRP/ABCG2), a 72kDa plasma membrane transporter protein is a member of ABC transporter superfamily. Increased expression of BCRP causes increased efflux and therefore, reduced intracellular accumulation of many unrelated chemotherapeutic agents leading to multidrug resistance (MDR). A series of 31 benzamide and phenyltetrazole derivatives with amide and urea linkers has been synthesized to serve as potential BCRP inhibitors in order to overcome BCRP-mediated MDR. The target derivatives were tested for their cytotoxicity and reversal effects in human non-small cell lung cancer cell line H460 and mitoxantrone resistant cell line H460/MX20 using the MTT assay. In the benzamide series, compounds 6 and 7 exhibited a fold resistance of 1.51 and 1.62, respectively at 10µM concentration which is similar to that of FTC, a known BCRP inhibitor. Compounds 27 and 31 were the most potent analogues in the phenyltetrazole series with amide linker with a fold resistance of 1.39 and 1.32, respectively at 10µM concentration. For the phenyltetrazole series with urea linker, 38 exhibited a fold resistance of 1.51 which is similar than that of FTC and is the most potent compound in this series. The target compounds did not exhibit reversal effect in P-gp overexpressing resistant cell line SW620/Ad300 suggesting that they are selective BCRP inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Discovery of new nanomolar inhibitors of GPa: Extension of 2-oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors.

    Science.gov (United States)

    Loughlin, Wendy A; Jenkins, Ian D; Karis, N David; Healy, Peter C

    2017-02-15

    Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold. Upon exploring a dimer strategy as part of the SAR analysis, the first extended 2-oxo-dihydropyridinyl-3-yl amide nanomolar based inhibitors of GPa (IC50 = 230 and 260 nM) were identified. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Bestatin Induces Specific Changes in Trypanosoma cruzi Dipeptide Pool

    OpenAIRE

    2015-01-01

    Proteases and peptidases in Trypanosoma cruzi are considered potential targets for antichagasic chemotherapy. We monitored changes in low-mass metabolites in T. cruzi epimastigotes treated with bestatin, a dipeptide metalloaminopeptidase inhibitor. After treatment, multiple dipeptides were shown to be increased, confirming in situ inhibition of the leucine aminopeptidase of T. cruzi (LAPTc) and probably other peptidases.

  5. Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors.

    Science.gov (United States)

    Jonckers, Tim H M; Rouan, Marie-Claude; Haché, Geerwin; Schepens, Wim; Hallenberger, Sabine; Baumeister, Judith; Sasaki, Jennifer C

    2012-08-01

    A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory properties as well as overall ADME profile of these amide derivatives. This led to the identification of thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole-6-carboxamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together with structurally similar analogues demonstrated excellent 'boosting' properties when tested in dogs. These findings warrant further evaluation of their properties in an effort to identify valuable alternatives to Ritonavir as pharmacokinetic enhancers.

  6. Secondary amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase.

    Science.gov (United States)

    Aicher, T D; Anderson, R C; Gao, J; Shetty, S S; Coppola, G M; Stanton, J L; Knorr, D C; Sperbeck, D M; Brand, L J; Vinluan, C C; Kaplan, E L; Dragland, C J; Tomaselli, H C; Islam, A; Lozito, R J; Liu, X; Maniara, W M; Fillers, W S; DelGrande, D; Walter, R E; Mann, W R

    2000-01-27

    N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.

  7. O-(triazolyl)methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors.

    Science.gov (United States)

    Colombano, Giampiero; Albani, Clara; Ottonello, Giuliana; Ribeiro, Alison; Scarpelli, Rita; Tarozzo, Glauco; Daglian, Jennifer; Jung, Kwang-Mook; Piomelli, Daniele; Bandiera, Tiziano

    2015-02-01

    Inhibition of fatty acid amide hydrolase (FAAH) activity is under investigation as a valuable strategy for the treatment of several disorders, including pain and drug addiction. A number of potent FAAH inhibitors belonging to different chemical classes have been disclosed to date; O-aryl carbamates are one of the most representative families. In the search for novel FAAH inhibitors, a series of O-(1,2,3-triazol-4-yl)methyl carbamate derivatives were designed and synthesized exploiting a copper- catalyzed [3+2] cycloaddition reaction between azides and alkynes (click chemistry). Exploration of the structure-activity relationships within this new class of compounds identified potent inhibitors of both rat and human FAAH with IC50 values in the single-digit nanomolar range. In addition, these derivatives showed improved stability in rat plasma and kinetic solubility in buffer with respect to the lead compound. Based on the results of the study, the novel analogues identified can be considered to be promising starting point for the development of new FAAH inhibitors with improved drug-like properties. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Steric effects on the rate of hydrolysis by palladium(II) complexes of the C-terminal amide bond in a series of methionine-containing dipeptides AcMet-Aa

    OpenAIRE

    NENAD M. KOSTIC; T. WADE JOHNSON

    2004-01-01

    A series of N-acetylated, methionine-containing dipeptides designated AcMet-Aa containing various C-terminal amino acids designated Aa are hydrolyzed in aqueous solution at 50 ºC and 0.95 < pD < 1.10 in the presence of three cis-[Pd(L)(H2O)2]2+ complexes, in which L are bidentate ligands en, Me4en, and 3-OH-dtco. The reactions were monitored by 1H-NMR spectroscopy. The rate constant for hydrolytic cleavage of the Met-Aa bond decreases as the steric bulk of the amino acid Aa increases. Correla...

  9. Structure-based and property-compliant library design of 11β-HSD1 adamantyl amide inhibitors.

    Science.gov (United States)

    Paderes, Genevieve D; Dress, Klaus; Huang, Buwen; Elleraas, Jeff; Rejto, Paul A; Pauly, Tom

    2011-01-01

    Multiproperty lead optimization that satisfies multiple biological endpoints remains a challenge in the pursuit of viable drug candidates. Optimization of a given lead compound to one having a desired set of molecular attributes often involves a lengthy iterative process that utilizes existing information, tests hypotheses, and incorporates new data. Within the context of a data-rich corporate setting, computational tools and predictive models have provided the chemists a means for facilitating and streamlining this iterative design process. This chapter discloses an actual library design scenario for following up a lead compound that inhibits 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. The application of computational tools and predictive models in the targeted library design of adamantyl amide 11β-HSD1 inhibitors is described. Specifically, the multiproperty profiling using our proprietary PGVL (Pfizer Global Virtual Library) Hub is discussed in conjunction with the structure-based component of the library design using our in-house docking tool AGDOCK. The docking simulations were based on a piecewise linear potential energy function in combination with an efficient evolutionary programming search engine. The library production protocols and results are also presented.

  10. Lecithin:retinol acyltransferase is responsible for amidation of retinylamine, a potent inhibitor of the retinoid cycle.

    Science.gov (United States)

    Golczak, Marcin; Imanishi, Yoshikazu; Kuksa, Vladimir; Maeda, Tadao; Kubota, Ryo; Palczewski, Krzysztof

    2005-12-23

    Lecithin:retinol acyltransferase (LRAT) catalyzes the transfer of an acyl group from the sn-1 position of phosphatidylcholine to all-trans-retinol (vitamin A) and plays an essential role in the regeneration of visual chromophore as well as in the metabolism of vitamin A. Here we demonstrate that retinylamine (Ret-NH2), a potent and selective inhibitor of 11-cis-retinal biosynthesis (Golczak, M., Kuksa, V., Maeda, T., Moise, A. R., and Palczewski, K. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 8162-8167), is a substrate for LRAT. LRAT catalyzes the transfer of the acyl group onto Ret-NH2 leading to the formation of N-retinylpalmitamide, N-retinylstearamide, and N-retinylmyristamide with a ratio of 15:6:2, respectively. The presence of N-retinylamides was detected in vivo in mice supplemented with Ret-NH2. N-Retinylamides are thus the main metabolites of Ret-NH2 in the liver and the eye and can be mobilized by hydrolysis/deamidation back to Ret-NH2. Using two-photon microscopy and the intrinsic fluorescence of N-retinylamides, we showed that newly formed amides colocalize with the retinyl ester storage particles (retinosomes) in the retinal pigment epithelium. These observations provide new information concerning the substrate specificity of LRAT and explain the prolonged effect of Ret-NH2 on the rate of 11-cis-retinal recovery in vivo.

  11. Design and Synthesis of Bis-amide and Hydrazide-containing Derivatives of Malonic Acid as Potential HIV-1 Integrase Inhibitors

    Directory of Open Access Journals (Sweden)

    Nouri Neamati

    2008-10-01

    Full Text Available HIV-1 integrase (IN is an attractive and validated target for the development of novel therapeutics against AIDS. In the search for new IN inhibitors, we designed and synthesized three series of bis-amide and hydrazide-containing derivatives of malonic acid. We performed a docking study to investigate the potential interactions of the title compounds with essential amino acids on the IN active site.

  12. Chemistry around imidazopyrazine and ibuprofen: discovery of novel fatty acid amide hydrolase (FAAH) inhibitors.

    Science.gov (United States)

    De Wael, Frédéric; Muccioli, Giulio G; Lambert, Didier M; Sergent, Thérèse; Schneider, Yves-Jacques; Rees, Jean-François; Marchand-Brynaert, Jacqueline

    2010-09-01

    Based on the imidazo-[1,2-a]-pyrazin-3-(7H)-one scaffold, a dual action prodrug has been designed for combining antioxidant and anti-inflammatory activities, possibly unmasked upon oxidation. The construction of the target-molecule requires two building blocks, namely a 2-amino-1,4-pyrazine and a 2-ketoaldehyde. Attempts to synthesize the 2-ketoaldehyde (5a) derived from ibuprofen failed, but led to the corresponding 2-ketoaldoxime (7a) which could not be condensed with the pyrazine synthons. However, a model compound, i.e. phenylglyoxal aldoxime, reacted well under microwave activation to furnish novel imidazo[1,2-a]-pyrazine-3-(7H)-imine derivatives (18a,b). These heterobicycles behave as antioxidants by inhibiting the lipid peroxidation, and one compound (18b) is endowed with a significant anti-inflammatory effect in a cellular test. Unexpectedly, all the synthetic intermediates derived from ibuprofen are good inhibitors of FAAH, the most active compound (4a) featuring the 1,3-dithian-2-yl motif.

  13. Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors.

    Science.gov (United States)

    Ruff, Michael R; Polianova, Maria; Yang, Quan-en; Leoung, Gifford S; Ruscetti, Francis W; Pert, Candace B

    2003-01-01

    Peptide T, named for its high threonine content (ASTTTNYT), was derived by a database search which assumed that a relevant receptor binding epitope within env (gp120) would have sequence homology to a known signaling peptide. Binding of radiolabeled gp120 to brain membranes was displaced by peptide T and three octapeptide analogs (including "DAPTA", Dala1-peptide T-amide, the protease-resistant analog now in Phase II clinical trials) with the same potency that these four octapeptides blocked infectivity of an early passage patient isolate. This 1986 report was controversial due to a number of laboratories' failure to find peptide T antiviral effects; we now know that peptide T is a potent HIV entry inhibitor selectively targeting CCR5 receptors with minimal effects on the X4 tropic lab adapted virus exclusively in use at that time. Early clinical trials, which demonstrated lack of toxicity and focused on neurological and neurocognitive benefits, are reviewed and data from a small ongoing Phase II trial--the first to assess peptide T's antiviral effects--are presented. Studies using infectivity, receptor binding, chemotaxis, and blockade of gp120-induced neurotoxicity in vitro and in vivo are reviewed, discussed and presented here. Peptide T and analogs of its core pentapeptide, present near the V2 stem of numerous gp120 isolates, are potent ligands for CCR5. Clinical data showing peptide T's immunomodulation of plasma cytokine levels and increases in the percentage of IFNgamma secreting CD8+ T cells in patients with HIV disease are presented and suggests additional therapeutic mechanisms via regulation of specific immunity.

  14. 2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study.

    Science.gov (United States)

    Loughlin, Wendy A; Jenkins, Ian D; Karis, N David; Schweiker, Stephanie S; Healy, Peter C

    2016-03-23

    Glycogen phosphorylase (GP), which plays a crucial role in the conversion of glycogen to glucose-1-phosphate, is a target for therapeutic intervention in diabetes. In this study, we report the design and synthesis of 29 new derivatives of 2-oxo-1,2-dihydro pyridin-3-yl amides, as potential inhibitors of GP. The hit rate (45%) was high with 13 compounds inhibiting GPa (between 33% at 4.40 mM and an IC50 of 1.92 μM). Two lead compounds were identified as compounds exhibiting good GPa inhibition (IC50 = 2.1 and 1.92 μM). SAR analysis of these compounds revealed sensitivity of GPa to the length of the 2-oxo-1,2-dihydro pyridin-3-yl amide derivative and a preference for inclusion of a 3,4-dichlorobenzyl moiety. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Synthesis and Structure-activity Relationship Studies of O-Biphenyl-3-yl Carbamates as Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitors

    Science.gov (United States)

    Moreno-Sanz, Guillermo; Duranti, Andrea; Melzig, Laurin; Fiorelli, Claudio; Ruda, Gian Filippo; Colombano, Giampiero; Mestichelli, Paola; Sanchini, Silvano; Tontini, Andrea; Mor, Marco; Bandiera, Tiziano; Scarpelli, Rita; Tarzia, Giorgio; Piomelli, Daniele

    2014-01-01

    The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3’-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3’-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date. PMID:23822179

  16. Amidate prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine as inhibitors of adenylate cyclase toxin from Bordetella pertussis.

    Science.gov (United States)

    Šmídková, Markéta; Dvoráková, Alexandra; Tloust'ová, Eva; Česnek, Michal; Janeba, Zlatko; Mertlíková-Kaiserová, Helena

    2014-01-01

    Adenylate cyclase toxin (ACT) is the key virulence factor of Bordetella pertussis that facilitates its invasion into the mammalian body. 9-[2-(Phosphonomethoxy)ethyl]adenine diphosphate (PMEApp), the active metabolite of the antiviral drug bis(POM)PMEA (adefovir dipivoxil), has been shown to inhibit ACT. The objective of this study was to evaluate six novel amidate prodrugs of PMEA, both phenyloxy phosphonamidates and phosphonodiamidates, for their ability to inhibit ACT activity in the J774A.1 macrophage cell line. The two phenyloxy phosphonamidate prodrugs exhibited greater inhibitory activity (50% inhibitory concentration [IC50] = 22 and 46 nM) than the phosphonodiamidates (IC50 = 84 to 3,960 nM). The inhibitory activity of the prodrugs correlated with their lipophilicity and the degree of their hydrolysis into free PMEA in J774A.1 cells. Although the prodrugs did not inhibit ACT as effectively as bis(POM)PMEA (IC50 = 6 nM), they were significantly less cytotoxic. Moreover, they all reduced apoptotic effects of ACT and prevented an ACT-induced elevation of intracellular [Ca(2+)]i. The amidate prodrugs were less susceptible to degradation in Caco-2 cells compared to bis(POM)PMEA, while they exerted good transepithelial permeability in this assay. As a consequence, a large amount of intact amidate prodrug is expected to be available to target macrophages in vivo. This feature makes nontoxic amidate prodrugs attractive candidates for further investigation as novel antimicrobial agents.

  17. Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain.

    Science.gov (United States)

    Hama, Aldric T; Germano, Peter; Varghese, Matthew S; Cravatt, Benjamin F; Milne, G Todd; Pearson, James P; Sagen, Jacqueline

    2014-01-01

    Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.

  18. P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile

    Energy Technology Data Exchange (ETDEWEB)

    Nair, Latha G.; Sannigrahi, Mousumi; Bogen, Stephane; Pinto, Patrick; Chen, Kevin X.; Prongay, Andrew; Tong, Xiao; Cheng, K.-C.; Girijavallabhann, Viyyoor; Njoroge, F. George (Merck)

    2010-09-03

    SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4,4-dimethyl lactam as the new P4 cap unit with improved potency (K*{sub i}, EC 90 = 70 nM) and pharmacokinetic properties (Rat AUC (PO) = 3.52 {micro}M h) compared to 1.

  19. Conformational analysis of PKI(5-22)amide, the active inhibitory fragment of the inhibitor protein of the cyclic AMP-dependent protein kinase.

    Science.gov (United States)

    Reed, J; De Ropp, J S; Trewhella, J; Glass, D B; Liddle, W K; Bradbury, E M; Kinzel, V; Walsh, D A

    1989-12-01

    Fourier-transform i.r. spectroscopy, 1H-n.m.r. spectroscopy and X-ray scattering were used to study the conformation and shape of the peptide PKI(5-22)amide, which contains the active site of the inhibitor protein of the cyclic AMP-dependent protein kinase [Cheng, Van Pattern, Smith & Walsh (1985) Biochem. J. 231, 655-661]. The X-ray-scattering solution studies show that the peptide has a compact structure with Rg 0.9 nm (9.0 A) and a linear maximum dimension of 2.5 nm (25A). Compatible with this, Fourier-transform i.r. and n.m.r. determinations indicate that the peptide contains approx. 26% alpha-helix located in the N-terminal one-third of the molecule. This region contains the phenylalanine residue that is one essential recognition determinant for high-affinity binding to the protein kinase catalytic site.

  20. Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.

    Science.gov (United States)

    Swidorski, Jacob J; Liu, Zheng; Sit, Sing-Yuen; Chen, Jie; Chen, Yan; Sin, Ny; Venables, Brian L; Parker, Dawn D; Nowicka-Sans, Beata; Terry, Brian J; Protack, Tricia; Rahematpura, Sandhya; Hanumegowda, Umesh; Jenkins, Susan; Krystal, Mark; Dicker, Ira B; Meanwell, Nicholas A; Regueiro-Ren, Alicia

    2016-04-15

    We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Use of enzyme inhibitors to evaluate the conversion pathways of ester and amide prodrugs: a case study example with the prodrug ceftobiprole medocaril.

    Science.gov (United States)

    Eichenbaum, Gary; Skibbe, Jennifer; Parkinson, Andrew; Johnson, Mark D; Baumgardner, Dawn; Ogilvie, Brian; Usuki, Etsuko; Tonelli, Fred; Holsapple, Jeff; Schmitt-Hoffmann, Anne

    2012-03-01

    An approach was developed that uses enzyme inhibitors to support the assessment of the pathways that are responsible for the conversion of intravenously administered ester and amide prodrugs in different biological matrices. The methodology was applied to ceftobiprole medocaril (BAL5788), the prodrug of the cephalosporin antibiotic, ceftobiprole. The prodrug was incubated in plasma, postmitochondrial supernatant fractions from human liver (impaired and nonimpaired), kidney, and intestine as well as erythrocytes, in the presence and absence of different enzyme inhibitors (acetylcholinesterase, pseudocholinesterase, retinyl palmitoyl hydrolase, serine esterases, amidases, and cholinesterase). Hydrolysis was rapid, extensive, and not dependent on the presence of β-nicotinamide-adenine dinucleotide phosphate (reduced form) in all matrices tested, suggesting the involvement of carboxylesterases but not P450 enzymes. Hydrolysis in healthy human plasma was rapid and complete and only partially inhibited in the presence of paraoxonase inhibitors or in liver from hepatic impaired patients, suggesting involvement of nonparaoxonase pathways. The results demonstrate the utility of this approach in confirming the presence of multiple conversion pathways of intravenously administered prodrugs and in the case of BAL5788 demonstrated that this prodrug is unlikely to be affected by genetic polymorphisms, drug interactions, or other environmental factors that might inhibit or induce the enzymes involved in its conversion.

  2. Amide hydrolysis of a novel chemical series of microsomal prostaglandin E synthase-1 inhibitors induces kidney toxicity in the rat

    National Research Council Canada - National Science Library

    Bylund, Johan; Annas, Anita; Hellgren, Dennis; Bjurström, Sivert; Andersson, Håkan; Svanhagen, Alexander

    2013-01-01

    A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats...

  3. Exploring the Phe-Gly Dipeptide-Derived Piperazinone Scaffold in the Search for Antagonists of the Thrombin Receptor PAR1

    Directory of Open Access Journals (Sweden)

    Ángel M. Valdivielso

    2014-04-01

    Full Text Available A series of Phe-Gly dipeptide-derived piperazinones containing an aromatic urea moiety and a basic amino acid has been synthesized and evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cells. The synthetic strategy involves coupling of a protected basic amino acid benzyl amide to 1,2- and 1,2,4-substituted-piperazinone derivatives, through a carbonylmethyl group at the N1-position, followed by formation of an aromatic urea at the exocyclic moiety linked at the C2 position of the piperazine ring and removal of protecting groups. None of the compounds showed activity in the biological evaluation.

  4. Probing ligand-binding modes and binding mechanisms of benzoxazole-based amide inhibitors with soluble epoxide hydrolase by molecular docking and molecular dynamics simulation.

    Science.gov (United States)

    Chen, Hang; Zhang, Ying; Li, Liang; Han, Ju-Guang

    2012-08-30

    Soluble epoxide hydrolase (sEH) has become a new therapeutic target for treating a variety of human diseases. The inhibition of human sEH hydrolase activity was studied by molecular docking and molecular dynamics (MD) simulation techniques. A set of six benzoxazole-based amide inhibitors binding to sEH has been studied through molecular docking, MD simulation, free energy calculations, and energy decomposition analysis. On the basis of molecular mechanics-generalized Born/surface area (MM-GB/SA) computation and normal-mode analysis (NMA), the obtained results indicate that the rank of calculated binding free energies (ΔΔGTOT) of these inhibitors is in excellent agreement with that of experimental bioactivity data (IC50). The correlation coefficient (r(2)) between the predicted ΔΔGTOT and IC50 is 0.88. van der Waals energies are the largest component of the total energies, and the entropy changes play an indispensable role in determining the ΔΔGTOT. Rational binding modes were discussed and determined by the docking results and binding free energies. The free energy decomposition of each residue reveals that the residue Trp334 dominates the most binding free energies among all residues and that the activities for these molecules to the sEH are not decided by hydrogen bonds or a certain residue but by the common effect of multiple side chains in the active site.

  5. Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: synthesis, biological activity, and computational evaluation.

    Science.gov (United States)

    Botta, Cinzia B; Cabri, Walter; Cini, Elena; De Cesare, Lucia; Fattorusso, Caterina; Giannini, Giuseppe; Persico, Marco; Petrella, Antonello; Rondinelli, Francesca; Rodriquez, Manuela; Russo, Adele; Taddei, Maurizio

    2011-04-14

    Several oxime containing molecules, characterized by a SAHA-like structure, were explored to select a potentially new biasing binding element for the zinc in HDAC catalytic site. All compounds were evaluated for their in vitro inhibitory activity against the 11 human HDACs isoforms. After identification of a "hit" molecule, a programmed variation at the cap group and at the linker was carried out in order to increase HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed increased activity against a number of HDAC isoforms, even if their overall activity range is still far from the inhibition values reported for SAHA. Moreover, different from what was reported for their hydroxamic acid analogues the new α-oxime amide derivatives do not select between class I and class II HDACs; rather they target specific isoforms in each class. These somehow contradictory results were finally rationalized by a computational assisted SAR, which gave us the chance to understand how the oxime derivatives interact with the catalytic site and justify the observed activity profile.

  6. Cardioprotective effects of fatty acid amide hydrolase inhibitor URB694, in a rodent model of trait anxiety.

    Science.gov (United States)

    Carnevali, Luca; Vacondio, Federica; Rossi, Stefano; Macchi, Emilio; Spadoni, Gilberto; Bedini, Annalida; Neumann, Inga D; Rivara, Silvia; Mor, Marco; Sgoifo, Andrea

    2015-12-14

    In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol. In HAB rats, acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), with URB694 (0.3 mg/kg), (i) decreased anxiety-like behavior in the elevated plus maze, (ii) increased anandamide levels in the heart, (iii) reduced isoproterenol-induced occurrence of ventricular tachyarrhythmias, and (iv) corrected alterations of ventricular refractoriness. The anti-arrhythmic effect of URB694 was prevented by pharmacological blockade of the cannabinoid type 1 (CB1), but not of the CB2, receptor. These findings suggest that URB694 exerts anxiolytic-like and cardioprotective effects in HAB rats, the latter via anandamide-mediated activation of CB1 receptors. Thus, pharmacological inhibition of FAAH might be a viable pharmacological strategy for the treatment of anxiety-related cardiac dysfunction.

  7. Related dipeptide and characteristic dipeptide of optimal pH in alpha-amylase.

    Science.gov (United States)

    Zhang, Ge-Xin; Li, Wei-Jiang

    2002-12-13

    Alpha-amylase is an enzyme of great significance to industry, but most alpha-amylases are unstable at lower pH. In this paper, we have studied the related dipeptide and characteristic dipeptide of optimal pH in alpha-amylase. On analysis, it gives the explicit results as follows: (1) Ten dipeptides are associated with alpha-amylase's optimal pH. AH, DV, EH, HR, and YV are of positive correlation, AM, IC, NG, NL, and PS are of negative correlation. (2) GE, RE, GS, and KS are higher pH alpha-amylase characteristic dipeptides; AS, GS, DY, and GI are high pH alpha-amylase characteristic dipeptides; TE, VR, DS, and ET are middle pH alpha-amylase characteristic dipeptides; DK, NT, PT, and RV are low pH alpha-amylase characteristic dipeptides; AT, DS, GR, and SR are lower pH alpha-amylase characteristic dipeptides.

  8. Inhibition of polyphenol oxidases activity by various dipeptides.

    Science.gov (United States)

    Girelli, Anna M; Mattei, Enrico; Messina, Antonella; Tarola, Anna M

    2004-05-19

    In an effort to develop natural and nontoxic inhibitors on the activity of mushroom polyphenol oxidase (PPO) the effect of various glycyl-dipeptides (GlyAsp, GlyGly, GlyHis, GlyLeu, GlyLys, GlyPhe, GlyPro, GlyTyr) was investigated. The inhibition study with dihydroxyphenylalanine (DOPA) as substrate is based on separation of the enzymatic reaction components by reversed phase HPLC and the UV detection of the dopachrome formed. The results have evidenced that several of tested dipeptides inhibited PPO activity in the range of 20-40% while GlyPro and GlyLeu had no effect. The study has also permitted the characterization of the following kinetic pattern: a linear-mixed-type mechanism for GlyAsp, GlyGly, GlyLys, and GlyPhe and a hyperbolic-mixed-type for GlyTyr. It was not possible to identify the inhibition mechanism for GlyHis, although it affects PPO activity. In addition the effects of GlyAsp, GlyLys and GlyHis were evaluated for lessening the browning of fresh Golden Delicious apple and Irish White Skinned potato. The effectiveness of such inhibitors was determined by the difference between the colors observed in the dipeptide-treated sample and the controls using the color space CIE-Lab system. The % browning inhibition on potato (20-50%) was greater than of apple (20-30%) by the all tested dipeptides. Only GlyLys presented the significant value of 50%.

  9. Glutamate-containing dipeptides do not modulate ligand binding at excitatory amino acid receptors.

    Science.gov (United States)

    Baud, J; Fagg, G E

    1986-10-08

    Dipeptides of the structure X-Glu (e.g. X = Phe, Leu) have been proposed as allosteric modulators of excitatory amino acid receptors in rat brain membranes. Here we report that these dipeptides reduce the binding of L-[3H]Glu (predominantly N-methyl-D-aspartate-sensitive sites) and of [3H]kainate to postsynaptic density preparations isolated from rat brain. However, several observations indicate that the effects of these dipeptides are mediated not by allosteric modulation, but by free L-Glu liberated by the actions of a membrane-associated aminopeptidase. The absolute and relative potencies of the dipeptides are similar at all acidic amino acid binding sites examined to date, suggesting the involvement of a factor with similar activity at each site (e.g. L-Glu). N-Acetyl-Met-Glu is a weak inhibitor of L-Glu and kainate binding, and N-blocked peptides are known to be poor substrates of aminopeptidases. Bestatin, an inhibitor of aminopeptidases, decreases or abolishes the effects of substrate dipeptides on L-Glu and kainate receptor binding, while having no effect itself.

  10. Effects of structural differences on the NMR chemical shifts in isostructural dipeptides.

    Science.gov (United States)

    Altheimer, Benjamin D; Mehta, Manish A

    2014-04-10

    Porous crystalline dipeptides have gained recent attention for their potential as gas-storage materials. Within this large class is a group of dipeptides containing alanine, valine, and isoleucine with very similar crystal structures. We report the (13)C (carbonyl and Cα) and (15)N (amine and amide) solid-state NMR isotropic chemical shifts in a series of seven such isostructural porous dipeptides as well as shift tensor data for the carbonyl and amide sites. Using their known crystal structures and aided by ab initio quantum chemical calculations for the resonance assignments, we elucidate trends relating local structure, hydrogen-bonding patterns, and chemical shift. We find good correlation between the backbone dihedral angles and the Cα1 and Cα2 shifts. For the C1 shift tensor, the δ11 value shifts downfield as the hydrogen-bond distance increases, δ22 shifts upfield, and δ33 shows little variation. The C2 shift tensor shows no appreciable correlation with structural parameters. For the N2 tensor, δ11 shows little dependence on the hydrogen-bond length, whereas δ22 and δ33 both show a decrease in shielding as the hydrogen bond shortens. Our analysis teases apart some, but not all, structural contributors to the observed differences the solid-state NMR chemical shifts.

  11. N-( p-Ethynylbenzoyl) derivatives of amino acid and dipeptide methyl esters - Synthesis and structural study

    Science.gov (United States)

    Eißmann, Frank; Weber, Edwin

    2011-11-01

    A series of N-( p-ethynylbenzoyl) derivatives ( 1-4) of the amino acids glycine and L-alanine as well as the dipeptides glycylglycine and L-alanylglycine has been synthesized via a two-step reaction sequence including the reaction of an appropriate N-( p-bromobenzoyl) precursor with trimethylsilylacetylene followed by deprotection of the trimethylsilyl protecting group, respectively. X-ray crystal structures of the amino acid and dipeptide methyl esters 1-4 are reported. The amide and peptide bonds within each molecular structure are planar and adopt the trans-configuration. The packing structures are governed by N sbnd H⋯O interactions leading to the formation of characteristic strand motifs. Further stabilization results from weaker C sbnd H⋯O and C sbnd H⋯π contacts.

  12. Development of sub-nanomolar dipeptidic ligands of neuropeptide FF receptors.

    Science.gov (United States)

    Gealageas, Ronan; Schneider, Séverine; Humbert, Jean-Paul; Bertin, Isabelle; Schmitt, Martine; Laboureyras, Emilie; Dugave, Christophe; Mollereau, Catherine; Simonnet, Guy; Bourguignon, Jean-Jacques; Simonin, Frédéric; Bihel, Frédéric

    2012-12-15

    Based on our earlier reported neuropeptide FF receptors antagonist (RF9), we carried out an extensive structural exploration of the N-terminus part of the amidated dipeptide Arg-Phe-NH(2) in order to establish a structure-activity relationships (SAR) study towards both NPFF receptor subtypes. This SAR led to the discovery of dipeptides (12, 35) with subnanomolar affinities towards NPFF1 receptor subtype, similar to endogenous ligand NPVF. More particularly, compound 12 exhibited a potent in vivo preventive effect on opioid-induced hyperalgesia at low dose. The significant selectivity of 12 toward NPFF1-R indicates that this receptor subtype may play a critical role in the anti-opioid activity of NPFF-like peptides.

  13. Investigation of the energy barrier to the rotation of amide CN bonds in ACE inhibitors by NMR, dynamic HPLC and DFT.

    Science.gov (United States)

    Bouabdallah, S; Ben Dhia, M T; Driss, M R; Touil, S

    2016-09-01

    The isomerizations of Enalapril, Perindopril, Enalaprilat and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and DFT theoretical calculations. The thermodynamic parameters (ΔH, ΔS and ΔG) were determined by varying the temperature in the NMR experiments. At the coalescence temperature, we can evaluate the isomerization barrier to the rotation (ΔG(≠)) around the amide bond. Using dynamics chromatography and an unified equation introduced by Trap, we can determine isomerization rate constants and Gibbs activation energies. Molecular mechanics calculations also provided evidence for the presence of low energy conformers for the ACE due to restricted amide rotation. With the value of barriers (ΔE) between them of the order of (20kJmol(-1)), which is in agreement with the dynamic NMR results and DFT calculations.

  14. Dipeptides from the red alga Acanthopora spicifera

    Digital Repository Service at National Institute of Oceanography (India)

    Wahidullah, S.; DeSouza, L.; Kamat, S.Y.

    An investigation of red alga Acanthophora spicifera afforded the known peptide, aurantiamide acetate and a new diastereoisomer of this dipeptide (dia-aurantiamide acetate). This is a first report of aurantiamide acetate from a marine source...

  15. The Novel Dipeptide Translocator Protein Ligand, Referred to As GD-23, Exerts Anxiolytic and Nootropic Activities

    OpenAIRE

    2015-01-01

    The translocator protein (TSPO) promotes the translocation of cholesterol to the inner mitochondrial membrane and mediates steroid formation. In this study, we first report on a biological evaluation of the dipeptide GD-23 (N-carbobenzoxy-L tryptophanyl-L isoleucine amide), a structural analogue of Alpidem, the principal TSPO ligand. We show that GD-23 in a dose range of 0.05 to 0.5 mg/kg (i.p.) exhibits anxiolytic activity in the elevated plus maze test and nootropic activity in the object r...

  16. Novel dipeptide nanoparticles for effective curcumin delivery

    Directory of Open Access Journals (Sweden)

    Alam S

    2012-08-01

    Full Text Available Shadab Alam,* Jiban J Panda,* Virander S Chauhan International Centre for Genetic Engineering and Biotechnology, New Delhi, India*Both authors contributed equally to this workBackground: Curcumin, the principal curcuminoid of the popular Indian spice turmeric, has a wide spectrum of pharmaceutical properties such as antitumor, antioxidant, antiamyloid, and anti-inflammatory activity. However, poor aqueous solubility and low bioavailability of curcumin is a major challenge in its development as a useful drug. To enhance the aqueous solubility and bioavailability of curcumin, attempts have been made to encapsulate it in liposomes, polymeric nanoparticles (NPs, lipid-based NPs, biodegradable microspheres, cyclodextrin, and hydrogels.Methods: In this work, we attempted to entrap curcumin in novel self-assembled dipeptide NPs containing a nonprotein amino acid, α,β-dehydrophenylalanine, and investigated the biological activity of dipeptide-curcumin NPs in cancer models both in vitro and in vivo.Results: Of the several dehydrodipeptides tested, methionine-dehydrophenylalanine was the most suitable one for loading and release of curcumin. Loading of curcumin in the dipeptide NPs increased its solubility, improved cellular availability, enhanced its toxicity towards different cancerous cell lines, and enhanced curcumin’s efficacy towards inhibiting tumor growth in Balb/c mice bearing a B6F10 melanoma tumor.Conclusion: These novel, highly biocompatible, and easy to construct dipeptide NPs with a capacity to load and release curcumin in a sustained manner significantly improved curcumin’s cellular uptake without altering its anticancer or other therapeutic properties. Curcumin-dipeptide NPs also showed improved in vitro and in vivo chemotherapeutic efficacy compared to curcumin alone. Such dipeptide-NPs may also improve the delivery of other potent hydrophobic drug molecules that show poor cellular uptake, bioavailability, and efficacy

  17. Deamidation Reactions of Asparagine- and Glutamine-Containing Dipeptides Investigated by Ion Spectroscopy

    Science.gov (United States)

    Kempkes, Lisanne J. M.; Martens, Jonathan; Grzetic, Josipa; Berden, Giel; Oomens, Jos

    2016-11-01

    Deamidation is a major fragmentation channel upon activation by collision induced dissociation (CID) for protonated peptides containing glutamine (Gln) and asparagine (Asn) residues. Here, we investigate these NH3-loss reactions for four Asn- and Gln-containing protonated peptides in terms of the resulting product ion structures using infrared ion spectroscopy with the free electron laser FELIX. The influence of the side chain length (Asn versus Gln) and of the amino acid sequence on the deamidation reaction has been examined. Molecular structures for the product ions are determined by comparison of experimental IR spectra with spectra predicted by density functional theory (DFT). The reaction mechanisms identified for the four dipeptides AlaAsn, AsnAla, AlaGln, and GlnAla are not the same. For all four dipeptides, primary deamidation takes place from the amide side chain (and not from the N-terminus) and, in most cases, resembles the mechanisms previously identified for the protonated amino acids asparagine and glutamine. Secondary fragmentation reactions of the deamidation products have also been characterized and provide further insight in - and confirmation of - the identified mechanisms. Overall, this study provides a comprehensive molecular structure map of the deamidation chemistry of this series of dipeptides.

  18. A Novel Preparation Method of C-Terminal Glutamine Dipeptides

    Institute of Scientific and Technical Information of China (English)

    QIAN Shao-Song; LIU Yi; CHEN Ran; LI Jia-You; WU Xiao-Yan; JIAO Qing-Cai

    2006-01-01

    A novel synthesis method of dipeptides containing glutamine is reported. Protected L-amino acids were prepared by using inexpensive phthaloyl as the protecting group. Then the phthaloyl-L-amino acids were condensed with glutamine salts by the mixed anhydride method to afford phthaloyl dipeptides. Subsequently, the phthaloyl was removed from the dipeptides with hydrazine hydrate. As a result, optically pure glutamine-containing dipeptides were obtained in good yields.

  19. Dipeptide catalysed prebiotic polymerization of RNA

    DEFF Research Database (Denmark)

    Wieczorek, Rafal; Luisi, Pier Luigi; Monnard, Pierre-Alain

    2011-01-01

    toward more peptide synthesis. In the present work we describe a prebiotically plausible system in which the SerHis dipeptide acts as catalyst for the formation of RNA oligomers from imidazole derivatives of mononucleotides. The thermodynamic shift towards condensation was achieved using water......-concentrated in the remaining liquid microinclusions, thus creating an environment with low water activity in which condensation reactions can occur. Successful oligomerization of RNA monomers catalysed by the SerHis dipeptide was observed in a broad range of pH, and with all four natural nucleobases. The isomeric dipeptide...... HisSer did not exhibit any catalytic properties thus indicating that the specific, spatial arrangement of amino acid residues in the SerHis structure is responsible for its catalytic activity. Establishing novel synthetic pathways to RNA polymerization is important, as to date no convincing prebiotic...

  20. Electrochemical Study of a New Fatty Amide Derivative Inhibitor for Carbon Steel%脂肪酰胺类缓蚀剂对碳钢缓蚀作用的电化学研究

    Institute of Scientific and Technical Information of China (English)

    陶蕾; 陈军; 王超; 秦立娟

    2012-01-01

    A new "green" corrosion inhibitor named N-alkyl-N-fatty acylamino fatty acid salt (TS-417) was synthesized and characterized. The corrosion inhibition performance of TS-417 on low carbon steel in simulated circulation cooling water conditions was studied by polarization curves, electrochemical impedance spectroscopy (EIS). The results show that the new fatty amide derivative inhibitor TS-417 was a good corrosion inhibitor for low carbon steel, which behaved as a type of anodic inhibitor. The inhibition efficiency increases with the TS-417 concentration increased, which can attain 90 % at 100 mg/L.%开发了一种新型环境友好型N-烷基-N-脂肪酰基氨基脂肪酸盐(TS-417)无磷缓蚀剂。采用极化曲线和电化学阻抗谱方法研究了TS一417对低碳钢在模拟中碱中硬循环冷却水中的缓蚀作用。结果表明:TS-417缓蚀剂对碳钢具有良好的缓蚀作用,属于阳极抑制型缓蚀剂;其缓蚀效率随着缓蚀剂浓度的增大而增大,当添加浓度为100mg/L时,缓蚀剂效率即可达到90%。

  1. Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide

    Energy Technology Data Exchange (ETDEWEB)

    Jobson, Andrew G.; Lountos, George T.; Lorenzi, Philip L.; Llamas, Jenny; Connelly, John; Cerna, David; Tropea, Joseph E.; Onda, Akikazu; Zoppoli, Gabriele; Kondapaka, Sudhir; Zhang, Guangtao; Caplen, Natasha J.; Cardellina, II, John H.; Yoo, Stephen S.; Monks, Anne; Self, Christopher; Waugh, David S.; Shoemaker, Robert H.; Pommier, Yves; (NIH)

    2010-04-05

    Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {l_brace}4-[1-(guanidinohydrazone)-ethyl]-phenyl{r_brace}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential.

  2. 1-(3-biaryloxy-2-oxopropyl)indole-5-carboxylic acids and related compounds as dual inhibitors of human cytosolic phospholipase A2α and fatty acid amide hydrolase.

    Science.gov (United States)

    Zahov, Stefan; Drews, Andreas; Hess, Mark; Schulze Elfringhoff, Alwine; Lehr, Matthias

    2011-03-07

    Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are enzymes that have emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. We recently reported that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5) is a dual inhibitor of cPLA2α and FAAH. Structure-activity relationship studies revealed that substituents at the indole 3- and 5-positions and replacement of the indole scaffold of this compound by other heterocycles strongly influences the inhibitory potency against cPLA2α and FAAH, respectively. Herein we report the effect of variation of the 4-octyl residue of 5 and an exchange of its carboxylic acid moiety by some bioisosteric functional groups. Several of the compounds assayed were favorably active against both enzymes, and could therefore represent agents with improved analgesic and anti-inflammatory qualities in comparison with selective cPLA2 α and FAAH inhibitors.

  3. Synthesis and Biological Evaluation of an (18)Fluorine-Labeled COX Inhibitor--[(18)F]Fluorooctyl Fenbufen Amide--For Imaging of Brain Tumors.

    Science.gov (United States)

    Huang, Ying-Cheng; Chang, Yu-Chia; Yeh, Chun-Nan; Yu, Chung-Shan

    2016-03-21

    Molecular imaging of brain tumors remains a great challenge, despite the advances made in imaging technology. An anti-inflammatory compound may be a useful tool for this purpose because there is evidence of inflammatory processes in brain tumor micro-environments. Fluorooctylfenbufen amide (FOFA) was prepared from 8-chlorooctanol via treatment with potassium phthalimide, tosylation with Ts2O, fluorination with KF under phase transfer catalyzed conditions, deprotection using aqueous hydrazine, and coupling with fenbufen. The corresponding radiofluoro product [(18)F]FOFA, had a final radiochemical yield of 2.81 mCi and was prepared from activated [(18)F]F(-) (212 mCi) via HPLC purification and concentration. The radiochemical purity was determined to be 99%, and the specific activity was shown to exceed 22 GBq/μmol (EOS) based on decay-corrected calculations. Ex-vivo analysis of [(18)F]FOFA in plasma using HPLC showed that the agent had a half-life of 15 min. PET scanning showed significant accumulation of [(18)F]FOFA over tumor loci with reasonable contrast in C6-glioma bearing rats. These results suggest that this molecule is a promising agent for the visualization of brain tumors. Further investigations should focus on tumor micro-environments.

  4. Muramyl dipeptide responsive pathways in Crohn's disease

    DEFF Research Database (Denmark)

    Salem, Mohammad; Seidelin, Jakob Benedict; Rogler, Gerhard

    2012-01-01

    Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP...

  5. 1-Heteroaryl-3-phenoxypropan-2-ones as inhibitors of cytosolic phospholipase A₂α and fatty acid amide hydrolase: Effect of the replacement of the ether oxygen with sulfur and nitrogen moieties on enzyme inhibition and metabolic stability.

    Science.gov (United States)

    Sundermann, Tom; Fabian, Jörg; Hanekamp, Walburga; Lehr, Matthias

    2015-05-15

    Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are enzymes, which have emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. We recently reported that certain 3-phenoxy-substituted 1-heteroarylpropan-2-ones are inhibitors of cPLA2α and/or FAAH. Starting from 1-[2-oxo-3-(4-phenoxyphenoxy)propyl]indole-5-carboxylic acid (3) and 1-(1H-benzotriazol-1-yl)-3-(4-phenoxyphenoxy)propan-2-one (4), the effect of the replacement of the oxygen in position 3 of the propan-2-one scaffold by sulfur and nitrogen containing moieties on inhibition of cPLA2α and fatty acid amide hydrolase as well as on metabolic stability in rat liver S9 fractions was investigated. As a result of these structure-activity relationship studies it was found that the ether oxygen is of great importance for enzyme inhibitory potency. Replacement by sulfur led to an about 100-fold decrease of enzyme inhibition, nitrogen and substituted nitrogen atoms at this position even resulted in inactivity of the compounds. The effect of the structural variations performed on metabolic stability of the important ketone pharmacophore was partly different in the two series of compounds. While introduction of SO and SO2 significantly increased stability of the ketone against reduction in case of the indole-5-carboxylic acid 3, it had no effect in case of the benzotriazole 4. Further analysis of the metabolism of 3 and 4 in rat liver S9 fractions revealed that the major metabolite of 3 was the alcohol 53 formed by reduction of the keto group. In contrast, in case of 4 beside keto reduction an excessive hydroxylation of the terminal phenoxy group occurred leading to the dihydroxy compound 50. Experiments with enzyme inhibitors showed that the phenylhydroxylation of 4 was catalyzed by tranylcypromine sensitive cytochrome P450 isoforms, while the reduction of the ketone function of 3 and 4 was mainly caused by cytosolic short chain dehydrogenases

  6. Reliable determination of amidicity in acyclic amides and lactams.

    Science.gov (United States)

    Glover, Stephen A; Rosser, Adam A

    2012-07-06

    Two independent computational methods have been used for determination of amide resonance stabilization and amidicities relative to N,N-dimethylacetamide for a wide range of acyclic and cyclic amides. The first method utilizes carbonyl substitution nitrogen atom replacement (COSNAR). The second, new approach involves determination of the difference in amide resonance between N,N-dimethylacetamide and the target amide using an isodesmic trans-amidation process and is calibrated relative to 1-aza-2-adamantanone with zero amidicity and N,N-dimethylacetamide with 100% amidicity. Results indicate excellent coherence between the methods, which must be regarded as more reliable than a recently reported approach to amidicities based upon enthalpies of hydrogenation. Data for acyclic planar and twisted amides are predictable on the basis of the degrees of pyramidalization at nitrogen and twisting about the C-N bonds. Monocyclic lactams are predicted to have amidicities at least as high as N,N-dimethylacetamide, and the β-lactam system is planar with greater amide resonance than that of N,N-dimethylacetamide. Bicyclic penam/em and cepham/em scaffolds lose some amidicity in line with the degree of strain-induced pyramidalization at the bridgehead nitrogen and twist about the amide bond, but the most puckered penem system still retains substantial amidicity equivalent to 73% that of N,N-dimethylacetamide.

  7. Reducing endocannabinoid metabolism with the fatty acid amide hydrolase inhibitor, URB597, fails to modify reinstatement of morphine-induced conditioned floor preference and naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance.

    Science.gov (United States)

    McCallum, Amanda L; Limebeer, Cheryl L; Parker, Linda A

    2010-10-01

    The potential of the fatty acid amide hydrolase (FAAH) inhibitor, URB597, to modify drug prime-induced reinstatement of morphine-induced conditioned floor preference or naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance was evaluated. In Experiment 1, morphine-induced conditioned floor preference was established across 4 conditioning trials. Following extinction training (4 trials), rats were pretreated with URB597 or vehicle prior to a morphine prime or a saline prime. Morphine reinstated the previously extinguished floor preference, but URB597 did not modify the strength of the reinstated preference. In Experiment 2, naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance was established across 2 conditioning trials. Following extinction training (14 trials), rats were pretreated with URB597 or vehicle prior to a saline prime or a morphine withdrawal prime. The morphine withdrawal prime reinstated the previously extinguished floor avoidance, but URB597 did not modify the strength of reinstated avoidance. These results suggest that under the conditions in which URB597 promotes extinction (e.g., Manwell et al. (2009)) it does not interfere with drug-induced reinstatement of either conditioned floor preference or avoidance. That is, although activation of the endocannabinoid (eCB) system promotes extinction of aversive learning, it may not prevent reinstatement of that aversion by re-exposure to the aversive treatment.

  8. Incorporation of different crystallizable amide blocks in segmented poly(ester amide)s

    NARCIS (Netherlands)

    Lips, P.A.M.; Broos, R.; Heeringen, van M.J.M.; Dijkstra, P.J.; Feijen, J.

    2005-01-01

    High molecular weight segmented poly(ester amide)s were prepared by melt polycondensation of dimethyl adipate, 1,4-butanediol and a symmetrical bisamide-diol based on ε-caprolactone and 1,2-diaminoethane or 1,4-diaminobutane. FT-IR and WAXD analysis revealed that segmented poly(ester amide)s based

  9. Dipeptides Increase Functional Activity of Human Skin Fibroblasts.

    Science.gov (United States)

    Malinin, V V; Durnova, A O; Polyakova, V O; Kvetnoi, I M

    2015-05-01

    We analyzed the effect of dipeptide Glu-Trp and isovaleroyl-Glu-Trp in concentrations of 0.2, 2 and 20 μg/ml and Actovegin preparation on functional activity of human skin fibroblasts. Dipeptides, especially Glu-Trp, produce a stimulating effect on human skin fibroblasts and their effect is equivalent to that of Actovegin. Dipeptides stimulate cell renewal processes by activating synthesis of Ki-67 and reducing expression of caspase-9 and enhance antioxidant function of the cells by stimulating the expression of Hsp-90 and inducible NO-synthase. These findings suggest that dipeptides are promising candidates for preparations stimulating reparative processes.

  10. The Role of a Dipeptide Outer-Coordination Sphere on H2 -Production Catalysts: Influence on Catalytic Rates and Electron Transfer

    Energy Technology Data Exchange (ETDEWEB)

    Reback, Matthew L.; Ginovska-Pangovska, Bojana; Ho, Ming-Hsun; Jain, Avijita; Squier, Thomas C.; Raugei, Simone; Roberts, John A.; Shaw, Wendy J.

    2013-02-04

    The outer-coordination sphere of enzymes acts to fine-tune the active site reactivity and control catalytic rates, suggesting that incorporation of analogous structural elements into molecular catalysts may be necessary to achieve rates comparable to those observed in enzyme systems at low overpotentials. In this work, we evaluate the effect of an amino acid and dipeptide outer-coordination sphere on [Ni(PPh2NPh-R2)2]2+ hydrogen production catalysts. A series of 12 new complexes containing non-natural amino acids or dipeptides were prepared to test the effects of positioning, size, polarity and aromaticity on catalytic activity. The non-natural amino acid was either 3-(meta- or para-aminophenyl)propionic acid terminated as an acid, an ester or an amide. Dipeptides consisted of one of the non-natural amino acids coupled to one of four amino acid esters: alanine, serine, phenylalanine or tyrosine. All of the catalysts are active for hydrogen production, with rates averaging ~1000 s-1, 40% faster than the unmodified catalyst. Structure and polarity of the aliphatic or aromatic side chains of the C-terminal peptide do not strongly influence rates. However, the presence of an amide bond increases rates, suggesting a role for the amide in assisting catalysis. Overpotentials were lower with substituents at the N-phenyl meta position. This is consistent with slower electron transfer in the less compact, para-substituted complexes, as shown in digital simulations of catalyst cyclic voltammograms and computational modeling of the complexes. Combining the current results with insights from previous results, we propose a mechanism for the role of the amino acid and dipeptide based outer-coordination sphere in molecular hydrogen production catalysts.

  11. Conformational distributions of denatured and unstructured proteins are similar to those of 20 Multiplication-Sign 20 blocked dipeptides

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Kwang-Im [Korea University, Department of Chemistry (Korea, Republic of); Jung, Young-Sang; Hwang, Geum-Sook, E-mail: gshwang@kbsi.re.kr [Korea Basic Science Institute (Korea, Republic of); Cho, Minhaeng, E-mail: mcho@korea.ac.kr [Korea University, Department of Chemistry (Korea, Republic of)

    2012-05-15

    Understanding intrinsic conformational preferences of amino-acids in unfolded proteins is important for elucidating the underlying principles of their stability and re-folding on biological timescales. Here, to investigate the neighbor interaction effects on the conformational propensities of amino-acids, we carried out {sup 1}H NMR experiments for a comprehensive set of blocked dipeptides and measured the scalar coupling constants between alpha protons and amide protons as well as their chemical shifts. Detailed inspection of these NMR properties shows that, irrespective of amino-acid side-chain properties, the distributions of the measured coupling constants and chemical shifts of the dipeptides are comparatively narrow, indicating small variances of their conformation distributions. They are further compared with those of blocked amino-acids (Ac-X-NHMe), oligopeptides (Ac-GGXGG-NH{sub 2}), and native (lysozyme), denatured (lysozyme and outer membrane protein X from Escherichia coli), unstructured (Domain 2 of the protein 5A of Hepatitis C virus), and intrinsically disordered (hNlg3cyt: intracellular domain of human NL3) proteins. These comparative investigations suggest that the conformational preferences and local solvation environments of the blocked dipeptides are quite similar to not only those of other short oligopeptides but also those of denatured and natively unfolded proteins.

  12. Luciferin Amides Enable in Vivo Bioluminescence Detection of Endogenous Fatty Acid Amide Hydrolase Activity.

    Science.gov (United States)

    Mofford, David M; Adams, Spencer T; Reddy, G S Kiran Kumar; Reddy, Gadarla Randheer; Miller, Stephen C

    2015-07-15

    Firefly luciferase is homologous to fatty acyl-CoA synthetases. We hypothesized that the firefly luciferase substrate d-luciferin and its analogs are fatty acid mimics that are ideally suited to probe the chemistry of enzymes that release fatty acid products. Here, we synthesized luciferin amides and found that these molecules are hydrolyzed to substrates for firefly luciferase by the enzyme fatty acid amide hydrolase (FAAH). In the presence of luciferase, these molecules enable highly sensitive and selective bioluminescent detection of FAAH activity in vitro, in live cells, and in vivo. The potency and tissue distribution of FAAH inhibitors can be imaged in live mice, and luciferin amides serve as exemplary reagents for greatly improved bioluminescence imaging in FAAH-expressing tissues such as the brain.

  13. The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation

    Directory of Open Access Journals (Sweden)

    Murphy Niamh

    2012-04-01

    Full Text Available Abstract Background Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1β (IL-1β. In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA, have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP. Methods Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30% DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry. Results The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL-1β and tumor necrosis factor-α (TNFα which were attenuated by treatment with URB597. Coupled with these changes, we

  14. N,C-Capped dipeptides with selectivity for mycobacterial proteasome over human proteasomes: role of S3 and S1 binding pockets.

    Science.gov (United States)

    Lin, Gang; Chidawanyika, Tamutenda; Tsu, Christopher; Warrier, Thulasi; Vaubourgeix, Julien; Blackburn, Christopher; Gigstad, Kenneth; Sintchak, Michael; Dick, Lawrence; Nathan, Carl

    2013-07-10

    We identified N,C-capped dipeptides that are selective for the Mycobacterium tuberculosis proteasome over human constitutive and immunoproteasomes. Differences in the S3 and S1 binding pockets appeared to account for the species selectivity. The inhibitors can penetrate mycobacteria and kill nonreplicating M. tuberculosis under nitrosative stress.

  15. Synthesis of Biologically Active Dipeptide in a Multiphase Enzyme Membrane Reactor%多相酶膜反应器合成生物活性二肽

    Institute of Scientific and Technical Information of China (English)

    姜忠义; 贾琦鹏; 刘家祺; 陈洪钫

    2001-01-01

    A multiphase enzyme membrane reactor using aqueous-organicbiphase instead of water phase alone as the reaction medium was employed to investigate the lipase-catalyzed synthesis of bioactive dipeptides. The medium effect on dipeptide yield was first studied. When N-acetyl-L-phenylalanine ethyl ester(APEE) was used as a carboxyl component, the reactivity order of amino acid amides was found to be L-Leu-NH2>L-Val-NH2>L-Ala-NH2>L-Gly-NH2. The didpetide, N-Ac-L-Phe-L-Leu-NH2, could be synthesized in the multiphase enzyme membrane reactor in a high yield and purity due to the simultaneous separation and reaction.

  16. Density functional theory calculations on dipeptide gallic acid interaction

    Science.gov (United States)

    Madhan, B.; Parthasarathi, R.; Subramanian, V.; Raghava Rao, J.; Nair, Balachandran Unni; Ramasami, T.

    2003-02-01

    In the present investigation, an attempt has been made to study the interaction of dipeptides with gallic acid, using Becke3 parameter Lee Yang Parr (B3LYP) method employing 3-21G*, 6-31G* and 6-31+G* basis sets. The interaction energies of the dipeptide-gallic acid complexes are in the range of -5 to -18 kcal/mol depending on the mode of intermolecular complexation. Calculated molecular electrostatic potential (MESP) for the various intermolecular complexes revealed the electrostatic nature of the interaction. Qualitative estimations based on chemical hardness and chemical potential demonstrated fractional electron transfer from dipeptide to gallic acid.

  17. Electrospray Ionization Mass Spectra of Dipeptide Derivatives

    Institute of Scientific and Technical Information of China (English)

    LUO, Zaigang; ZENG, Chengchu; YANG, Daoshan; HUANG, Yali; WANG, Fang; DU, Hongguang; HU, Liming

    2009-01-01

    Based on the structure of the HIV integrase core domain, dipeptide derivatives, as a type of HIV integrase in- hibitor, were synthesized, and their fragmentation pathways were investigated by electrospray ionization mass spec- trometry (ESI-MSN) in conjunction with tandem mass spectrometry (MS/MS). In order to better understand the fragmentation pathways, the MS2 and MS3 spectra of the title compound were obtained. The main fragmentation pathways occur by the cleavage of the C-CO bonds between N-(benzothiazol-2-yl)aminocarbonyl and methylene, NH-CO bonds between the NH groups and carbonyl groups. Electrospray ionization was proven to be a good method for the structural characterization and identification of this kind of compound.

  18. 2D IR spectroscopy of histidine: probing side-chain structure and dynamics via backbone amide vibrations.

    Science.gov (United States)

    Ghosh, Ayanjeet; Tucker, Matthew J; Gai, Feng

    2014-07-17

    It is well known that histidine is involved in many biological functions due to the structural versatility of its side chain. However, probing the conformational transitions of histidine in proteins, especially those occurring on an ultrafast time scale, is difficult. Herein we show, using a histidine dipeptide as a model, that it is possible to probe the tautomer and protonation status of a histidine residue by measuring the two-dimensional infrared (2D IR) spectrum of its amide I vibrational transition. Specifically, for the histidine dipeptide studied, the amide unit of the histidine gives rise to three spectrally resolvable amide I features at approximately 1630, 1644, and 1656 cm(-1), respectively, which, based on measurements at different pH values and frequency calculations, are assigned to a τ tautomer (1630 cm(-1) component) and a π tautomer with a hydrated (1644 cm(-1) component) or dehydrated (1656 cm(-1) component) amide. Because of the intrinsic ultrafast time resolution of 2D IR spectroscopy, we believe that the current approach, when combined with the isotope editing techniques, will be useful in revealing the structural dynamics of key histidine residues in proteins that are important for function.

  19. Carbamoyl anion addition to N-sulfinyl imines: highly diastereoselective synthesis of α-amino amides.

    Science.gov (United States)

    Reeves, Jonathan T; Tan, Zhulin; Herbage, Melissa A; Han, Zhengxu S; Marsini, Maurice A; Li, Zhibin; Li, Guisheng; Xu, Yibo; Fandrick, Keith R; Gonnella, Nina C; Campbell, Scot; Ma, Shengli; Grinberg, Nelu; Lee, Heewon; Lu, Bruce Z; Senanayake, Chris H

    2013-04-17

    Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.

  20. ON THE FORMATION OF DIPEPTIDES IN INTERSTELLAR MODEL ICES

    Energy Technology Data Exchange (ETDEWEB)

    Kaiser, R. I.; Kim, Y. S. [Department of Chemistry, University of Hawaii at Manoa, Honolulu, HI 96822 (United States); Stockton, A. M.; Jensen, E. C.; Mathies, R. A. [Department of Chemistry, University of California, Berkeley, CA 94720 (United States)

    2013-03-10

    The hypothesis of an exogenous origin and delivery of biologically important molecules to early Earth presents an alternative route to their terrestrial in situ formation. Dipeptides like Gly-Gly detected in the Murchison meteorite are considered as key molecules in prebiotic chemistry because biofunctional dipeptides present the vital link in the evolutionary transition from prebiotic amino acids to early proteins. However, the processes that could lead to the exogenous abiotic synthesis of dipeptides are unknown. Here, we report the identification of two proteinogenic dipeptides-Gly-Gly and Leu-Ala-formed via electron-irradiation of interstellar model ices followed by annealing the irradiated samples to 300 K. Our results indicate that the radiation-induced, non-enzymatic formation of proteinogenic dipeptides in interstellar ice analogs is facile. Once synthesized and incorporated into the ''building material'' of solar systems, biomolecules at least as complex as dipeptides could have been delivered to habitable planets such as early Earth by meteorites and comets, thus seeding the beginning of life as we know it.

  1. Jet Cooled Rotational Studies of Dipeptides

    Science.gov (United States)

    Cabezas, C.; Mata, M. Varela S.; López, J. C.; Alonso, J. L.

    2011-06-01

    Rotational spectra of Gly-Pro and Pro-Gly dipeptides have been examined with laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy. Three conformers for Gly-Pro and one for Pro-Gly have been unequivocally identified in the supersonic expansion by the comparison of the experimental rotational and 14N (I=1) nuclear quadrupole coupling constants with those predicted by ab initio methods. The quadrupole hyperfine structure of two 14N nuclei has been totally resolved and it allows to experimentally characterize the main intramolecular forces which stabilize the assigned conformers. The biomimetic molecule Ac-Ala-NH_2 has been also studied. The C_7 and C_5 peptide conformations (intramolecularly hydrogen-bonded seven- or five-membered cycle, respectively) have been unequivocally identified in the supersonic expansion. The ability to identify peptide conformations suggest that it soon may be possible to explore the structures of larger peptides using LA-MB-FTMW spectroscopy. J. L. Alonso, C. Pérez, M. E. Sanz, J. C. López, S. Blanco, Phys. Chem. Chem. Phys. 11,617-627 (2009)and references therein

  2. On the Formation of Dipeptides in Interstellar Model Ices

    Science.gov (United States)

    Kaiser, R. I.; Stockton, A. M.; Kim, Y. S.; Jensen, E. C.; Mathies, R. A.

    2013-03-01

    The hypothesis of an exogenous origin and delivery of biologically important molecules to early Earth presents an alternative route to their terrestrial in situ formation. Dipeptides like Gly-Gly detected in the Murchison meteorite are considered as key molecules in prebiotic chemistry because biofunctional dipeptides present the vital link in the evolutionary transition from prebiotic amino acids to early proteins. However, the processes that could lead to the exogenous abiotic synthesis of dipeptides are unknown. Here, we report the identification of two proteinogenic dipeptides—Gly-Gly and Leu-Ala—formed via electron-irradiation of interstellar model ices followed by annealing the irradiated samples to 300 K. Our results indicate that the radiation-induced, non-enzymatic formation of proteinogenic dipeptides in interstellar ice analogs is facile. Once synthesized and incorporated into the ''building material'' of solar systems, biomolecules at least as complex as dipeptides could have been delivered to habitable planets such as early Earth by meteorites and comets, thus seeding the beginning of life as we know it.

  3. Communication: Quantitative multi-site frequency maps for amide I vibrational spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Reppert, Mike [Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (United States); Department of Chemistry, University of Chicago, Chicago, Illinois 60637 (United States); Tokmakoff, Andrei, E-mail: tokmakoff@uchicago.edu [Department of Chemistry, University of Chicago, Chicago, Illinois 60637 (United States)

    2015-08-14

    An accurate method for predicting the amide I vibrational spectrum of a given protein structure has been sought for many years. Significant progress has been made recently by sampling structures from molecular dynamics simulations and mapping local electrostatic variables onto the frequencies of individual amide bonds. Agreement with experiment, however, has remained largely qualitative. Previously, we used dipeptide fragments and isotope-labeled constructs of the protein G mimic NuG2b as experimental standards for developing and testing amide I frequency maps. Here, we combine these datasets to test different frequency-map models and develop a novel method to produce an optimized four-site potential (4P) map based on the CHARMM27 force field. Together with a charge correction for glycine residues, the optimized map accurately describes both experimental datasets, with average frequency errors of 2–3 cm{sup −1}. This 4P map is shown to be convertible to a three-site field map which provides equivalent performance, highlighting the viability of both field- and potential-based maps for amide I spectral modeling. The use of multiple sampling points for local electrostatics is found to be essential for accurate map performance.

  4. [Antifibrillatory activity of dipeptide antagonist of nerve growth factor].

    Science.gov (United States)

    Kryzhanovskiĭ, S A; Stoliarchuk, V N; Vititnova, M B; Tsorin, I B; Pekel'dina, E S; Gudasheva, T A

    2012-01-01

    In experiments on anesthetized rats were assessed antifibrillatoty action of dipeptide GK-1. This compound is the fragment of fourth loop of nerve growth factor (NGF) and manifests antagonistic activity in respect to TrkA receptor, that specified for NGF. It is shown that this compound is able to significantly increase the threshold of electrical fibrillation of the heart and its effectiveness is not inferior to the reference antiarrhythmics I and III class on Vaughan Williams classification. However, unlike the latter, antifibrillatory action of dipeptide GK-1 was delayed and realized within 40-60 minutes after its administration. It is discussed possible mechanisms underlying antifibrillatory action of dipeptide GK-1, that, to some extent, may be associated with its ability to change the reactivity of beta-adrenergic structures of the heart.

  5. Synthesis and antiproliferative activity of glutamic acid-based dipeptides.

    Science.gov (United States)

    Silveira-Dorta, Gastón; Martín, Víctor S; Padrón, José M

    2015-08-01

    A small and focused library of 22 dipeptides derived from N,N-dibenzylglutamic acid α- and γ-benzyl esters was prepared in a straightforward manner. The evaluation of the antiproliferative activity in the human solid tumor cell lines HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast), and WiDr (colon) provided γ-glutamyl methionine (GI50 = 6.0-41 μM) and α-glutamyl proline (GI50 = 7.5-18 μM) as lead compounds. In particular, glutamyl serine and glutamyl proline dipeptides were more active in the resistant cancer cell line WiDr than the conventional anticancer drugs cisplatin and etoposide. Glutamyl tryptophan dipeptides did not affect cell growth of HBL-100, while in T-47D cells, proliferation was inhibited. This result might be attributed to the inhibition of the ATB(0,+) transporter.

  6. Branched-chain amino acid-containing dipeptides, identified from whey protein hydrolysates, stimulate glucose uptake rate in L6 myotubes and isolated skeletal muscles.

    Science.gov (United States)

    Morifuji, Masashi; Koga, Jinichiro; Kawanaka, Kentaro; Higuchi, Mitsuru

    2009-02-01

    In earlier studies we showed that dietary whey protein increased skeletal muscle and liver glycogen content in exercise-trained rats. However, little is known about whether ingredients of whey protein stimulate skeletal muscle glycogen accumulation. The aim of this study was to identify bioactive peptides in whey protein hydrolysates (WPH) which stimulated glucose uptake and glycogen synthesis rate in skeletal muscles. Branched-chain amino acid (BCAA)-containing dipeptides in WPH were identified using LC/MS/MS. L6 myotubes and isolated epitrochlearis muscles were used for the glucose uptake assays. The myotubes and muscles were incubated with or without 1 mM dipeptides, LY294002 a phosphoinositide 3-kinase (PI3-kinase) inhibitor, or GF102903X an atypical protein kinase C (aPKC) inhibitor, followed by measurement of 2-deoxyglucose uptake. Isolated muscles were incubated for 3 h with or without 1 mM Ile-Leu to determine glycogen synthesis rate. The BCAA-containing dipeptides, Ile-Val, Leu-Val, Val-Leu, Ile-Ile, Leu-Ile, Ile-Leu, and Leu-Leu were detected in the WPH by LC/MS/MS. These dipeptides caused significant stimulation in glucose uptake rate in the L6 myotubes. Ile-Leu, the main component in WPH, also stimulated glucose uptake in isolated skeletal muscles. Stimulation of glucose uptake by Ile-Leu was completely inhibited by treatment with either LY294002, or GF109203X in both L6 cells and isolated muscles. Ile-Leu increased glycogen contents in isolated muscles. These results suggest that BCAA-containing bioactive dipeptides in WPH stimulate glucose uptake in skeletal muscles via the PI3-kinase and aPKC pathways, resulting in increased skeletal muscle glycogen contents.

  7. Formation of RNA phosphodiester bond by histidine-containing dipeptides

    DEFF Research Database (Denmark)

    Wieczorek, Rafal; Dörr, Mark; Chotera, Agata;

    2013-01-01

    A new scenario for prebiotic formation of nucleic acid oligomers is presented. Peptide catalysis is applied to achieve condensation of activated RNA monomers into short RNA chains. As catalysts, L-dipeptides containing a histidine residue, primarily Ser-His, were used. Reactions were carried out....... Details of the mechanism and kinetics, which were elucidated with a set of control experiments, further establish that the imidazole side chain of a histidine at the carboxyl end of the dipeptide plays a crucial role in the catalysis. These results suggest that this oligomerisation catalysis occurs...

  8. Long-Lived Foams Stabilized by a Hydrophobic Dipeptide Hydrogel

    OpenAIRE

    2016-01-01

    A hydrogel of hydrophobic dipeptides can be used to create a wet foam with long-term stability. The dipeptide molecules self-assemble into fiber-like networks (due to the presence of metal ions) both at air-water interfaces and in the continuous phase. The former creates an interfacial film stabilizing the air bubbles while the latter forms a bulk gel, which prevents bubble movement and retards growth. If the storage modulus (G’) of the bulk hydrogel is sufficientlyhigh it can stop the coarse...

  9. A novel and orally active poly(ADP-ribose) polymerase inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl) methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], attenuates injury in in vitro model of cell death and in vivo model of cardiac ischemia.

    Science.gov (United States)

    Oh, Kwang-Seok; Lee, Sunkyung; Yi, Kyu Yang; Seo, Ho Won; Koo, Hyun-Na; Lee, Byung Ho

    2009-01-01

    Blocking of poly(ADP-ribose) polymerase (PARP)-1 has been expected to protect the heart from ischemia-reperfusion injury. We have recently identified a novel and orally active PARP-1 inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl)-methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], and its major metabolite, KR-34285 [2-[carboxy(4-methoxyphenyl)methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide]. KR-33889 potently inhibited PARP-1 activity with an IC(50) value of 0.52 +/- 0.10 microM. In H9c2 myocardial cells, KR-33889 (0.03-30 microM) showed a resistance to hydrogen peroxide (2 mM)-mediated oxidative insult and significantly attenuated activation of intracellular PARP-1. In anesthetized rats subjected to 30 min of coronary occlusion and 3 h of reperfusion, KR-33889 (0.3-3 mg/kg i.v.) dose-dependently reduced myocardial infarct size. KR-34285, a major metabolite of KR-33889, exerted similar patterns to the parent compound with equi- or weaker potency in the same studies described above. In separate experiments for the therapeutic time window study, KR-33889 (3 mg/kg i.v.) given at preischemia, at reperfusion or in both, in rat models also significantly reduced the myocardial infarction compared with their respective vehicle-treated group. Furthermore, the oral administration of KR-33889 (1-10 mg/kg p.o.) at 1 h before occlusion significantly reduced myocardial injury. The ability of KR-33889 to inhibit PARP in the rat model of ischemic heart was confirmed by immunohistochemical detection of poly(ADP-ribose) activation. These results indicate that the novel PARP inhibitor KR-33889 exerts its cardioprotective effect in in vitro and in vivo studies of myocardial ischemia via potent PARP inhibition and also suggest that KR-33889 could be an attractive therapeutic candidate with oral activity for several cardiovascular disorders, including myocardial infarction.

  10. Dipeptide analogues containing 4-ethoxy-3-pyrrolin-2-ones

    DEFF Research Database (Denmark)

    Hosseini, Masood; Kringelum, Henriette; Murray, A.;

    2006-01-01

    Pyrrolidine-2,4-diones (1) are naturally occurring analogues of amino acids. We herein present a facile synthesis of N-acylated, O-alkylated pyrrolin-2-ones (2) in high yield and excellent enantiopurity. Molecular mechanics calculations suggest that the resulting dipeptide analogues adopt a linea...

  11. The Dipeptide Ala-Gly in the Gas Phase

    Science.gov (United States)

    Bermúdez, Celina; Varela, Marcelino; Cabezas, Carlos; Peña, Isabel; Alonso, José L.

    2014-06-01

    The dipeptide Ala-Gly has been examined in gas phase by laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy in the frequency region 3-12 GHz. Three rotamers have been detected in the supersonic expansion. The quadrupole hyperfine structure of two 14N (I=1) nuclei has been totally resolved allowing the conclusive identification of one conformer.

  12. Design and Synthesis of Muramyl Dipeptide Cyclic Analogue

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    A new conformationally restricted cyclic analogue of muramyl dipeptide was designed and manually synthesized by our "Meshed-Bag Gathered-Bunch" method with a combination of Fmoc, allyl and N-1-(4,4-dimethyl-2,6-dioxocyclo-hexylidene)ethyl chemical protection strategy.

  13. Solution-phase synthesis of a muramyl dipeptide analogue MDA

    Institute of Scientific and Technical Information of China (English)

    Nan Zhao; Yao Ma; Gang Liu

    2011-01-01

    The solution-phase synthesis of a muramyl dipeptide (MDP) analogue of Nα- [4-chlorocinnamoyl-L-alanyl-D-isoglutaminyl]-L-lysine (MDA, 2) is reported that possesses the features of easy feasibility, safety and low cost in large scale of synthesis.

  14. Design and Synthesis of Muramyl Dipeptide Cyclic Analogue

    Institute of Scientific and Technical Information of China (English)

    SuoDeZHANG; GangLIU; 等

    2002-01-01

    A new conformationalloy restricted cyclic analogue of muramyl dipeptide was designed and manually synthesized by our “Meshed-Bag Gathered-Bunch” method with a combination of Fmoc,ally and N-1-(4,4-dimethyl-2,6-dioxocyclo-hexylidene) ethyl chemical protection strategy.

  15. The effect of the [{sup 18}F]-PEG group on tracer qualification of [4-(phenylamino)-quinazoline-6-YL]-amide moiety-An EGFR putative irreversible inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Dissoki, Samar [Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Hadassah University Hospital, P.O.B. 12000, Jerusalem 91120 (Israel); Aviv, Yoel [Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Hadassah University Hospital, P.O.B. 12000, Jerusalem 91120 (Israel); Unit of Cellular Signaling, Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904 (Israel); Laky, Desideriu [Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Hadassah University Hospital, P.O.B. 12000, Jerusalem 91120 (Israel); Abourbeh, Galith [Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Hadassah University Hospital, P.O.B. 12000, Jerusalem 91120 (Israel); Unit of Cellular Signaling, Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904 (Israel); Levitzki, Alexander [Unit of Cellular Signaling, Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904 (Israel); Mishani, Eyal [Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University, Hadassah University Hospital, P.O.B. 12000, Jerusalem 91120 (Israel)], E-mail: mishani@md.huji.ac.il

    2007-10-15

    Previous reports have designated the labeled derivatives of [4-(phenylamino)-quinazoline-6-yl]-amide group as the most promising EGFR-PET imaging agent candidates. To further improve tracer qualifications and increase stability and solubility, additional derivatives of this group substituted at the 7-position with various lengths of fluoro-polyethyleneglycol (F-PEG) chains were synthesized. These novel derivatives inhibited EGFR autophosphorylation with IC{sub 50} values of 5-40 nM. The compounds were successfully labeled with fluorine-18 at the PEG chain via a three-step radiosynthesis route. The labeled final products were obtained with a 13-32% decay corrected radiochemical yield, 99% radiochemical purity, and high specific activity.

  16. Muramyl dipeptide-Lys stimulates the function of human dendritic cells.

    Science.gov (United States)

    Todate, A; Suda, T; Kuwata, H; Chida, K; Nakamura, H

    2001-11-01

    Muramyl dipeptide (MDP)-Lys (L18), a synthetic MDP analogue derived from bacterial cell walls, has been reported to be a potent immunoadjuvant that enhances protective immunity against pathogens and tumors by stimulating immune-competent cells, such as monocytes and macrophages. However, it is not known whether MDP-Lys modulates the function of dendritic cells (DCs), which are the most potent antigen-presenting cells and play a crucial role in initiating T cell-mediated immunity. Therefore, we examined the effects of MDP-Lys on the expression of surface molecules, cytokine production, and antigen-presenting function of human DCs generated from peripheral blood cells in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. We found that MDP-Lys markedly up-regulated the expression of CD80, CD83, CD86, and CD40, but not human leukocyte antigen-DR, and stimulated the production of tumor necrosis factor-alpha, IL-6, IL-8, IL-10, and IL-12 (p40) by human DCs in a dose-dependent manner. Furthermore, MDP-Lys-treated DCs showed enhanced antigen-presenting function compared with untreated DCs, as assessed by an allogeneic mixed lymphocyte reaction. These results suggested that the immunoadjuvant activity of MDP-Lys in vivo is mediated, in part, by its stimulation of DC function.

  17. Effective representation of amide III, II, I, and A modes on local vibrational modes: Analysis of ab initio quantum calculation results

    Science.gov (United States)

    Hahn, Seungsoo

    2016-10-01

    The Hamiltonian matrix for the first excited vibrational states of a protein can be effectively represented by local vibrational modes constituting amide III, II, I, and A modes to simulate various vibrational spectra. Methods for obtaining the Hamiltonian matrix from ab initio quantum calculation results are discussed, where the methods consist of three steps: selection of local vibrational mode coordinates, calculation of a reduced Hessian matrix, and extraction of the Hamiltonian matrix from the Hessian matrix. We introduce several methods for each step. The methods were assessed based on the density functional theory calculation results of 24 oligopeptides with four different peptide lengths and six different secondary structures. The completeness of a Hamiltonian matrix represented in the reduced local mode space is improved by adopting a specific atom group for each amide mode and reducing the effect of ignored local modes. The calculation results are also compared to previous models using C=O stretching vibration and transition dipole couplings. We found that local electric transition dipole moments of the amide modes are mainly bound on the local peptide planes. Their direction and magnitude are well conserved except amide A modes, which show large variation. Contrary to amide I modes, the vibrational coupling constants of amide III, II, and A modes obtained by analysis of a dipeptide are not transferable to oligopeptides with the same secondary conformation because coupling constants are affected by the surrounding atomic environment.

  18. 40 CFR 721.3720 - Fatty amide.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Fatty amide. 721.3720 Section 721.3720... Fatty amide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a fatty amide (PMN P-91-87) is subject to reporting under this...

  19. 40 CFR 721.2120 - Cyclic amide.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Cyclic amide. 721.2120 Section 721... Cyclic amide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a cyclic amide (PMN P-92-131) is subject to reporting under this section for...

  20. Depression of jejunal dipeptide transport by pyridoxine deficiency in the rat.

    Science.gov (United States)

    Gupta, V J; Edwards, K D; Asatoor, A M

    1975-02-01

    Three dipeptides (L-alanyl-L-alanine, beta-alanyl-L-histidine and L-prolylglycine), representative of distinctly different transport groups, and a dicarboxylic acid dipeptide (L-glutamyl-L-glutamic acid) showed a quantitatively equivalent decrease of absorption (mean difference, 12% disappearance 15 min-1 5 cm-1) from jejunal loops in vivo in pyridoxine deficient rats, compared with pyridoxine-repleted controls. Analysis of results for seven dipeptides, including three studied previously, indicated that pyridoxine deficiency caused a general or non-specific reduction in dipeptide transport, similar for all dipeptides. Decrease in dipeptide transport in vitamin deficiency ran parallel to, but was significantly less than, the decrease in amino acid transport, suggesting in theory involvement of pyridoxine in a common cellular efflux mechanism or, less likely, in the energetics of active transport.

  1. Intestinal absorption of two dipeptides in Hartnup disease.

    Science.gov (United States)

    Asatoor, A M; Cheng, B; Edwards, K D; Lant, A F; Matthews, D M; Milne, M D; Navab, F; Richards, A J

    1970-05-01

    The results of oral tolerance tests of two dipeptides and of their constitutent amino acids are compared in normal subjects and in a case of Hartnup disease. In the control subjects the rate of absorption of phenylalanine from phenylalanyl-phenylalanine and of tryptophan from glycyl-tryptophan was slower than after the equivalent amount of the free amino acids. Absorption of the two essential amino acids (tryptophan and phenylalanine) in the patient was almost zero after administration in the free form, but was much greater after the dipeptide. Results of experiments on absorption and hydrolysis of the two peptides in the rat small intestine are also reported. It is suggested that whereas normal subjects absorb essential amino acids by a dual mechanism of mucosal uptake of free amino acids and oligopeptides, nutrition in Hartnup disease is largely dependent on uptake of oligopeptides containing the amino acids affected by the intestinal transport defect of the disease.

  2. Intestinal absorption of two dipeptides in Hartnup disease 1

    Science.gov (United States)

    Asatoor, A. M.; Cheng, B.; Edwards, K. D. G.; Lant, A. F.; Matthews, D. M.; Milne, M. D.; Navab, F.; Richards, A. J.

    1970-01-01

    The results of oral tolerance tests of two dipeptides and of their constitutent amino acids are compared in normal subjects and in a case of Hartnup disease. In the control subjects the rate of absorption of phenylalanine from phenylalanyl-phenylalanine and of tryptophan from glycyl-tryptophan was slower than after the equivalent amount of the free amino acids. Absorption of the two essential amino acids (tryptophan and phenylalanine) in the patient was almost zero after administration in the free form, but was much greater after the dipeptide. Results of experiments on absorption and hydrolysis of the two peptides in the rat small intestine are also reported. It is suggested that whereas normal subjects absorb essential amino acids by a dual mechanism of mucosal uptake of free amino acids and oligopeptides, nutrition in Hartnup disease is largely dependent on uptake of oligopeptides containing the amino acids affected by the intestinal transport defect of the disease. PMID:5428040

  3. Synthesis and characterization of novel dipeptide ester prodrugs of acyclovir

    Science.gov (United States)

    Nashed, Yasser E.; Mitra, Ashim K.

    2003-07-01

    Four dipeptide (Gly-Gly, Gly-Val, Val-Val, Val-Gly) ester prodrugs of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir, ACV) were synthesized. LC/MS was used to characterize the new prodrugs. Both 1H NMR and 13C NMR spectra of the four prodrugs of ACV were measured and assigned based on spectral comparison with compounds of similar structures.

  4. Nanoporous dipeptide crystals as selective gas sorbents and polymerization nanovessels

    OpenAIRE

    Distefano,, E.

    2012-01-01

    Hydrophobic dipeptide crystals recently emerged as novel “organic zeolites” featuring tailorable pore size. In fact, seven out of nine pairwise combinations of L-isoleucine, L-valine and L-alanine amino acids crystallize according to the same charge-assisted hydrogen bond pattern, generating a family of microporous materials with right-handed 1D channels, having diameters in the sub-nanometer domain (

  5. Temperature dependence of C-terminal carboxylic group IR absorptions in the amide I' region.

    Science.gov (United States)

    Anderson, Benjamin A; Literati, Alex; Ball, Borden; Kubelka, Jan

    2015-01-01

    Studies of structural changes in peptides and proteins using IR spectroscopy often rely on subtle changes in the amide I' band as a function of temperature. However, these changes can be obscured by the overlap with other absorptions, namely the side-chain and terminal carboxylic groups. The former were the subject of our previous report (Anderson et al., 2014). In this paper we investigate the IR spectra of the asymmetric stretch of α-carboxylic groups for amino acids representing all major types (Gly, Ala, Val, Leu, Ser, Thr, Asp, Glu, Lys, Asn, His, Trp, Pro) as well as the C-terminal groups of three dipeptides (Gly-Gly, Gly-Ala, Ala-Gly) in D₂O at neutral pH. Experimental temperature dependent IR spectra were analyzed by fitting of both symmetric and asymmetric pseudo-Voigt functions. Qualitatively the spectra exhibit shifts to higher frequency, loss in intensity and narrowing with increased temperature, similar to that observed previously for the side-chain carboxylic groups of Asp. The observed dependence of the band parameters (frequency, intensity, width and shape) on temperature is in all cases linear: simple linear regression is therefore used to describe the spectral changes. The spectral parameters vary between individual amino acids and show systematic differences between the free amino acids and dipeptides, particularly in the absolute peak frequencies, but the temperature variations are comparable. The relative variations between the dipeptide spectral parameters are most sensitive to the C-terminal amino acid, and follow the trends observed in the free amino acid spectra. General rules for modeling the α-carboxylic IR absorption bands in peptides and proteins as the function of temperature are proposed.

  6. Temperature dependence of C-terminal carboxylic group IR absorptions in the amide I‧ region

    Science.gov (United States)

    Anderson, Benjamin A.; Literati, Alex; Ball, Borden; Kubelka, Jan

    2015-01-01

    Studies of structural changes in peptides and proteins using IR spectroscopy often rely on subtle changes in the amide I‧ band as a function of temperature. However, these changes can be obscured by the overlap with other absorptions, namely the side-chain and terminal carboxylic groups. The former were the subject of our previous report (Anderson et al., 2014). In this paper we investigate the IR spectra of the asymmetric stretch of α-carboxylic groups for amino acids representing all major types (Gly, Ala, Val, Leu, Ser, Thr, Asp, Glu, Lys, Asn, His, Trp, Pro) as well as the C-terminal groups of three dipeptides (Gly-Gly, Gly-Ala, Ala-Gly) in D2O at neutral pH. Experimental temperature dependent IR spectra were analyzed by fitting of both symmetric and asymmetric pseudo-Voigt functions. Qualitatively the spectra exhibit shifts to higher frequency, loss in intensity and narrowing with increased temperature, similar to that observed previously for the side-chain carboxylic groups of Asp. The observed dependence of the band parameters (frequency, intensity, width and shape) on temperature is in all cases linear: simple linear regression is therefore used to describe the spectral changes. The spectral parameters vary between individual amino acids and show systematic differences between the free amino acids and dipeptides, particularly in the absolute peak frequencies, but the temperature variations are comparable. The relative variations between the dipeptide spectral parameters are most sensitive to the C-terminal amino acid, and follow the trends observed in the free amino acid spectra. General rules for modeling the α-carboxylic IR absorption bands in peptides and proteins as the function of temperature are proposed.

  7. Separation of Cyclic Dipeptides (Diketopiperazines from Their Corresponding Linear Dipeptides by RP-HPLC and Method Validation

    Directory of Open Access Journals (Sweden)

    Mareike Perzborn

    2013-01-01

    Full Text Available Simple, rapid, sensitive, precise, and accurate methods for detection and separation of seven diketopiperazines (DKPs, cyclo(Gly-Gly, cyclo(dl-Ala-dl-Ala, cyclo(l-Asp-l-Phe, cyclo(l-Asp-l-Asp, cyclo(Gly-l-Phe, cyclo(l-Pro-l-Tyr, and cyclo(l-Arg-l-Arg, from their corresponding linear dipeptides and related amino acids l-Phe and l-Tyr by reversed-phase high-performance liquid chromatography (RP-HPLC were established. Moreover, for the racemic DKP cyclo(dl-Ala-dl-Ala and dipeptide dl-Ala-dl-Ala, separation of the diastereomers was achieved. All methods can be performed within 15 min. For all DKPs, dipeptides, and amino acids, linear ranges with correlation coefficients R2 greater than 0.998 were determined. Lowest limits of detection were found to be between 0.05 and 10 nmol per 10 μL injection, depending on the substance. For all tested substances intrarun and interrun precision ranged from 0.5 to 4.7% and 0.7 to 9.9% relative standard deviation, and accuracy was between −4.2 and 8.1% relative error. Short-term and freeze-thaw stabilities were 93% or greater for all substances. Recovery rate after heat treatment was determined to be at least 97%. These methods will be useful for quantitative determination of DKPs and their potential biodegradation products: dipeptides and amino acids

  8. Distinct C9orf72-Associated Dipeptide Repeat Structures Correlate with Neuronal Toxicity

    Science.gov (United States)

    Krans, Amy; Sawaya, Michael R.; Paulson, Henry L.; Todd, Peter K.; Barmada, Sami J.; Ivanova, Magdalena I.

    2016-01-01

    Hexanucleotide repeat expansions in C9orf72 are the most common inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansions elicit toxicity in part through repeat-associated non-AUG (RAN) translation of the intronic (GGGGCC)n sequence into dipeptide repeat-containing proteins (DPRs). Little is known, however, about the structural characteristics and aggregation propensities of the dipeptide units comprising DPRs. To address this question, we synthesized dipeptide units corresponding to the three sense-strand RAN translation products, analyzed their structures by circular dichroism, electron microscopy and dye binding assays, and assessed their relative toxicity when applied to primary cortical neurons. Short, glycine-arginine (GR)3 dipeptides formed spherical aggregates and selectively reduced neuronal survival compared to glycine-alanine (GA)3 and glycine-proline (GP)3 dipeptides. Doubling peptide length had little effect on the structure of GR or GP peptides, but (GA)6 peptides formed β-sheet rich aggregates that bound thioflavin T and Congo red yet lacked the typical fibrillar morphology of amyloids. Aging of (GA)6 dipeptides increased their β-sheet content and enhanced their toxicity when applied to neurons. We also observed that the relative toxicity of each tested dipeptide was proportional to peptide internalization. Our results demonstrate that different C9orf72-related dipeptides exhibit distinct structural properties that correlate with their relative toxicity. PMID:27776165

  9. Ocular sustained release nanoparticles containing stereoisomeric dipeptide prodrugs of acyclovir.

    Science.gov (United States)

    Jwala, Jwala; Boddu, Sai H S; Shah, Sujay; Sirimulla, Suman; Pal, Dhananjay; Mitra, Ashim K

    2011-04-01

    The objective of this study was to develop and characterize polymeric nanoparticles of appropriate stereoisomeric dipeptide prodrugs of acyclovir (L-valine-L-valine-ACV, L-valine-D-valine-ACV, D-valine-L-valine-ACV, and D-valine-D-valine-ACV) for the treatment of ocular herpes keratitis. Stereoisomeric dipeptide prodrugs of acyclovir (ACV) were screened for bioreversion in various ocular tissues, cell proliferation, and uptake across the rabbit primary corneal epithelial cell line. Docking studies were carried out to examine the affinity of prodrugs to the peptide transporter protein. Prodrugs with optimum characteristics were selected for the preparation of nanoparticles using various grades of poly (lactic-co-glycolic acid) (PLGA). Nanoparticles were characterized for the entrapment efficiency, surface morphology, size distribution, and in vitro release. Further, the effect of thermosensitive gels on the release of prodrugs from nanoparticles was also studied. L-valine-L-valine-ACV and L-valine-D-valine-ACV were considered to be optimum in terms of enzymatic stability, uptake, and cytotoxicity. Docking results indicated that L-valine in the terminal position increases the affinity of the prodrugs to the peptide transporter protein. Entrapment efficiency values of L-valine-L-valine-ACV and L-valine-D-valine-ACV were found to be optimal with PLGA 75:25 and PLGA 65:35 polymers, respectively. In vitro release of prodrugs from nanoparticles exhibited a biphasic release behavior with initial burst phase followed by sustained release. Dispersion of nanoparticles in thermosensitive gels completely eliminated the burst release phase. Novel nanoparticulate systems of dipeptide prodrugs of ACV suspended in thermosensitive gels may provide sustained delivery after topical administration.

  10. Stimulation of chemiluminescence by synthetic muramyl dipeptide and analogs.

    OpenAIRE

    Masihi, K N; Azuma, I; Brehmer, W; Lange, W.

    1983-01-01

    The effect on respiratory burst of murine splenic cells after in vitro exposure to synthetic muramyl dipeptide (MDP) and 6-O-acyl and quinonyl derivatives was studied at an early phase of interaction by luminol-dependent chemiluminescence (CL) in response to stimulation by zymosan. The MDP molecule enhanced CL, but the degree of CL response varied with the kinds of fatty acids introduced in the chemical structure of synthetic glycopeptide analogs. A 6-O-acyl derivative possessing an alpha-bra...

  11. The Prototype Dipeptide Gly-Gly a Rotational Study

    Science.gov (United States)

    Varela, M.; Cabezas, C.; Mata, S.; Alonso, J. L.

    2013-06-01

    The simplest dipeptide Gly-Gly has been examined for the first time in the gas phase by laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy. The nuclear quadrupole hyperfine structure of two ^{14}N nuclei has been totally resolved allowing the conclusive identification of three conformers in the supersonic expansion. Intramolecular hydrogen bonding interactions have been analyzed on the bases of the structure of the observed conformers. Present results indicate that it is possible to face the study larger peptides using LA-MB-FTMW spectroscopy.

  12. Borate esters as convenient reagents for direct amidation of carboxylic acids and transamidation of primary amides.

    Science.gov (United States)

    Starkov, Pavel; Sheppard, Tom D

    2011-03-07

    Simple borates serve as effective promoters for amide bond formation with a variety of carboxylic acids and amines. With trimethyl or tris(2,2,2-trifluoroethyl) borate, amides are obtained in good to excellent yield and high purity after a simple work-up procedure. Tris(2,2,2-trifluoroethyl) borate can also be used for the straightforward conversion of primary amides to secondary amides via transamidation.

  13. Nucleoside phosphorylation in amide solutions

    Science.gov (United States)

    Schoffstall, A. M.; Kokko, B.

    1978-01-01

    The paper deals with phosphorylation in possible prebiotic nonaqueous solvents. To this end, phosphorylation of nucleosides using inorganic phosphates in amide solutions is studied at room and elevated temperatures. Reaction proceeds most readily in formamide and N-methylformamide. Products obtained at elevated temperature are nucleotides, nucleoside 2',3'-cyclic phosphates, and when the phosphate concentration is high, nucleoside diphosphates. At room temperature, adenosine afforded a mixture of nucleotides, but none of the cyclic nucleotide. Conditions leading to the highest relative percentage of cyclic nucleotide involve the use of low concentrations of phosphate and an excess of nucleoside.

  14. Evaluating the role of acidic, basic, and polar amino acids and dipeptides on a molecular electrocatalyst for H 2 oxidation

    Energy Technology Data Exchange (ETDEWEB)

    Boralugodage, Nilusha Priyadarshani; Arachchige, Rajith Jayasingha; Dutta, Arnab; Buchko, Garry W.; Shaw, Wendy J.

    2017-01-01

    Amino acids and peptides have been shown to have a significant influence on the H2 production and oxidation reactivity of Ni(PR2NR’2)2, where PR2NR’2 = 1,5-diaza-3,7-diphosphacyclooctane, R is either phenyl (Ph) or cyclohexyl (Cy), and R’ is either an amino acid or peptide. Most recently, the Ni(PCy2Naminoacid2)2 complexes (CyAA) have shown enhanced H2 oxidation rates, water solubility, and in the case of arginine (CyArg) and phenylalanine (CyPhe), electrocatalytic reversibility. Both the backbone –COOH and side chain interactions were shown to be critical to catalytic performance. Here we further investigate the roles of the outer coordination sphere by evaluating amino acids with acidic, basic, and hydrophilic side chains, as well as dipeptides which combine multiple successful features from previous complexes. Six new complexes were prepared, three containing single amino acids: aspartic acid (CyAsp), lysine (CyLys), and serine (CySer) and three containing dipeptides: glycine-phenylalanine (Cy(GlyPhe)), phenylalanine-glycine (Cy(PheGly)), and aspartic acid-phenylananine (Cy(AspPhe)). The resulting catalytic performance demonstrates that complexes need both interactions between side chain and –COOH groups for fast, efficient catalysis. The fastest of all of the catalysts, Cy(AspPhe), had both of these features, while the other dipeptide complexes with an amide replacing the -COOH were both slower; however, the amide group was demonstrated to participate in the proton pathway when side chain interactions are present to position it. Both the hydrophilic and basic side chains, notably lacking in side chain interactions, significantly increased the overpotential, with only modest increases in TOF. Of all of the complexes, only CyAsp was reversible at room temperature, and only in water, the first of these

  15. Biocompatibility and degradation of aliphatic segmented poly(ester amide)s : in vitro and in vivo evaluation

    NARCIS (Netherlands)

    Lips, PAM; van Luyn, MJA; Chiellini, F; Brouwer, LA; Velthoen, IW; Dijkstra, PJ; Feijen, J

    2006-01-01

    Aliphatic segmented poly(ester amide)s, comprising a crystallizable amide phase and a flexible amorphous ester phase, were investigated for potential use in biomedical applications. By varying the amide content and the type of crystallizable amide segments, the polymer's thermal and mechanical prope

  16. Biocompatibility and degradation of aliphatic segmented poly(ester amide)s : in vitro and in vivo evaluation

    NARCIS (Netherlands)

    Lips, PAM; van Luyn, MJA; Chiellini, F; Brouwer, LA; Velthoen, IW; Dijkstra, PJ; Feijen, J

    2006-01-01

    Aliphatic segmented poly(ester amide)s, comprising a crystallizable amide phase and a flexible amorphous ester phase, were investigated for potential use in biomedical applications. By varying the amide content and the type of crystallizable amide segments, the polymer's thermal and mechanical prope

  17. Metabolism of amino acids, dipeptides and tetrapeptides by Lactobacillus sakei.

    Science.gov (United States)

    Sinz, Quirin; Schwab, Wilfried

    2012-04-01

    The microbial degradation of proteins, peptides and amino acids generates volatiles involved in the typical flavor of dry fermented sausage. The ability of three Lactobacillus sakei strains to form aroma compounds was investigated. Whole resting cells were fermented in phosphate buffer with equimolar amounts of substrates consisting of dipeptides, tetrapeptides and free amino acids, respectively. Dipeptides disappeared quickly from the solutions whereas tetrapeptides were only partially degraded. In both approaches the concentration of free amino acids increased in the reaction mixture but did not reach the equimolar amount of the initial substrates. When free amino acids were fed to the bacteria their levels decreased only slightly. Although peptides were more rapidly degraded and/or transported into the cells, free amino acids produced higher amounts of volatiles. It is suggested, that after transport into the cell peptides are only partially hydrolyzed to their amino acids, while the rest is metabolized via alternative metabolic pathways. The three L. sakei strains differed to some extend in their ability to metabolize the substrates to volatile compounds. In a few cases this was due to the position of the amino acids within the peptides. Compared to other starter cultures used for the production of dry fermented sausages, the metabolic impact of the L. sakei strains on the formation of volatiles was very low.

  18. Papain-specific activating esters in aqueous dipeptide synthesis.

    Science.gov (United States)

    de Beer, Roseri J A C; Zarzycka, Barbara; Mariman, Michiel; Amatdjais-Groenen, Helene I V; Mulders, Marc J; Quaedflieg, Peter J L M; van Delft, Floris L; Nabuurs, Sander B; Rutjes, Floris P J T

    2012-06-18

    Enzymatic peptide synthesis has the potential to be a viable alternative for chemical peptide synthesis. Because of the increasing commercial interest in peptides, new and improved enzymatic synthesis methods are desirable. In recently developed enzymatic strategies such as substrate mimetic approaches and enzyme-specific activation, use of the guanidinophenyl ester (OGp) group has been shown to suffer from some drawbacks. OGp esters are sensitive to spontaneous chemical hydrolysis and the group is expensive to synthesize and therefore not suitable for large-scale applications. On the basis of earlier computational studies, we hypothesized that OGp might be replaceable by simpler ester groups to make the enzyme-specific activation approach to peptide bond formation more accessible. To this end, a set of potential activating esters (Z-Gly-Act) was designed, synthesized, and evaluated. Both the benzyl (OBn) and the dimethylaminophenyl (ODmap) esters gave promising results. For these esters, the scope of a model dipeptide synthesis reaction under aqueous conditions was investigated by varying the amino acid donor. The results were compared with those obtained from a previous study of Z-X(AA) -OGp esters. Computational docking analysis of the set of esters was performed in order to provide insight into the differences in the reactivities of all the potential activating esters. Finally, selected ODmap- and OBn-activated amino acids were applied in the synthesis of two biologically active dipeptides on preparative scales. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Design and Synthesis of Caspase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    BAI; Xu

    2001-01-01

    Apoptosis (programmed cell death) is an evolutionarily conserved process of cell suicide. It requires specialized machinery which involving a family of proteases named caspases. Manipulation of apoptosis through inhibiting or activating caspases has been of great therapeutic interests in the pharmaceutical industry.  Using substrate based approach, a systematic investigation of conformationally constrained peptidomimetic inhibitors has led to the discovery of highly selective ones against selected members of the caspase family. It also resulted novel dipeptide inhibitors as useful tools and possible therapeutic agents against diseases caused by excessive apoptotic cell death. This presentation will focus on the design, synthesis and application of novel caspase inhibitors.  ……

  20. Design and Synthesis of Caspase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    BAI Xu

    2001-01-01

    @@ Apoptosis (programmed cell death) is an evolutionarily conserved process of cell suicide. It requires specialized machinery which involving a family of proteases named caspases. Manipulation of apoptosis through inhibiting or activating caspases has been of great therapeutic interests in the pharmaceutical industry. Using substrate based approach, a systematic investigation of conformationally constrained peptidomimetic inhibitors has led to the discovery of highly selective ones against selected members of the caspase family. It also resulted novel dipeptide inhibitors as useful tools and possible therapeutic agents against diseases caused by excessive apoptotic cell death. This presentation will focus on the design, synthesis and application of novel caspase inhibitors.

  1. Mass Spectrometry Identification of N-Chlorinated Dipeptides in Drinking Water.

    Science.gov (United States)

    Huang, Guang; Jiang, Ping; Li, Xing-Fang

    2017-03-14

    We report the identification of N-chlorinated dipeptides as chlorination products in drinking water using complementary high-resolution quadrupole time-of-flight (QTOF) and quadrupole ion-trap mass spectrometry techniques. First, three model dipeptides, tyrosylglycine (Tyr-Gly), tyrosylalanine (Tyr-Ala), and phenylalanylglycine (Phe-Gly), reacted with sodium hypochlorite, and these reaction solutions were analyzed by QTOF. N-Cl-Tyr-Gly, N,N-di-Cl-Tyr-Gly, N-Cl-Phe-Gly, N,N-di-Cl-Phe-Gly, N-Cl-Tyr-Ala, and N,N-di-Cl-Tyr-Ala were identified as the major products based on accurate masses, (35)Cl/(37)Cl isotopic patterns, and MS/MS spectra. These identified N-chlorinated dipeptides were synthesized and found to be stable in water over 10 days except N,N-di-Cl-Phe-Gly. To enable sensitive detection of N-chlorinated dipeptides in authentic water, we developed a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method with multiple reaction monitoring (MRM) mode. N-Cl-Tyr-Gly, N,N-di-Cl-Tyr-Gly, N-Cl-Phe-Gly, N-Cl-Tyr-Ala, and N,N-di-Cl-Tyr-Ala along with their corresponding dipeptides were detected in authentic tap water samples. The dipeptides were clearly detected in the raw water, but the N-chlorinated dipeptides were at background levels. These results suggest that the N-chlorinated dipeptides are produced by chlorination. This study has identified N-chlorinated dipeptides as new disinfection byproducts in drinking water. The strategy developed in this study can be used to identify chlorination products of other peptides in drinking water.

  2. Antibodies against conserved amidated neuropeptide epitopes enrich the comparative neurobiology toolbox

    Directory of Open Access Journals (Sweden)

    Conzelmann Markus

    2012-10-01

    Full Text Available Abstract Background Neuronal antibodies that show immunoreactivity across a broad range of species are important tools for comparative neuroanatomy. Nonetheless, the current antibody repertoire for non-model invertebrates is limited. Currently, only antibodies against the neuropeptide RFamide and the monoamine transmitter serotonin are extensively used. These antibodies label respective neuron-populations and their axons and dendrites in a large number of species across various animal phyla. Results Several other neuropeptides also have a broad phyletic distribution among invertebrates, including DLamides, FVamides, FLamides, GWamides and RYamides. These neuropeptides show strong conservation of the two carboxy-terminal amino acids and are α-amidated at their C-termini. We generated and affinity-purified specific polyclonal antibodies against each of these conserved amidated dipeptide motifs. We thoroughly tested antibody reactivity and specificity both by peptide pre-incubation experiments and by showing a close correlation between the immunostaining signals and mRNA expression patterns of the respective precursor genes in the annelid Platynereis. We also demonstrated the usefulness of these antibodies by performing immunostainings on a broad range of invertebrate species, including cnidarians, annelids, molluscs, a bryozoan, and a crustacean. In all species, the antibodies label distinct neuronal populations and their axonal projections. In the ciliated larvae of cnidarians, annelids, molluscs and bryozoans, a subset of antibodies reveal peptidergic innervation of locomotor cilia. Conclusions We developed five specific cross-species-reactive antibodies recognizing conserved two-amino-acid amidated neuropeptide epitopes. These antibodies allow specific labelling of peptidergic neurons and their projections in a broad range of invertebrates. Our comparative survey across several marine phyla demonstrates a broad occurrence of peptidergic

  3. Identification of benzimidazole diamides as selective inhibitors of the nucleotide-binding oligomerization domain 2 (NOD2 signaling pathway.

    Directory of Open Access Journals (Sweden)

    David J Rickard

    Full Text Available NOD2 is an intracellular pattern recognition receptor that assembles with receptor-interacting protein (RIP-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP in the host cell cytoplasm, thereby inducing signals leading to the production of pro-inflammatory cytokines. The dysregulation of NOD2 signaling has been associated with various inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. To identify inhibitors of the NOD2 signaling pathway, we utilized a cell-based screening approach and identified a benzimidazole diamide compound designated GSK669 that selectively inhibited an MDP-stimulated, NOD2-mediated IL-8 response without directly inhibiting RIP2 kinase activity. Moreover, GSK669 failed to inhibit cytokine production in response to the activation of Toll-like receptor (TLR-2, tumor necrosis factor receptor (TNFR-1 and closely related NOD1, all of which share common downstream components with the NOD2 signaling pathway. While the inhibitors blocked MDP-induced NOD2 responses, they failed to block signaling induced by NOD2 over-expression or single stranded RNA, suggesting specificity for the MDP-induced signaling complex and activator-dependent differences in NOD2 signaling. Investigation of structure-activity relationship allowed the identification of more potent analogs that maintained NOD2 selectivity. The largest boost in activity was achieved by N-methylation of the C2-ethyl amide group. These findings demonstrate that the NOD2 signaling pathway is amenable to modulation by small molecules that do not target RIP2 kinase activity. The compounds we identified should prove useful tools to investigate the importance of NOD2 in various inflammatory processes and may have potential clinical utility.

  4. Identification of Benzimidazole Diamides as Selective Inhibitors of the Nucleotide-Binding Oligomerization Domain 2 (NOD2) Signaling Pathway

    Science.gov (United States)

    Rickard, David J.; Sehon, Clark A.; Kasparcova, Viera; Kallal, Lorena A.; Zeng, Xin; Montoute, Monica N.; Chordia, Tushar; Poore, Derek D.; Li, Hu; Wu, Zining; Eidam, Patrick M.; Haile, Pamela A.; Yu, Jong; Emery, John G.; Marquis, Robert W.; Gough, Peter J.; Bertin, John

    2013-01-01

    NOD2 is an intracellular pattern recognition receptor that assembles with receptor-interacting protein (RIP)-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP) in the host cell cytoplasm, thereby inducing signals leading to the production of pro-inflammatory cytokines. The dysregulation of NOD2 signaling has been associated with various inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. To identify inhibitors of the NOD2 signaling pathway, we utilized a cell-based screening approach and identified a benzimidazole diamide compound designated GSK669 that selectively inhibited an MDP-stimulated, NOD2-mediated IL-8 response without directly inhibiting RIP2 kinase activity. Moreover, GSK669 failed to inhibit cytokine production in response to the activation of Toll-like receptor (TLR)-2, tumor necrosis factor receptor (TNFR)-1 and closely related NOD1, all of which share common downstream components with the NOD2 signaling pathway. While the inhibitors blocked MDP-induced NOD2 responses, they failed to block signaling induced by NOD2 over-expression or single stranded RNA, suggesting specificity for the MDP-induced signaling complex and activator-dependent differences in NOD2 signaling. Investigation of structure-activity relationship allowed the identification of more potent analogs that maintained NOD2 selectivity. The largest boost in activity was achieved by N-methylation of the C2-ethyl amide group. These findings demonstrate that the NOD2 signaling pathway is amenable to modulation by small molecules that do not target RIP2 kinase activity. The compounds we identified should prove useful tools to investigate the importance of NOD2 in various inflammatory processes and may have potential clinical utility. PMID:23936340

  5. Microorganisms hydrolyse amide bonds; knowledge enabling read-across of biodegradability of fatty acid amides.

    Science.gov (United States)

    Geerts, Roy; Kuijer, Patrick; van Ginkel, Cornelis G; Plugge, Caroline M

    2014-07-01

    To get insight in the biodegradation and potential read-across of fatty acid amides, N-[3-(dimethylamino)propyl] cocoamide and N-(1-ethylpiperazine) tall oil amide were used as model compounds. Two bacteria, Pseudomonas aeruginosa PK1 and Pseudomonas putida PK2 were isolated with N-[3-(dimethylamino)propyl] cocoamide and its hydrolysis product N,N-dimethyl-1,3-propanediamine, respectively. In mixed culture, both strains accomplished complete mineralization of N-[3-(dimethylamino)propyl] cocoamide. Aeromonas hydrophila PK3 was enriched with N-(1-ethylpiperazine) tall oil amide and subsequently isolated using agar plates containing dodecanoate. N-(2-Aminoethyl)piperazine, the hydrolysis product of N-(1-ethylpiperazine) tall oil amide, was not degraded. The aerobic biodegradation pathway for primary and secondary fatty acid amides of P. aeruginosa and A. hydrophila involved initial hydrolysis of the amide bond producing ammonium, or amines, where the fatty acids formed were immediately metabolized. Complete mineralization of secondary fatty acid amides depended on the biodegradability of the released amine. Tertiary fatty acid amides were not transformed by P. aeruginosa or A. hydrophila. These strains were able to utilize all tested primary and secondary fatty acid amides independent of the amine structure and fatty acid. Read-across of previous reported ready biodegradability results of primary and secondary fatty acid amides is justified based on the broad substrate specificity and the initial hydrolytic attack of the two isolates PK1 and PK3.

  6. Stimulation of chemiluminescence by synthetic muramyl dipeptide and analogs.

    Science.gov (United States)

    Masihi, K N; Azuma, I; Brehmer, W; Lange, W

    1983-04-01

    The effect on respiratory burst of murine splenic cells after in vitro exposure to synthetic muramyl dipeptide (MDP) and 6-O-acyl and quinonyl derivatives was studied at an early phase of interaction by luminol-dependent chemiluminescence (CL) in response to stimulation by zymosan. The MDP molecule enhanced CL, but the degree of CL response varied with the kinds of fatty acids introduced in the chemical structure of synthetic glycopeptide analogs. A 6-O-acyl derivative possessing an alpha-branched fatty acid chain, B30-MDP, stimulated maximum levels of CL activity. High CL responses were obtained with L8-MDP having a short chain of linear fatty acids and with QS-10-MDP-66 containing a ubiquinone compound. CL was also stimulated by MDP and its analogs in the spleen cells of nude mice lacking mature T lymphocytes, but the extent of stimulation was decreased compared with that of normal spleen cells.

  7. Two Trypanocidal Dipeptides from the Roots of Zapoteca portoricensis (Fabaceae

    Directory of Open Access Journals (Sweden)

    Ngozi Justina Nwodo

    2014-04-01

    Full Text Available Zapoteca portoricensis (Jacq HM Hernández is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate and anabellamide, were isolated from the methanol root extract of Zapoteca portoricensis and their chemical structures deduced by one dimensional and two dimensional NMR and mass spectrometry. These compounds were isolated for the first time from this plant, and no report has been found on their previous isolation from the genus Zapoteca. Evaluation of their trypanocidal activity showed that compound 1 exhibited potent activity against Trypanosoma brucei rhodesiense with an IC50 value of 3.63 μM and selectivity index of 25.3.

  8. Genetic variants of the human dipeptide transporter PEPT1

    DEFF Research Database (Denmark)

    Anderle, Pascale; Nielsen, Carsten Uhd; Pinsonneault, Julia

    2006-01-01

    We tested whether genetic polymorphisms affect activity of the dipeptide transporter PEPT1, which mediates bioavailability of peptidomimetic drugs. All 23 exons and adjoining intronic sections of PEPT1 (SLC15A1) were sequenced in 247 individuals of various ethnic origins (Coriell collection). Of 38...... single nucleotide polymorphisms (SNPs), 21 occurred in intronic and non-coding regions and 17 in exonic coding region, of which nine were nonsynonymous. Eight nonsynonymous variants were cloned into expression vectors and functionally characterized after transient transfection into Cos7 and Chinese...... formation of a splice variant (PEPT1-RF). PEPT1-RF mRNA levels ranged from 2 to 44% of total PEPT1-related mRNA, with potential consequences for drug absorption. Together with previous results, this study reveals a relatively low level of genetic variability in polymorphisms affecting both protein function...

  9. Integrating diffusion maps with umbrella sampling: application to alanine dipeptide.

    Science.gov (United States)

    Ferguson, Andrew L; Panagiotopoulos, Athanassios Z; Debenedetti, Pablo G; Kevrekidis, Ioannis G

    2011-04-07

    Nonlinear dimensionality reduction techniques can be applied to molecular simulation trajectories to systematically extract a small number of variables with which to parametrize the important dynamical motions of the system. For molecular systems exhibiting free energy barriers exceeding a few k(B)T, inadequate sampling of the barrier regions between stable or metastable basins can lead to a poor global characterization of the free energy landscape. We present an adaptation of a nonlinear dimensionality reduction technique known as the diffusion map that extends its applicability to biased umbrella sampling simulation trajectories in which restraining potentials are employed to drive the system into high free energy regions and improve sampling of phase space. We then propose a bootstrapped approach to iteratively discover good low-dimensional parametrizations by interleaving successive rounds of umbrella sampling and diffusion mapping, and we illustrate the technique through a study of alanine dipeptide in explicit solvent.

  10. Design and Solid-Phase Synthesis of Multiple Muramyl Dipeptide (MMD)

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    As a non-specific modulator of macrophage, multiplied muramyl dipeptide (MMD) is solid-phase synthesized by application of standard Fmoc chemistry strategy. Tam's multiple antigen system (MAS) is used as our four branched-linker on Lysine.

  11. Amide Rotation Hindrance Predicts Proteolytic Resistance of Cystine-Knot Peptides.

    Science.gov (United States)

    Zhou, Yanzi; Xie, Daiqian; Zhang, Yingkai

    2016-04-07

    Cystine-knot peptides have remarkable stability against protease degradation and are attractive scaffolds for peptide-based therapeutic and diagnostic agents. In this work, by studying the hydrolysis reaction of a cystine-knot inhibitor MCTI-A and its variants with ab initio QM/MM molecular dynamics simulations, we have elucidated an amide rotation hindrance mechanism for proteolysis resistance: The proteolysis of MCTI-A is retarded due to the higher free energy cost during the rotation of NH group around scissile peptide bond at the tetrahedral intermediate of acylation, and covalent constraint provided by disulfide bonds is the key factor to hinder this rotation. A nearly linear correlation has been revealed between free energy barriers of the peptide hydrolysis reaction and the amide rotation free energy changes at the protease-peptide Michaelis complex state. This suggests that amide rotation hindrance could be one useful feature to estimate peptide proteolysis stability.

  12. On the fragmentation of biomolecules: fragmentation of alanine dipeptide along the polypeptide chain

    DEFF Research Database (Denmark)

    Solov'yov, Ilia; Yakubovich, Alexander; Solov'yov, Andrey

    2006-01-01

    . The fragmentation of dipeptide along the polypeptide chain, as well as the interaction between alanines, has been considered. The energy of the system has been analyzed as a function of the distance between fragments for all possible dipeptide fragmentation channels. Analysis of the energy barriers makes...... it possible to estimate the characteristic fragmentation times and to determine the degree of applicability of classical electrodynamics for describing the system energy....

  13. Effects of Lysine deficiency and Lys-Lys dipeptide on cellular apoptosis and amino acids metabolism.

    Science.gov (United States)

    Yin, Jie; Li, Yuying; Han, Hui; Zheng, Jie; Wang, Lijian; Ren, Wenkai; Chen, Shuai; Wu, Fei; Fang, Rejun; Huang, Xingguo; Li, Chunyong; Tan, Bie; Xiong, Xia; Zhang, Yuzhe; Liu, Gang; Yao, Jiming; Li, Tiejun; Yin, Yulong

    2017-09-01

    Lysine (Lys) is a common limiting amino acids (AA) for humans and animals and plays an important role in cell proliferation and metabolism, while metabolism of Lys deficiency and its dipeptide is still obscure. Thus, this study mainly investigated the effects of Lys deficiency and Lys-Lys dipeptide on apoptosis and AA metabolism in vitro and in vivo models. Lys deficiency induced cell-cycle arrest and apoptosis and upregulated Lys transporters in vitro and in vivo. SLC7A11, a cystine-glutamate antiporter, was markedly upregulated by Lys deficiency and then further mediated cystine uptake and glutamate release, which was negatively regulated by cystine and glutamate transporters. Meanwhile, Lys deprivation upregulated pept1 expression, which might improve Lys-Lys dipeptide absorption to compensate for the reduced Lys availability. Lys-Lys dipeptide alleviated Lys deficiency induced cell-cycle arrest and apoptosis and influenced AA metabolism. Furthermore, the mammalian target of rapamycin signal might be involved in sensing cellular Lys starvation and Lys-Lys dipeptide. Altogether, these studies suggest that Lys deficiency impairs AA metabolism and causes apoptosis. Lys-Lys dipeptide serves as a Lys source and alleviates Lys deficiency induced cellular imbalance. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Synthesis and Characterization of Poly(ether amide)s Containing Bisphthalazinone and Ether Linkages

    Institute of Scientific and Technical Information of China (English)

    Cheng LIU; Shou Hai ZHANG; Ming Jing WANG; Qi Zhen LIANG; Xi Gao JIAN

    2005-01-01

    A novel aromatic diacid, 4, 4'-bis[2-(4-carboxyphenyl)phthalazin-1-one-4-yl]-bisphenyl ether Ⅲ, containing bisphthalazinone and ether linkages was prepared from nucleophilic substitution of p-chlorobenzonitrile with the bisphenol-like monomer Ⅰ, followed by alkaline hydrolysis of the intermediate dinitrile Ⅱ. A series of poly(ether amide)s containing bisphthalazinone and ether linkages derived from diacid Ⅲ and aromatic diamines were synthesized by one-step solution condensation polymerization using triphenyl phosphite and pyridine as condensing agents. Moreover, the properties of poly(ether amide)s including thermal stability,solubility and crystallinity were also studied.

  15. How amide hydrogens exchange in native proteins.

    Science.gov (United States)

    Persson, Filip; Halle, Bertil

    2015-08-18

    Amide hydrogen exchange (HX) is widely used in protein biophysics even though our ignorance about the HX mechanism makes data interpretation imprecise. Notably, the open exchange-competent conformational state has not been identified. Based on analysis of an ultralong molecular dynamics trajectory of the protein BPTI, we propose that the open (O) states for amides that exchange by subglobal fluctuations are locally distorted conformations with two water molecules directly coordinated to the N-H group. The HX protection factors computed from the relative O-state populations agree well with experiment. The O states of different amides show little or no temporal correlation, even if adjacent residues unfold cooperatively. The mean residence time of the O state is ∼100 ps for all examined amides, so the large variation in measured HX rate must be attributed to the opening frequency. A few amides gain solvent access via tunnels or pores penetrated by water chains including native internal water molecules, but most amides access solvent by more local structural distortions. In either case, we argue that an overcoordinated N-H group is necessary for efficient proton transfer by Grotthuss-type structural diffusion.

  16. Structures of Highly Twisted Amides Relevant to Amide N-C Cross-Coupling: Evidence for Ground-State Amide Destabilization.

    Science.gov (United States)

    Pace, Vittorio; Holzer, Wolfgang; Meng, Guangrong; Shi, Shicheng; Lalancette, Roger; Szostak, Roman; Szostak, Michal

    2016-10-04

    Herein, we show that acyclic amides that have recently enabled a series of elusive transition-metal-catalyzed N-C activation/cross-coupling reactions are highly twisted around the N-C(O) axis by a new destabilization mechanism of the amide bond. A unique effect of the N-glutarimide substituent, leading to uniformly high twist (ca. 90°) irrespective of the steric effect at the carbon side of the amide bond has been found. This represents the first example of a twisted amide that does not bear significant steric hindrance at the α-carbon atom. The (15) N NMR data show linear correlations between electron density at nitrogen and amide bond twist. This study strongly supports the concept of amide bond ground-state twist as a blueprint for activation of amides toward N-C bond cleavage. The new mechanism offers considerable opportunities for organic synthesis and biological processes involving non-planar amide bonds.

  17. Synthesis of Taste-Active γ-Glutamyl Dipeptides during Sourdough Fermentation by Lactobacillus reuteri.

    Science.gov (United States)

    Zhao, Cindy J; Gänzle, Michael G

    2016-10-12

    This study aimed to assess whether peptides influence the taste of sourdough bread. γ-Glutamyl dipeptides with known kokumi taste threshold, namely γ-Glu-Glu, γ-Glu-Leu, γ-Glu-Ile, γ-Glu-Phe, γ-Glu-Met, and γ-Glu-Val, were identified in sourdough by liquid chromatography-tandem mass spectrometry in MRM mode. γ-Glutamyl dipeptides were found in higher concentrations in sourdough fermented with Lactobacillus reuteri when compared to the chemically acidified controls. Proteolysis was an important factor for generation of γ-glutamyl dipeptides. Sourdoughs fermented with four strains of L. reuteri had different concentrations of γ-Glu-Glu, γ-Glu-Leu, and γ-Glu-Met, indicating strain-specific differences in enzyme activity. Buffer fermentations with L. reuteri confirmed the ability of the strains to convert amino acids to γ-glutamyl dipeptides as well as the strain-specific differences. Sensory evaluation of bread revealed that sourdough bread with higher concentrations of γ-glutamyl dipeptides ranked higher with respect to the taste intensity when compared to regular bread and type I sourdough bread. Sourdough breads fermented with L. reuteri LTH5448 and L. reuteri 100-23 differed with respect to the intensity of the salty taste; this difference corresponded to a different concentration of γ-glutamyl dipeptides. These results suggest a strain-specific contribution of γ-glutamyl dipeptides to the taste of bread. The use of sourdough fermented with glutamate and kokumi peptide accumulating lactobacilli improved the taste of bread without adverse effect on other taste or quality attributes.

  18. Amide-induced phase separation of hexafluoroisopropanol-water mixtures depending on the hydrophobicity of amides.

    Science.gov (United States)

    Takamuku, Toshiyuki; Wada, Hiroshi; Kawatoko, Chiemi; Shimomura, Takuya; Kanzaki, Ryo; Takeuchi, Munetaka

    2012-06-21

    Amide-induced phase separation of hexafluoro-2-propanol (HFIP)-water mixtures has been investigated to elucidate solvation properties of the mixtures by means of small-angle neutron scattering (SANS), (1)H and (13)C NMR, and molecular dynamics (MD) simulation. The amides included N-methylformamide (NMF), N-methylacetamide (NMA), and N-methylpropionamide (NMP). The phase diagrams of amide-HFIP-water ternary systems at 298 K showed that phase separation occurs in a closed-loop area of compositions as well as an N,N-dimethylformamide (DMF) system previously reported. The phase separation area becomes wider as the hydrophobicity of amides increases in the order of NMF amides due to the hydrophobic interaction gives rise to phase separation of the mixtures. In contrast, the disruption of HFIP clusters causes the recovery of the homogeneity of the ternary systems. The present results showed that HFIP clusters are evolved with increasing amide content to the lower phase separation concentration in the same mechanism among the four amide systems. However, the disruption of HFIP clusters in the NMP and DMF systems with further increasing amide content to the upper phase separation concentration occurs in a different way from those in the NMF and NMA systems.

  19. Microorganisms hydrolyse amide bonds; knowledge enabling read-across of biodegradability of fatty acid amides

    NARCIS (Netherlands)

    Geerts, R.; Kuijer, P.; Ginkel, van C.G.; Plugge, C.M.

    2014-01-01

    To get insight in the biodegradation and potential read-across of fatty acid amides, N-[3-(dimethylamino)propyl] cocoamide and N-(1-ethylpiperazine) tall oil amide were used as model compounds. Two bacteria, Pseudomonas aeruginosa PK1 and Pseudomonas putida PK2 were isolated with

  20. Preparation and evaluation of some amide ether carboxylate surfactants

    Directory of Open Access Journals (Sweden)

    M.M.A. El-Sukkary

    2012-06-01

    Full Text Available A homologous series of new mild surfactants, namely: Alkyl amide ether carboxylates surfactants (AEC RCO–NHCH2CH2O (CH2CH2O6CH2COONa, were synthesized by esterification, amidation, ethoxylation and carboxymethylation reaction steps of fatty acids (Lauric, Myristic, palmitic, stearic, oleic or linoleic. The chemical structures of the prepared compounds were confirmed using different spectroscopic techniques, FTIR spectroscopy, mass spectra and HNMR. The surface properties including surface and interfacial tensions, foaming height, emulsification power, calcium ion stability, stability to hydrolysis and critical micelle concentration (cmc were determined. The study of their surface properties showed their stability in hard water and in acidic and alkaline media. These compounds have high calcium ion stability. The low foaming power could have an application in the dyeing auxiliary industry. The lower values of the interfacial tension values indicate the ability of using these surfactants in several applications as corrosion inhibitors and biocides. The data revealed various advantages and potentials as a main surfactant as well as co- surfactants.

  1. Salt forms of the pharmaceutical amide dihydrocarbamazepine.

    Science.gov (United States)

    Buist, Amanda R; Kennedy, Alan R

    2016-02-01

    Carbamazepine (CBZ) is well known as a model active pharmaceutical ingredient used in the study of polymorphism and the generation and comparison of cocrystal forms. The pharmaceutical amide dihydrocarbamazepine (DCBZ) is a less well known material and is largely of interest here as a structural congener of CBZ. Reaction of DCBZ with strong acids results in protonation of the amide functionality at the O atom and gives the salt forms dihydrocarbamazepine hydrochloride {systematic name: [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium chloride, C15H15N2O(+)·Cl(-)}, dihydrocarbamazepine hydrochloride monohydrate {systematic name: [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium chloride monohydrate, C15H15N2O(+)·Cl(-)·H2O} and dihydrocarbamazepine hydrobromide monohydrate {systematic name: [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium bromide monohydrate, C15H15N2O(+)·Br(-)·H2O}. The anhydrous hydrochloride has a structure with two crystallographically independent ion pairs (Z' = 2), wherein both cations adopt syn conformations, whilst the two hydrated species are mutually isostructural and have cations with anti conformations. Compared to neutral dihydrocarbamazepine structures, protonation of the amide group is shown to cause changes to both the molecular (C=O bond lengthening and C-N bond shortening) and the supramolecular structures. The amide-to-amide and dimeric hydrogen-bonding motifs seen for neutral polymorphs and cocrystalline species are replaced here by one-dimensional polymeric constructs with no direct amide-to-amide bonds. The structures are also compared with, and shown to be closely related to, those of the salt forms of the structurally similar pharmaceutical carbamazepine.

  2. Sequential backbone assignment based on dipolar amide-to-amide correlation experiments.

    Science.gov (United States)

    Xiang, ShengQi; Grohe, Kristof; Rovó, Petra; Vasa, Suresh Kumar; Giller, Karin; Becker, Stefan; Linser, Rasmus

    2015-07-01

    Proton detection in solid-state NMR has seen a tremendous increase in popularity in the last years. New experimental techniques allow to exploit protons as an additional source of information on structure, dynamics, and protein interactions with their surroundings. In addition, sensitivity is mostly improved and ambiguity in assignment experiments reduced. We show here that, in the solid state, sequential amide-to-amide correlations turn out to be an excellent, complementary way to exploit amide shifts for unambiguous backbone assignment. For a general assessment, we compare amide-to-amide experiments with the more common (13)C-shift-based methods. Exploiting efficient CP magnetization transfers rather than less efficient INEPT periods, our results suggest that the approach is very feasible for solid-state NMR.

  3. Sequential backbone assignment based on dipolar amide-to-amide correlation experiments

    Energy Technology Data Exchange (ETDEWEB)

    Xiang, ShengQi; Grohe, Kristof; Rovó, Petra; Vasa, Suresh Kumar; Giller, Karin; Becker, Stefan; Linser, Rasmus, E-mail: rali@nmr.mpibpc.mpg.de [Max Planck Institute for Biophysical Chemistry, Department for NMR-Based Structural Biology (Germany)

    2015-07-15

    Proton detection in solid-state NMR has seen a tremendous increase in popularity in the last years. New experimental techniques allow to exploit protons as an additional source of information on structure, dynamics, and protein interactions with their surroundings. In addition, sensitivity is mostly improved and ambiguity in assignment experiments reduced. We show here that, in the solid state, sequential amide-to-amide correlations turn out to be an excellent, complementary way to exploit amide shifts for unambiguous backbone assignment. For a general assessment, we compare amide-to-amide experiments with the more common {sup 13}C-shift-based methods. Exploiting efficient CP magnetization transfers rather than less efficient INEPT periods, our results suggest that the approach is very feasible for solid-state NMR.

  4. Rational and combinatorial tailoring of bioactive cyclic dipeptides

    Directory of Open Access Journals (Sweden)

    Tobias Wolfgang Giessen

    2015-07-01

    Full Text Available Modified cyclic dipeptides represent a diverse family of microbial secondary metabolites. They display a broad variety of biological and pharmacological activities and have long been recognized as privileged structures with the ability to bind to a wide range of receptors. This is due to their conformationally constrained 2, 5-diketopiperazine (DKP scaffold and the diverse set of DKP tailoring enzymes present in nature. After initial DKP assembly through different biosynthetic systems modifying enzymes are responsible for installing functional groups crucial for the biological activities of the resulting modified DKPs. They represent a vast and largely untapped enzyme repository very useful for synthetic biology approaches aiming at introducing structural variations into DKP scaffolds. In this review we focus on these DKP modification enzymes found in various microbial secondary metabolite gene clusters. We will give a brief overview of their distribution and highlight a select number of characterized DKP tailoring enzymes before turning to their application potential in combinatorial biosynthesis with the aim of producing molecules with improved or entirely new biological and medicinally relevant properties.

  5. Fatty Acid Amide Hydrolase (FAAH) Inhibition Enhances Memory Acquisition through Activation of PPAR-alpha Nuclear Receptors

    Science.gov (United States)

    Mazzola, Carmen; Medalie, Julie; Scherma, Maria; Panlilio, Leigh V.; Solinas, Marcello; Tanda, Gianluigi; Drago, Filippo; Cadet, Jean Lud; Goldberg, Steven R.; Yasar, Sevil

    2009-01-01

    Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB[subscript 1]-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain.…

  6. Fatty Acid Amide Hydrolase (FAAH) Inhibition Enhances Memory Acquisition through Activation of PPAR-alpha Nuclear Receptors

    Science.gov (United States)

    Mazzola, Carmen; Medalie, Julie; Scherma, Maria; Panlilio, Leigh V.; Solinas, Marcello; Tanda, Gianluigi; Drago, Filippo; Cadet, Jean Lud; Goldberg, Steven R.; Yasar, Sevil

    2009-01-01

    Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB[subscript 1]-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain.…

  7. Preparation of amidated derivatives of carboxymethylcellulose.

    Science.gov (United States)

    Taubner, Tomáš; Synytsya, Andriy; Čopíková, Jana

    2015-01-01

    Carboxymethylcellulose (CMC) was selected as substrate for amidation based on previous results described for monocarboxy cellulose (MCC) with the aim to prepare highly substituted products. In comparison with MCC containing uronic carboxyl groups at C-6 position, O-carboxymethyl groups in CMC should be more accessible for reagents because they are more distant from the polysaccharide chain. Two-step way of amidation was based on the esterification of CMC carboxyls by reaction with methanol and further amino-de-alkoxylation (aminolysis) of the obtained methyl ester with amidation reagents (n-alkylamines, hydrazine and hydroxylamine). Purity and substitution degree of the products were monitored by the vibration spectroscopic methods (FTIR and Raman) and organic elemental analysis. Analytical methods confirmed the preparation of highly or moderately substituted N-alkylamides, hydrazide and hydroxamic acid of CMC.

  8. Synthesis of Calix[4]resorcinarene Amide Derivatives

    Institute of Scientific and Technical Information of China (English)

    Chao Guo YAN; Yun GE

    2004-01-01

    Three different synthetic routes were developed to introduce carbamoyloxy functional groups at the upper periphery of two calix[4]resorcinarenes. By treating activated esters 2a-b with excess corresponding amine such as 3-(dimethylamino)propylamine 3, α-phenethylamine 4 and triethylenetetramine 5, six amide derivatives 6a~8b were obtained in high yield (Route 1). The pyridine-linked amide derivatives 9a-b were prepared by using acid chloride intermediate (Route 2). The amide derivatives 10a-b were obtained in moderate yields by direct alkylation of phenolic hydroxyl groups of 1a-b with N,N-dipropylchloroacetoamide in the presence of K2CO3/KI in acetone (Route 3).

  9. New GABA amides activating GABAA-receptors.

    Science.gov (United States)

    Raster, Peter; Späth, Andreas; Bultakova, Svetlana; Gorostiza, Pau; König, Burkhard; Bregestovski, Piotr

    2013-01-01

    We have prepared a series of new and some literature-reported GABA-amides and determined their effect on the activation of GABAA-receptors expressed in CHO cells. Special attention was paid to the purification of the target compounds to remove even traces of GABA contaminations, which may arise from deprotection steps in the synthesis. GABA-amides were previously reported to be partial, full or superagonists. In our hands these compounds were not able to activate GABAA-receptor channels in whole-cell patch-clamp recordings. New GABA-amides, however, gave moderate activation responses with a clear structure-activity relationship suggesting some of these compounds as promising molecular tools for the functional analysis of GABAA-receptors.

  10. New GABA amides activating GABAA-receptors

    Directory of Open Access Journals (Sweden)

    Peter Raster

    2013-02-01

    Full Text Available We have prepared a series of new and some literature-reported GABA-amides and determined their effect on the activation of GABAA-receptors expressed in CHO cells. Special attention was paid to the purification of the target compounds to remove even traces of GABA contaminations, which may arise from deprotection steps in the synthesis. GABA-amides were previously reported to be partial, full or superagonists. In our hands these compounds were not able to activate GABAA-receptor channels in whole-cell patch-clamp recordings. New GABA-amides, however, gave moderate activation responses with a clear structure–activity relationship suggesting some of these compounds as promising molecular tools for the functional analysis of GABAA-receptors.

  11. Synthesis of a new pi-deficient phenylalanine derivative from a common 1,4-diketone intermediate and study of the influence of aromatic density on prolyl amide isomer population.

    Science.gov (United States)

    Dörr, Aurélie; Lubell, William D

    2007-01-01

    Enantiopure (2S)-N-(Boc)-3-(6-methylpyridazinyl)alanine (14) has been synthesized to serve as a phenylalanine analog lacking significant pi-donor capability. Two approaches were developed to furnish the target compound from L-aspartic acid as chiral educt in respectively six and nine steps and 13% and 12% yields. In both routes, a key homoallylic ketone intermediate was synthesized by a copper-catalyzed cascade addition of vinylmagnesium bromide to a carboxylic ester. Dipeptide models Ac-Xaa-Pro-NHMe (21a-c) were prepared and the relative populations of prolyl cis- and trans-amide isomers were measured in chloroform, dimethylsulfoxide, and water by proton NMR spectroscopy in order to assess the significance of the electron density of the neighboring aromatic residue on the prolyl amide geometry.

  12. Polyimides Containing Amide And Perfluoroisopropyl Links

    Science.gov (United States)

    Dezem, James F.

    1993-01-01

    New polyimides synthesized from reactions of aromatic hexafluoroisopropyl dianhydrides with asymmetric amide diamines. Soluble to extent of at least 10 percent by weight at temperature of about 25 degrees C in common amide solvents such as N-methylpyrrolidone, N,N-dimethylacetamide, and N,N-dimethylformamide. Polyimides form tough, flexible films, coatings, and moldings. Glass-transition temperatures ranged from 300 to 365 degrees C, and crystalline melting temperatures observed between 543 and 603 degrees C. Display excellent physical, chemical, and electrical properties. Useful as adhesives, laminating resins, fibers, coatings for electrical and decorative purposes, films, wire enamels, and molding compounds.

  13. Chirality of 4,4'-Biphenylene Bridged Polybissilsesquioxane Nanotubes Using the Dipeptides Derived from Valine.

    Science.gov (United States)

    Sang, Yunsen; Guo, Yongmin; Wang, Hairui; Li, Yi; Li, Baozong; Yang, Yonggang

    2015-03-01

    Four dipeptides with alkyl chains derived from L- and D-valines were synthesized, the handedness of their self-assemblies were controlled by the valine chirality at the terminals. The stacking of the carbonyl groups plays an important in the formation of chiral organic self-assemblies. Chiral 4,4'-biphenylene bridged polybissilsesquioxane nanotubes were prepared using the self-assemblies of these dipeptides as the templates. The chirality of the polysilsesquioxane nanotubes was mainly controlled by the valines at the terminals of the dipeptides, which was transferred from the valines at the terminals through electrostatic interaction. The valines near the alkyl chains could also affect the polysilsesquioxane chirality through hydrogen bonding.

  14. Synthèse des dipeptides d’intérêt biologique

    OpenAIRE

    ATMANI, Nadia

    2015-01-01

    des dipeptides d’intérêt biologique [texte imprimé] / ATMANI, Nadia, Auteur. - 2015. - 48p: ill.,...; 30cm. Résumé : Le sujet de ce mémoire est la synthèse des dipeptides à partir des aminoacides, avec comme objectif, l’élaboration de quelques précurseurs peptidiques qui peuvent être utilisés dans la préparation des molécules d’intérêt biologique. Trois acides α-aminés ont été utilisés dans cette synthèse, avec toutes les combinaisons possibles pour engendrer des dipeptides de différentes ...

  15. Discrete dynamic system oriented on the formation of prebiotic dipeptides from Rode's experiment.

    Science.gov (United States)

    Polanco, Carlos; Samaniego, José Lino; Buhse, Thomas; Castañón González, Jorge Alberto

    2014-01-01

    This work attempts to rationalize the possible prebiotic profile of the first dipeptides of about 4 billion years ago based on a computational discrete dynamic system that uses the final yields of the dipeptides obtained in Rode's experiments of salt-induced peptide formation (Rode et al., 1999, Peptides 20: 773-786). The system built a prebiotic scenario that allowed us to observe that (i) the primordial peptide generation was strongly affected by the abundances of the amino acid monomers, (ii) small variations in the concentration of the monomers have almost no effect on the final distribution pattern of the dipeptides and (iii) the most plausible chemical reaction of prebiotic peptide bond formation can be linked to Rode's hypothesis of a salt-induced scenario. The results of our computational simulations were related to former simulations of the Miller, and Fox & Harada experiments on amino acid monomer and oligomer generation, respectively, offering additional information to our approach.

  16. Probing micro-solvation in "numbers": the case of neutral dipeptides in water.

    Science.gov (United States)

    Takis, Panteleimon G; Papavasileiou, Konstantinos D; Peristeras, Loukas D; Melissas, Vasilios S; Troganis, Anastassios N

    2013-05-21

    How many solvent molecules and in what way do they interact directly with biomolecules? This is one of the most challenging questions regarding a deep understanding of biomolecular functionalism and solvation. We herein present a novel NMR spectroscopic study, achieving for the first time the quantification of the directly interacting water molecules with several neutral dipeptides. Our proposed method is supported by both molecular dynamics simulations and density functional theory calculations, advanced analysis of which allowed the identification of the direct interactions between solute-solvent molecules in the zwitterionic L-alanyl-L-alanine dipeptide-water system. Beyond the quantification of dipeptide-water molecule direct interactions, this NMR technique could be useful for the determination and elucidation of small to moderate bio-organic molecular groups' direct interactions with various polar solvent molecules, shedding light on the biomolecular micro-solvation processes and behaviour in various solvents.

  17. Enantioselective synthesis of α-oxy amides via Umpolung amide synthesis.

    Science.gov (United States)

    Leighty, Matthew W; Shen, Bo; Johnston, Jeffrey N

    2012-09-19

    α-Oxy amides are prepared through enantioselective synthesis using a sequence beginning with a Henry addition of bromonitromethane to aldehydes and finishing with Umpolung Amide Synthesis (UmAS). Key to high enantioselection is the finding that ortho-iodo benzoic acid salts of the chiral copper(II) bis(oxazoline) catalyst deliver both diastereomers of the Henry adduct with high enantiomeric excess, homochiral at the oxygen-bearing carbon. Overall, this approach to α-oxy amides provides an innovative complement to alternatives that focus almost entirely on the enantioselective synthesis of α-oxy carboxylic acids.

  18. Amide-transforming activity of Streptomyces: possible application to the formation of hydroxy amides and aminoalcohols.

    Science.gov (United States)

    Yamada, Shinya; Miyagawa, Taka-Aki; Yamada, Ren; Shiratori-Takano, Hatsumi; Sayo, Noboru; Saito, Takao; Takano, Hideaki; Beppu, Teruhiko; Ueda, Kenji

    2013-07-01

    To develop an efficient bioconversion process for amides, we screened our collection of Streptomyces strains, mostly obtained from soil, for effective transformers. Five strains, including the SY007 (NBRC 109343) and SY435 (NBRC 109344) of Streptomyces sp., exhibited marked conversion activities from the approximately 700 strains analyzed. These strains transformed diverse amide compounds such as N-acetyltetrahydroquinoline, N-benzoylpyrrolidine, and N-benzoylpiperidine into alcohols or N,O-acetals with high activity and regioselectivity. N,O-acetal was transformed into alcohol by serial tautomerization and reduction reactions. As such, Streptomyces spp. can potentially be used for the efficient preparation of hydroxy amides and aminoalcohols.

  19. Muscle histidine-containing dipeptides are elevated by glucose intolerance in both rodents and men.

    Directory of Open Access Journals (Sweden)

    Sanne Stegen

    Full Text Available Muscle carnosine and its methylated form anserine are histidine-containing dipeptides. Both dipeptides have the ability to quench reactive carbonyl species and previous studies have shown that endogenous tissue levels are decreased in chronic diseases, such as diabetes.Rodent study: Skeletal muscles of rats and mice were collected from 4 different diet-intervention studies, aiming to induce various degrees of glucose intolerance: 45% high-fat feeding (male rats, 60% high-fat feeding (male rats, cafeteria feeding (male rats, 70% high-fat feeding (female mice. Body weight, glucose-tolerance and muscle histidine-containing dipeptides were assessed. Human study: Muscle biopsies were taken from m. vastus lateralis in 35 males (9 lean, 8 obese, 9 prediabetic and 9 newly diagnosed type 2 diabetic patients and muscle carnosine and gene expression of muscle fiber type markers were measured.Diet interventions in rodents (cafeteria and 70% high-fat feeding induced increases in body weight, glucose intolerance and levels of histidine-containing dipeptides in muscle. In humans, obese, prediabetic and diabetic men had increased muscle carnosine content compared to the lean (+21% (p>0.1, +30% (p<0.05 and +39% (p<0.05, respectively. The gene expression of fast-oxidative type 2A myosin heavy chain was increased in the prediabetic (1.8-fold, p<0.05 and tended to increase in the diabetic men (1.6-fold, p = 0.07, compared to healthy lean subjects.Muscle histidine-containing dipeptides increases with progressive glucose intolerance, in male individuals (cross-sectional. In addition, high-fat diet-induced glucose intolerance was associated with increased muscle histidine-containing dipeptides in female mice (interventional. Increased muscle carnosine content might reflect fiber type composition and/or act as a compensatory mechanism aimed at preventing cell damage in states of impaired glucose tolerance.

  20. Studies on the effect of phosphorylation on the dipeptides actions by radiation chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Manwei; Wang Zhiyong; Chu Gaosheng; Zhang Zhicheng [Univ. of Science and Technology of China, Hefei (China)

    2000-03-01

    The electron transfer within several dipeptides and their corresponding phosphorylated dipeptides was studied by electron pulse radiolysis, laser photolysis and electron spin resonance. The electron transfer rate constants were calculated by data modeling and kinetic analysis. It is found that the phosphoryl group in peptides participates the electron transfer process, and reduces the electron transfer rate in all cases. These are very important in life science since every biological process refers to the phosphorylation and nonphosphorylation of protein. It may be concerned in personalities and individualities of the personae. (author)

  1. Current topics in the biotechnological production of essential amino acids, functional amino acids, and dipeptides.

    Science.gov (United States)

    Mitsuhashi, Satoshi

    2014-04-01

    Amino acids play important roles in both human and animal nutrition and in the maintenance of health. Here, amino acids are classified into three groups: first, essential amino acids, which are essential to nutrition; second, functional amino acids, recently found to be important in the promotion of physiological functions; and third, dipeptides, which are used to resolve problematic features of specific free amino acids, such as their instability or insolubility. This review focusses on recent researches concerning the microbial production of essential amino acids (lysine and methionine), functional amino acids (histidine and ornithine), and a dipeptide (L-alanyl-L-glutamine).

  2. Variation of protein backbone amide resonance by electrostatic field

    OpenAIRE

    Sharley, John N.

    2015-01-01

    Amide resonance is found to be sensitive to electrostatic field with component parallel or antiparallel the amide C-N bond. This effect is linear and without threshold in the biologically plausible electrostatic field range -0.005 to 0.005 au. Variation of amide resonance varies Resonance-Assisted Hydrogen Bonding such as occurs in the hydrogen bonded chains of backbone amides of protein secondary structures such as beta sheet and alpha helix, varying the stability of the secondary structure....

  3. Effects of indole amides on lettuce and onion germination and growth.

    Science.gov (United States)

    Borgati, Thiago F; Boaventura, Maria Amelia D

    2011-01-01

    Auxins, such as indole-3-acetic acid (IAA), are important in plant germination and growth, while physiological polyamines, such as putrescine, are involved in cell proliferation and differentiation, and their concentrations increase during germination. In this work, novel indole amides were synthesized in good yields by monoacylation of morpholine and unprotected symmetrical diamines with indole-3-carboxylic acid, a putative metabolite of IAA, possessing no auxin-like activity. These amides were tested for their effects on seed germination and growth of the radicles and shoots of Lactuca sativa (lettuce) and Allium cepa (onion) seedlings, at 100.0, 1.0, and 0.01 microM concentrations. Germination was generally stimulated, with the exception of amide 3, derived from morpholine, at 100 microM. On radicle and shoot growth, the effect of these compounds was predominantly inhibitory. Compound 3 was the best inhibitor of growth of lettuce and onion, at the highest concentration. Amides, such as propanil, among others, are described as having herbicidal activity.

  4. Metabolism of amino acid amides in Pseudomonas putida ATCC 12633

    NARCIS (Netherlands)

    Hermes, H.F.M.; Croes, L.M.; Peeters, W.P.H.; Peters, P.J.H.; Dijkhuizen, L.

    1993-01-01

    The metabolism of the natural amino acid L-valine, the unnatural amino acids D-valine, and D-, L-phenylglycine (D-, L-PG), and the unnatural amino acid amides D-, L-phenylglycine amide (D, L-PG-NH2) and L-valine amide (L-Val-NH2) was studied in Pseudomonas putida ATCC 12633. The organism possessed c

  5. Metabolism of amino acid amides in Pseudomonas putida ATCC 12633

    NARCIS (Netherlands)

    Hermes, H.F.M.; Croes, L.M.; Peeters, W.P.H.; Peters, P.J.H.; Dijkhuizen, L.

    1993-01-01

    The metabolism of the natural amino acid L-valine, the unnatural amino acids D-valine, and D-, L-phenylglycine (D-, L-PG), and the unnatural amino acid amides D-, L-phenylglycine amide (D, L-PG-NH2) and L-valine amide (L-Val-NH2) was studied in Pseudomonas putida ATCC 12633. The organism possessed

  6. ACRYLATE-AMIDE FOAM CARDIOVASCULAR PROSTHESES.

    Science.gov (United States)

    thoracic and abdominal aorta. The use of a composite construction utilizing acrylate-amide foam is being evaluated in prostheses for mitral valve ...bleeding. The success of the initial experimental work has led to a clinical trial in which 99 replacement , bypass, or patch-angioplasty procedures... replacement , superior vena cava patch venoplasty, and esophageal replacement . (Author)

  7. Efficient Amide Based Halogenide Anion Receptors

    Institute of Scientific and Technical Information of China (English)

    Hong Xing WU; Feng Hua LI; Hai LIN; Shou Rong ZHU; Hua Kuan LIN

    2005-01-01

    In this paper, we present the synthesis and anion recognition properties of the amide based phenanthroline derivatives 1, 2 and 3. In all cases 1:1 receptor: anion complexes were observed. The receptors were found to be selective for fluoride and chloride respectively over other putative anionic guest species.

  8. Platinum catalysed hydrolytic amidation of unactivated nitriles

    NARCIS (Netherlands)

    Cobley, Christopher J.; Heuvel, Marco van den; Abbadi, Abdelilah; Vries, Johannes G. de

    2000-01-01

    The platinum(II) complex, [(Me2PO··H··OPMe2)PtH(PMe2OH)], efficiently catalyses the direct conversion of unactivated nitriles to N-substituted amides with both primary and secondary amines. Possible mechanisms for this reaction are discussed and evidence for initial amidine formation is reported.

  9. Segmented blockcopolymers with uniform amide segments

    NARCIS (Netherlands)

    Husken, D.; Krijgsman, J.; Gaymans, R.J.

    2004-01-01

    Segmented blockcopolymers based on poly(tetramethylene oxide) (PTMO) soft segments and uniform crystallisable tetra-amide segments (TxTxT) are made via polycondensation. The PTMO soft segments, with a molecular weight of 1000 g/mol, are extended with terephthalic groups to a molecular weight of 6000

  10. Platinum catalysed hydrolytic amidation of unactivated nitriles

    NARCIS (Netherlands)

    Cobley, Christopher J.; Heuvel, Marco van den; Abbadi, Abdelilah; Vries, Johannes G. de

    2000-01-01

    The platinum(II) complex, [(Me2PO··H··OPMe2)PtH(PMe2OH)], efficiently catalyses the direct conversion of unactivated nitriles to N-substituted amides with both primary and secondary amines. Possible mechanisms for this reaction are discussed and evidence for initial amidine formation is reported. Is

  11. Determination of the equilibrium micelle-inserting position of the fusion peptide of gp41 of human immunodeficiency virus type 1 at amino acid resolution by exchange broadening of amide proton resonances

    Energy Technology Data Exchange (ETDEWEB)

    Chang, D.-K.; Cheng, S.-F. [Academia Sinica, Institute of Chemistry (China)

    1998-11-15

    The exchange broadening of backbone amide proton resonances of a 23-mer fusion peptide of the transmembrane subunit of HIV-1 envelope glycoprotein gp41, gp41-FP, was investigated at pH 5 and 7 at room temperature in perdeuterated sodium dodecyl sulfate (SDS) micellar solution. Comparison of resonance peaks for these pHs revealed an insignificant change in exchange rate between pH 5 and 7 for amide protons of residues 4 through 14, while the exchange rate increase at neutral pH was more prominent for amide protons of the remaining residues, with peaks from some protons becoming undetectable. The relative insensitivity to pH of the exchange for the amide protons of residues 4 through 14 is attributable to the drastic reduction in [OH-] in the micellar interior, leading to a decreased exchange rate. The A15-G16 segment represents a transition between these two regimes. The data are thus consistent with the notion that the peptide inserts into the hydrophobic core of a membrane-like structure and the A15-G16 dipeptide is located at the micellar-aqueous boundary.

  12. Endotoxin-induced antitumor activity in the mouse is highly potentiated by muramyl dipeptide

    NARCIS (Netherlands)

    Hofhuis, F.M.A.; Bloksma, N.; Willers, J.M.N.

    1984-01-01

    The ability of aqueous solutions of various endotoxin preparations, muramyl dipeptide (MDP) and combinations of endotoxin and MDP, to induce necrosis and regression of subcutaneous Meth A transplants in mice and their toxicity were studied. While intravenously injected toxic endotoxins, in contrast

  13. Profiling histidine dipeptides in plasma and urine after ingesting beef, chicken or chicken broth in humans

    Science.gov (United States)

    Reactive carbonyl species (RCS), oxidation products of polyunsaturated fatty acids, protein & sugars, play a role in the etiology of certain chronic diseases. Our previous studies revealed that histidine-dipeptides such as carnosine and anserine detoxify cytotoxic carbonyls such as 4-hydroxy-trans-...

  14. On the fragmentation of biomolecules: fragmentation of alanine dipeptide along the polypeptide chain

    DEFF Research Database (Denmark)

    Solov'yov, Ilia; Yakubovich, Alexander; Solov'yov, Andrey;

    2006-01-01

    The interaction potential between amino acids in alanine dipeptide has been studied for the first time taking into account exact molecular geometry. Ab initio calculation has been performed in the framework of density functional theory taking into account all electrons in the system. The fragment...

  15. Modulation of muramyl dipeptide stimulation of cytokine production by blood components.

    NARCIS (Netherlands)

    Meer, J.H. van der; Netea, M.G.; Dinarello, C.A.

    2009-01-01

    Muramyl dipeptide (MDP) is the minimal active fragment of peptidoglycan of the cell wall of Gram-positive bacteria, with potential beneficial effects as a vaccine adjuvant. Peptidoglycans and MDP are recognized by the intracellular receptor NOD2 (nucleotide-binding oligomerization domain 2), leading

  16. ENDOR and ELDOR studies of x-irradiated polycrystalline dipeptides, myosin, and actomyosin

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, J.S. (Univ. of Alabama, Tuscaloosa); Dickinson, A.C.; Kispert, L.D.

    1979-12-27

    ENDOR and ELDOR studies have been carried out for nine dipeptide powders as well as powders of myosin and actomyosin x ray irradiated at 77/sup 0/K in an attempt to characterize the final radical stable upon annealing between 183 and 260/sup 0/K. The dipeptides studied were glycylglycine, L-alanylglycine, glycyl-L-alanine, L-alanyl-L-alanine, glycyl-L-aspartic acid, glycyl-L-glutamic acid, glycyl-L-methionine, glycyl-L-serine, and L-lysyl-L-lysine. Nitrogen ENDOR spectra have been observed between 1 and 8 MHz for each powder and the nitrogen hyperfine and quadrupole tensor has been estimated. Analysis of the ENDOR, ELDOR, and ESR spectra indicates at least one of the final radicals in the dipeptide powders (except Gly-Gly, and possibly Gly-Glu, Gly-Ser) to be the decarboxylation product NH/sub 2/CHRCONHCHR' rather than just the abstraction type (NH/sub 3//sup +/-CHRONHCR'COO/sup -/) previously identified in irradiated dipeptide ices. A decarboxylation type radical is also present as a final radical in the irradiated myosin and actomyosin.

  17. CHEMOIMMUNOTHERAPY OF MURINE LIVER METASTASES WITH 5-FLUOROURACIL IN COMBINATION WITH LIPOSOME-ENCAPSULATED MURAMYL DIPEPTIDE

    NARCIS (Netherlands)

    DAEMEN, T; DONTJE, BHJ; REGTS, J; SCHERPHOF, GL

    1993-01-01

    The therapeutic effect of a combination of liposomal muramyl dipeptide (MDP) and 5-fluorouracil (5FU) was studied in a murine tumor model of hepatic metastases of the tumor cell line C26, a colon adenocarcinoma. Liposomal MDP (250 mug/kg body wt) and a low, nontoxic, dose of 5FU (10 mg/kg body wt) w

  18. Modulation of muramyl dipeptide stimulation of cytokine production by blood components.

    NARCIS (Netherlands)

    Meer, J.H. van der; Netea, M.G.; Dinarello, C.A.

    2009-01-01

    Muramyl dipeptide (MDP) is the minimal active fragment of peptidoglycan of the cell wall of Gram-positive bacteria, with potential beneficial effects as a vaccine adjuvant. Peptidoglycans and MDP are recognized by the intracellular receptor NOD2 (nucleotide-binding oligomerization domain 2), leading

  19. Influence of the synthesis conditions of gold nanoparticles on the structure and architectonics of dipeptide composites

    Science.gov (United States)

    Loskutov, Alexander I.; Guskova, Olga A.; Grigoriev, Sergey N.; Oshurko, Vadim B.; Tarasiuk, Aleksei V.; Uryupina, Olga Ya.

    2016-08-01

    A wide variety of peptides and their natural ability to self-assemble makes them very promising candidates for the fabrication of solid-state devices based on nano- and mesocrystals. In this work, we demonstrate an approach to form peptide composite layers with gold nanoparticles through in situ reduction of chloroauric acid trihydrate by dipeptide and/or dipeptide/formaldehyde mixture in the presence of potassium carbonate at different ratios of components. Appropriate composition of components for the synthesis of highly stable gold colloidal dispersion with particle size of 34-36 nm in dipeptide/formaldehyde solution is formulated. Infrared spectroscopy results indicate that dipeptide participates in the reduction process, conjugation with gold nanoparticles and the self-assembly in 2D, which accompanied by changing peptide chain conformations. The structure and morphology of the peptide composite solid layers with gold nanoparticles on gold, mica and silica surfaces are characterized by atomic force microscopy. In these experiments, the flat particles, dendrites, chains, mesocrystals and Janus particles are observed depending on the solution composition and the substrate/interface used. The latter aspect is studied on the molecular level using computer simulations of individual peptide chains on gold, mica and silica surfaces.

  20. Phage display-derived inhibitor of the essential cell wall biosynthesis enzyme MurF

    Directory of Open Access Journals (Sweden)

    Blewett Ann

    2008-12-01

    Full Text Available Abstract Background To develop antibacterial agents having novel modes of action against bacterial cell wall biosynthesis, we targeted the essential MurF enzyme of the antibiotic resistant pathogen Pseudomonas aeruginosa. MurF catalyzes the formation of a peptide bond between D-Alanyl-D-Alanine (D-Ala-D-Ala and the cell wall precursor uridine 5'-diphosphoryl N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid (UDP-MurNAc-Ala-Glu-meso-A2pm with the concomitant hydrolysis of ATP to ADP and inorganic phosphate, yielding UDP-N-acetylmuramyl-pentapeptide. As MurF acts on a dipeptide, we exploited a phage display approach to identify peptide ligands having high binding affinities for the enzyme. Results Screening of a phage display 12-mer library using purified P. aeruginosa MurF yielded to the identification of the MurFp1 peptide. The MurF substrate UDP-MurNAc-Ala-Glumeso-A2pm was synthesized and used to develop a sensitive spectrophotometric assay to quantify MurF kinetics and inhibition. MurFp1 acted as a weak, time-dependent inhibitor of MurF activity but was a potent inhibitor when MurF was pre-incubated with UDP-MurNAc-Ala-Glu-meso-A2pm or ATP. In contrast, adding the substrate D-Ala-D-Ala during the pre-incubation nullified the inhibition. The IC50 value of MurFp1 was evaluated at 250 μM, and the Ki was established at 420 μM with respect to the mixed type of inhibition against D-Ala-D-Ala. Conclusion MurFp1 exerts its inhibitory action by interfering with the utilization of D-Ala-D-Ala by the MurF amide ligase enzyme. We propose that MurFp1 exploits UDP-MurNAc-Ala-Glu-meso-A2pm-induced structural changes for better interaction with the enzyme. We present the first peptide inhibitor of MurF, an enzyme that should be exploited as a target for antimicrobial drug development.

  1. Analysis of the correlation between dipeptides and taste differences among soy sauces by using metabolomics-based component profiling.

    Science.gov (United States)

    Yamamoto, Shinya; Shiga, Kazuki; Kodama, Yukako; Imamura, Miho; Uchida, Riichiro; Obata, Akio; Bamba, Takeshi; Fukusaki, Eiichiro

    2014-07-01

    Characterizing the relationships between the components and taste differences among soy sauces can help evaluate and improve the quality of soy sauces. Although previous studies have reported that certain taste-active dipeptides, the relationships between taste differences and dipeptides of soy sauces are unknown. Therefore, our objective in this study was to investigate the correlations between the dipeptides and the taste differences among soy sauces. To analyze the dipeptides, we constructed an analytical method using liquid chromatography/tandem mass spectrometry (LC/MS/MS) in multiple reaction monitoring mode. Based on this method, we detected 237 dipeptides, the largest number ever detected in soy sauce research. Next, orthogonal projections to latent structures regressions were performed. The data matrix of components, including dipeptides and other low-molecular-weight hydrophilic components obtained from gas chromatography/mass spectrometry (GC/MS), served as explanatory variables (366 in total), whereas a sensory data matrix obtained using quantitative descriptive analysis served as the response variable. The accuracy of models for the sweetness and saltiness differences constructed using the LC/MS/MS and GC/MS data matrix were higher than did models constructed using only the GC/MS data matrix. As a result of investigation of the correlation between the dipeptides and taste differences among soy sauces by using variable importance in the projection (VIP) score, many dipeptides showed the high correlation with taste differences. Specifically, Ile-Gln, Pro-Lys, Ile-Glu, Thr-Phe, and Leu-Gln showed the high VIP score on sweet differences. This study is the first report that reveals the correlations between the dipeptides and taste differences among soy sauces.

  2. Polycondensation of Asparagine-comprising Dipeptides in Aqueous Media-A Simulation of Polypeptide Formation in Primordial Earth Hydrosphere

    Science.gov (United States)

    Munegumi, Toratane; Tanikawa, Naoya

    2017-07-01

    Asparagine and aspartic acid might have mutually transformed in the primordial hydrosphere of the earth, if ammonia and aspartic acid had existed in equilibrium. These amino acids seem to contribute to polypeptides, while the simple amino acids glycine and alanine easily form cyclic dipeptides and do not achieve long peptide chains. Asparagine-comprising dipeptides contribute some kinds of activation forms of dipeptides because these can polymerize faster than asparagine only. The new finding of polypeptide formation suggests a pathway of sequential polypeptides to evolve a diversity of polypeptides.

  3. Tertiary fatty amides as diesel fuel substitutes

    Energy Technology Data Exchange (ETDEWEB)

    Serdari, Aikaterini; Lois, Euripides; Stournas, Stamoulis [National Technical Univ. of Athens, Dept. of Chemical Engineering, Athens (Greece)

    2000-07-01

    This paper presents experimental results regarding the impact of adding different tertiary amides of fatty acids to mineral diesel fuel; an assessment of the behaviour of these compounds as possible diesel fuel extenders is also included. Measurements of cetane number, cold flow properties (cloud point, pour point and CFPP), density, kinematic viscosity, flash point and distillation temperatures are reported, while initial experiments concerning the effects on particulate emissions are also described. Most of the examined tertiary fatty amides esters have very good performance and they can be easily prepared from fatty acids (biomass). Such compounds or their blends could be used as mineral diesel fuel or even fatty acid methylesters (FAME, biodiesel) substitutes or extenders. (Author)

  4. An amidated carboxymethylcellulose hydrogel for cartilage regeneration.

    Science.gov (United States)

    Leone, Gemma; Fini, Milena; Torricelli, Paola; Giardino, Roberto; Barbucci, Rolando

    2008-08-01

    An amidic derivative of carboxymethylcellulose was synthesized (CMCA). The new polysaccharide was obtained by converting a large percentage of carboxylic groups ( approximately 50%) of carboxymethylcellulose into amidic groups rendering the macromolecule quite similar to hyaluronan. Then, the polysaccharide (CMCA) was crosslinked. The behavior of CMCA hydrogel towards normal human articular chondrocytes (NHAC) was in vitro studied monitoring the cell proliferation and synthesis of extra cellular matrix (ECM) components and compared with a hyaluronan based hydrogel (Hyal). An extracellular matrix rich in cartilage-specific collagen and proteoglycans was secreted in the presence of hydrogels. The injectability of the new hydrogels was also analysed. An experimental in vivo model was realized to study the effect of CMCA and Hyal hydrogels in the treatment of surgically created partial thickness chondral defects in the rabbit knee. The preliminary results pointed out that CMCA hydrogel could be considered as a potential compound for cartilage regeneration.

  5. Polyimides containing amide and perfluoroisopropylidene connecting groups

    Science.gov (United States)

    Dezern, James F. (Inventor)

    1993-01-01

    New, thermooxidatively stable polyimides were prepared from the reaction of aromatic dianhydrides containing isopropylidene bridging groups with aromatic diamines containing amide connecting groups between the rings. Several of these polyimides were shown to be semi-crystalline as evidenced by wide angle x ray scattering and differential scanning calorimetry. Most of the polyimides form tough, flexible films with high tensile properties. These polyimide films exhibit enhanced solubility in organic solvents.

  6. Amide-based Fluorescent Macrocyclic Anion Receptors

    Institute of Scientific and Technical Information of China (English)

    ZENG, Zhen-Ya(曾振亚); XU, Kuo-Xi(徐括喜); HE, Yong-Bing(何永炳); LIU, Shun-Ying(刘顺英); WU, Jin-Long(吴进龙); WEI, Lan-Hua(隗兰华); MENG, Ling-Zhi(孟令芝)

    2004-01-01

    Two fluorescent anion receptors (1 and 2) based on amide macrocycle were synthesized and corresponding fluorescence quenching induced by anion complexation was observed in different degree. Receptors form 1: 1 complexes with anions by hydrogen bonding interactions. Receptor 1 bound anions in the order of F->Cl->H2PO4->CH3COO->>Br-, I- and receptor 2 showed high selectivity to F- over other anions.

  7. An unusual intramolecular trans-amidation.

    Science.gov (United States)

    Rivera, Heriberto; Dhar, Sachin; La Clair, James J; Tsai, Shiou-Chuan; Burkart, Michael D

    2016-06-23

    Polyketide biosynthesis engages a series of well-timed biosynthetic operations to generate elaborate natural products from simple building blocks. Mimicry of these processes has offered practical means for total synthesis and provided a foundation for reaction discovery. We now report an unusual intramolecular trans-amidation reaction discovered while preparing stabilized probes for the study of actinorhodin biosynthesis. This rapid cyclization event offers insight into the natural cyclization process inherent to the biosynthesis of type II polyketide antibiotics.

  8. Interaction of dipeptide prodrugs of saquinavir with multidrug resistance protein-2 (MRP-2): evasion of MRP-2 mediated efflux.

    Science.gov (United States)

    Jain, Ritesh; Agarwal, Sheetal; Mandava, Nanda Kishore; Sheng, Ye; Mitra, Ashim K

    2008-10-01

    Saquinavir (SQV), the first protease inhibitor approved by FDA to treat HIV-1 infection. This drug is a well-known substrate for multidrug resistance protein-2 (MRP-2). The objective of this study was to investigate whether derivatization of SQV to dipeptide prodrugs, valine-valine-saquinavir (Val-Val-SQV) and glycine-valine-saquinavir (Gly-Val-SQV), targeting peptide transporter can circumvent MRP-2 mediated efflux. Uptake and transport studies were carried out across MDCKII-MRP2 cell monolayers to investigate the interaction of SQV and its prodrugs with MRP-2. In situ single pass intestinal perfusion experiments in rat jejunum were performed to calculate intestinal absorption rate constants and permeabilities of SQV, Val-Val-SQV and Gly-Val-SQV. Uptake studies demonstrated that the prodrugs have significantly lower interaction with MRP-2 relative to SQV. Transepithelial transport of Val-Val-SQV and Gly-Val-SQV across MDCKII-MRP2 cells exhibited an enhanced absorptive flux and reduced secretory flux as compared to SQV. Intestinal perfusion studies revealed that synthesized prodrugs have higher intestinal permeabilities relative to SQV. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. In the presence of MK-571, a MRP family inhibitor, there was a significant increase in the permeabilities of SQV and Gly-Val-SQV indicating that these compounds are probably substrates for MRP-2. However, there was no change in the permeability of Val-Val-SQV with MK-571 indicating lack of any interaction of Val-Val-SQV with MRP-2. In conclusion, peptide transporter targeted prodrug modification of MRP-2 substrates may lead to shielding of these drug molecules from MRP-2 efflux pumps.

  9. An Efficient Amide-Aldehyde-Alkene Condensation: Synthesis for the N-Allyl Amides.

    Science.gov (United States)

    Quan, Zheng-Jun; Wang, Xi-Cun

    2016-02-01

    The allylamine skeleton represents a significant class of biologically active nitrogen compounds that are found in various natural products and drugs with well-recognized pharmacological properties. In this personal account, we will briefly discuss the synthesis of allylamine skeletons. We will focus on showing a general protocol for Lewis acid-catalyzed N-allylation of electron-poor N-heterocyclic amides and sulfonamide via an amide-aldehyde-alkene condensation reaction. The substrate scope with respect to N-heterocyclic amides, aldehydes, and alkenes will be discussed. This method is also capable of preparing the Naftifine motif from N-methyl-1-naphthamide or methyl (naphthalene-1-ylmethyl)carbamate, with paraformaldehyde and styrene in a one-pot manner.

  10. Dipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells

    Science.gov (United States)

    Naka, Kazuhito; Jomen, Yoshie; Ishihara, Kaori; Kim, Junil; Ishimoto, Takahiro; Bae, Eun-Jin; Mohney, Robert P.; Stirdivant, Steven M.; Oshima, Hiroko; Oshima, Masanobu; Kim, Dong-Wook; Nakauchi, Hiromitsu; Takihara, Yoshihiro; Kato, Yukio; Ooshima, Akira; Kim, Seong-Jin

    2015-01-01

    Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK–Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment. PMID:26289811

  11. Conversion of amides to esters by the nickel-catalysed activation of amide C-N bonds.

    Science.gov (United States)

    Hie, Liana; Fine Nathel, Noah F; Shah, Tejas K; Baker, Emma L; Hong, Xin; Yang, Yun-Fang; Liu, Peng; Houk, K N; Garg, Neil K

    2015-08-06

    Amides are common functional groups that have been studied for more than a century. They are the key building blocks of proteins and are present in a broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond. Although amides can readily be cleaved by enzymes such as proteases, it is difficult to selectively break the carbon-nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon-nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon-heteroatom or carbon-carbon bonds using non-precious-metal catalysis.

  12. New Umami Amides: Structure-Taste Relationship Studies of Cinnamic Acid Derived Amides and the Natural Occurrence of an Intense Umami Amide in Zanthoxylum piperitum.

    Science.gov (United States)

    Frerot, Eric; Neirynck, Nathalie; Cayeux, Isabelle; Yuan, Yoyo Hui-Juan; Yuan, Yong-Ming

    2015-08-19

    A series of aromatic amides were synthesized from various acids and amines selected from naturally occurring structural frameworks. These synthetic amides were evaluated for umami taste in comparison with monosodium glutamate. The effect of the substitution pattern of both the acid and the amine parts on umami taste was investigated. The only intensely umami-tasting amides were those made from 3,4-dimethoxycinnamic acid. The amine part was more tolerant to structural changes. Amides bearing an alkyl- or alkoxy-substituted phenylethylamine residue displayed a clean umami taste as 20 ppm solutions in water. Ultraperformance liquid chromatography coupled with a high quadrupole-Orbitrap mass spectrometer (UPLC/MS) was subsequently used to show the natural occurrence of these amides. (E)-3-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenethyl)acrylamide was shown to occur in the roots and stems of Zanthoxylum piperitum, a plant of the family Rutaceae growing in Korea, Japan, and China.

  13. SYNTHESIS, CHARACTERIZATION OF CHIRAL POLY(ESTER AMIDE)S DERIVED FROM L-ISOLEUCINE

    Institute of Scientific and Technical Information of China (English)

    Xing-He Fan; Jing-Lun Zhou; Xiao-Fang Chen; Xin-Hua Wan; Qi-Feng Zhou

    2004-01-01

    A series of new optically active aromatic poly(ester amide)s containing a chiral group in the side chain prepared from the p-toluenesulfonic acid salt of o,o'-bis(leucyl)-hexanediol (TS-+LHD+TS-) and p-phthaloyl chloride and styrene-2,5-dicarbonyl chloride styrene have been synthesized by interfacial polymerization. The structure of the monomer is elucidated by FT-IR and elemental analysis. The thermal properties of the polymers were studied by DSC and TGA. The chiroptical properties of the above polymer have also been studied by circular dichroism (CD) spectroscopy. Results indicated that these polymers form helical structures.

  14. Synthesis of Novel Poly(aryl ether amide)s Containing the Phthalazinone Moiety

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Two novel heterocyclic diamine monomers: 1,2-dihydro-2-(4-aminophenyl)-4-[4-(4-amin- ophenoxy)phenyl](2H)phthalazin-1-one and 1,2-dihydro-2-(4-aminophenyl)-4-[4-(4-aminophenoxy)-3,5-dimethylphenyl](2H)phthalazin-1-one were successfully synthesized from readily available heterocyclic bisphenol-like monomers in two steps in high yield. A series of novel poly(aryl ether amide)s containing the phthalazinone moiety were successfully prepared by the direct polymerization of the novel diamines and aromatic dicarboxylic acids using triphenyl phosphite and pyridine as condensing agents.

  15. A new class of ghrelin O-acyltransferase inhibitors incorporating triazole-linked lipid mimetic groups.

    Science.gov (United States)

    Zhao, Feifei; Darling, Joseph E; Gibbs, Richard A; Hougland, James L

    2015-07-15

    Inhibitors of ghrelin O-acyltransferase (GOAT) have untapped potential as therapeutics targeting obesity and diabetes. We report the first examples of GOAT inhibitors incorporating a triazole linkage as a biostable isosteric replacement for the ester bond in ghrelin and amide bonds in previously reported GOAT inhibitors. These triazole-containing inhibitors exhibit sub-micromolar inhibition of the human isoform of GOAT (hGOAT), and provide a foundation for rapid future chemical diversification and optimization of hGOAT inhibitors.

  16. Variation of protein backbone amide resonance by electrostatic field

    CERN Document Server

    Sharley, John N

    2015-01-01

    Amide resonance is found to be sensitive to electrostatic field with component parallel or antiparallel the amide C-N bond. This effect is linear and without threshold in the biologically plausible electrostatic field range -0.005 to 0.005 au. Variation of amide resonance varies Resonance Assisted Hydrogen Bonding such as occurs in the hydrogen bonded chains of backbone amides of protein secondary structures such as beta sheet and non-polyproline helix such as alpha helix, varying the stability of the secondary structure. The electrostatic properties including permittivity of amino acid residue sidegroups influence the electrostatic field component parallel or antiparallel the C-N bond of each amide. The significance of this factor relative to other factors in protein folding depends on the magnitude of electrostatic field component parallel or antiparallel the C-N bond of each amide, and preliminary protein-scale calculations of the magnitude of these components suggest this factor warrants investigation in ...

  17. Oxidative activation of dihydropyridine amides to reactive acyl donors

    DEFF Research Database (Denmark)

    Funder, Erik Daa; Trads, Julie Brender; Gothelf, Kurt Vesterager

    2015-01-01

    Amides of 1,4-dihydropyridine (DHP) are activated by oxidation for acyl transfer to amines, alcohols and thiols. In the reduced form the DHP amide is stable towards reaction with amines at room temperature. However, upon oxidation with DDQ the acyl donor is activated via a proposed pyridinium int...... intermediate. The activated intermediate reacts with various nucleophiles to give amides, esters, and thio-esters in moderate to high yields....

  18. Analytical applications of resins containing amide and polyamine functional groups

    Energy Technology Data Exchange (ETDEWEB)

    Orf, Gene Michael [Iowa State Univ., Ames, IA (United States)

    1977-12-01

    A dibutyl amide resin is used for the separation of uranium(VI), thorium(IV), and zirconium(IV) from each other and several other metal ions. Uranium(VI) and thorium(IV) are determined in the presence of large excesses of foreign metal ions and anions. A practical application of the amide resin is studied by determining uranium in low grade uranium ores. The amide resin is also used for the selective concentration of gold(III) from sea water.

  19. Lipopolysaccharide-induced pulmonary inflammation is not accompanied by a release of anandamide into the lavage fluid or a down-regulation of the activity of fatty acid amide hydrolase

    DEFF Research Database (Denmark)

    Holt, S.; J. Fowler, C.; Rocksén, D.;

    2004-01-01

    The effect of lipopolysaccharide inhalation upon lung anandamide levels, anandamide synthetic enzymes and fatty acid amide hydrolase has been investigated. Lipopolysaccharide exposure produced a dramatic extravasation of neutrophils and release of tumour necrosis factor a into the bronchoalveolar......-acyltransferase and N-acylphosphatidylethanolamine phospholipase D and the activity of fatty acid amide hydrolase in lung membrane fractions did not change significantly following the exposure to lipopolysaccharide. The non-selective fatty acid amide hydrolase inhibitor phenylmethylsulfonyl fluoride was a less potent...... inhibitor of lung fatty acid amide hydrolase than expected from the literature, and a dose of 30 mg/kg i.p. of this compound, which produced a complete inhibition of brain anandamide metabolism, only partially inhibited the lung metabolic activity. © 2004 Elsevier Inc. All rights reserved....

  20. Papain-like protease (PLpro) inhibitory effects of cinnamic amides from Tribulus terrestris fruits.

    Science.gov (United States)

    Song, Yeong Hun; Kim, Dae Wook; Curtis-Long, Marcus John; Yuk, Heung Joo; Wang, Yan; Zhuang, Ningning; Lee, Kon Ho; Jeon, Kwon Seok; Park, Ki Hun

    2014-01-01

    Tribulus terrestris fruits are well known for their usage in pharmaceutical preparations and food supplements. The methanol extract of T. terrestris fruits showed potent inhibition against the papain-like protease (PLpro), an essential proteolylic enzyme for protection to pathogenic virus and bacteria. Subsequent bioactivity-guided fractionation of this extract led to six cinnamic amides (1-6) and ferulic acid (7). Compound 6 emerged as new compound possessing the very rare carbinolamide motif. These compounds (1-7) were evaluated for severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro inhibitory activity to identify their potencies and kinetic behavior. Compounds (1-6) displayed significant inhibitory activity with IC50 values in the range 15.8-70.1 µM. The new cinnamic amide 6 was found to be most potent inhibitor with an IC50 of 15.8 µM. In kinetic studies, all inhibitors exhibited mixed type inhibition. Furthermore, the most active PLpro inhibitors (1-6) were proven to be present in the native fruits in high quantities by HPLC chromatogram and liquid chromatography with diode array detection and electrospray ionization mass spectrometry (LC-DAD-ESI/MS).

  1. Synthesis of nitriles via palladium-catalyzed water shuffling from amides to acetonitrile.

    Science.gov (United States)

    Zhang, Wandi; Haskins, Christopher W; Yang, Yang; Dai, Mingji

    2014-12-07

    Palladium-catalyzed synthesis of nitriles from amides has been described. Two similar, but complementary reaction conditions have been identified to convert various amides including α,β,γ,δ-unsaturated amides, cinnamides, aromatic amides and alkyl amides to the corresponding nitriles in good to excellent yield.

  2. Electrochemical reduction of nitrate in the presence of an amide

    Science.gov (United States)

    Dziewinski, Jacek J.; Marczak, Stanislaw

    2002-01-01

    The electrochemical reduction of nitrates in aqueous solutions thereof in the presence of amides to gaseous nitrogen (N.sub.2) is described. Generally, electrochemical reduction of NO.sub.3 proceeds stepwise, from NO.sub.3 to N.sub.2, and subsequently in several consecutive steps to ammonia (NH.sub.3) as a final product. Addition of at least one amide to the solution being electrolyzed suppresses ammonia generation, since suitable amides react with NO.sub.2 to generate N.sub.2. This permits nitrate reduction to gaseous nitrogen to proceed by electrolysis. Suitable amides include urea, sulfamic acid, formamide, and acetamide.

  3. Experimental and computational investigations of the THz spectra of dipeptide nanotubes

    Science.gov (United States)

    Siegrist, K. M.; Pfefferkorn, C.; Schwarzkopf, A.; Podobedov, V. B.; Plusquellic, D. F.

    2008-02-01

    Continuous wave THz spectroscopy has been used to obtain spectra for four isostructural dipeptide nanotubes at 4.2K from 2 cm -1 to 100 cm -1 (0.05 to 3 THz). Line-narrowing of spectral features by a factor of 2 to 4 is observed for the crystalline dipeptide films investigated by absorption spectroscopy using a plane parallel waveguide, compared to spectra from pressed disks of polyethylene-diluted samples. The x-ray determined crystal structures of these peptides formed the basis for a parallel computational investigation. Spectral predictions from the ab initio level computational package DMOL 3 and the empirical force field model CHARMM22 are compared to the experimentally obtained THz absorption spectra. The THz waveguide spectroscopy technique can provide information on the orientation-dependent dipole coupling of the vibrational modes, which can aid in validating computational models.

  4. Surface Chirality of Gly-Pro Dipeptide Adsorbed on a Cu(110) Surface.

    Science.gov (United States)

    Cruguel, Hervé; Méthivier, Christophe; Pradier, Claire-Marie; Humblot, Vincent

    2015-07-01

    The adsorption of chiral Gly-Pro dipeptide on Cu(110) has been characterized by combining in situ polarization modulation infrared reflection absorption spectroscopy (PM-RAIRS) and X-ray photoelectron spectroscopy (XPS). The chemical state of the dipeptide, and its anchoring points and adsorption geometry, were determined at various coverage values. Gly-Pro molecules are present on Cu(110) in their anionic form (NH2 /COO(-)) and adsorb under a 3-point binding via both oxygen atoms of the carboxylate group and via the nitrogen atom of the amine group. Low-energy electron diffraction (LEED) and scanning tunneling microscopy (STM) have shown the presence of an extended 2D chiral array, sustained via intermolecular H-bonds interactions. Furthermore, due to the particular shape of the molecule, only one homochiral domain is formed, creating thus a truly chiral surface.

  5. Light-driven topochemical polymerization under organogel conditions of a symmetrical dipeptide-diacetylene system.

    Science.gov (United States)

    Mazzier, Daniela; Mosconi, Dario; Marafon, Giulia; Reheman, Aikebaier; Toniolo, Claudio; Moretto, Alessandro

    2017-02-01

    A symmetrical dipeptide-based diacetylene system (DAs) was found to be able to self-assemble in dichloromethane and to form a compact fiber network which resulted in a stable organogel. As a consequence of the organogel formation, we explored the possibility to run a light-induced topochemical polymerization. This is a typical reaction of ordered diacetylene moieties taking advantage from their organized packing mode resulting from fiber formation. Evidence for the generation of peptide-based polydiacetylenes is provided by Raman, UV-Vis, and CD spectroscopies and a set of microscopic techniques. Finally, we succeeded in processing a polymeric composite by use of the electrospinning technique, starting from a mixture of a dipeptide-based diacetylene and polymethyl methacrylate. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  6. N-(L-2-aminopentanoyl)-L-phenylalanine dihydrate, a hydrophobic dipeptide with a nonproteinogenic residue.

    Science.gov (United States)

    Görbitz, Carl Henrik; Yadav, Vitthal N

    2013-09-01

    The title dipeptide, better known as L-norvalyl-L-phenylalanine {systematic name: (S)-2-[(S)-2-aminopentanamido]-3-phenylpropanoic acid dihydrate}, C14H20N2O3·2H2O, has a nonproteinogenic N-terminal residue. In the solid state, it takes on a molecular conformation typical for one of the three classes of nanoporous dipeptides, but like two related compounds with a hydrophobic N-terminal residue and a C-terminal L-phenylalanine, it fails to form channels or pores. Instead, the crystal structure is divided into distinct hydrophobic and hydrophilic layers, the latter encompassing cocrystallized water molecules connecting the charged N- and C-terminal groups.

  7. AMID: autonomous modeler of intragenic duplication.

    Science.gov (United States)

    Kummerfeld, Sarah K; Weiss, Anthony S; Fekete, Alan; Jermiin, Lars S

    2003-01-01

    Intragenic duplication is an evolutionary process where segments of a gene become duplicated. While there has been much research into whole-gene or domain duplication, there have been very few studies of non-tandem intragenic duplication. The identification of intragenically replicated sequences may provide insight into the evolution of proteins, helping to link sequence data with structure and function. This paper describes a tool for autonomously modelling intragenic duplication. AMID provides: identification of modularly repetitive genes; an algorithm for identifying repeated modules; and a scoring system for evaluating the modules' similarity. An evaluation of the algorithms and use cases are presented.

  8. Synthesis of a Dopamimetic Thionated Dipeptide Prodrug of L-DOPA

    Institute of Scientific and Technical Information of China (English)

    Ye WANG; Zhan Zhu LIU; Shi Zhi CHEN

    2005-01-01

    L-DOPA has gained widespread credit over the past decades as being the mainstay of the pharmacological treatment of Parkinson's disease. However, there are many adverse effects associated with the use of L-DOPA. The prodrug approach is the most promising way to solve the problem. In this article, a thionated dipeptide prodrug of L-DOPA 11 was synthesized via 10steps in a total yield of 26.5% from L-DOPA.

  9. Glutamine dipeptide for parenteral nutrition in abdominal surgery: A meta-analysis of randomized controlled trials

    Institute of Scientific and Technical Information of China (English)

    Ya-Min Zheng; Fei Li; Ming-Ming Zhang; Xiao-Ting Wu

    2006-01-01

    AIM: To assess the clinical and economical validity of glutamine dipeptide supplemented to parenteral nutrition(PN) in patients undergoing abdominal surgery.METHODS: A meta-analysis of all the relevant randomized controlled trials (RCTs) was performed. The trials compared the standard PN and PN supplemented with glutamine dipeptide in abdominal surgery. RCTs were identified from the following electronic databases:the Cochrane Library, MEDLINE, EMBASE and ISI web of knowledge (SCI). The search was undertaken in April 2006. Literature references were checked by computer or hand at the same time. Clinical trials were extracted and evaluated by two reviewers independently. Statistical analysis was performed by RevMan4.2 software from Cochrane Collaboration. A P value of <0.05 was considered statistically significant.RESULTS: Nine RCTs involving 373 patients were included. The combined results showed that glutamine dipeptide has a positive effect in improving postoperative cumulative nitrogen balance (weighted mean difference (WMD = 8.35, 95% CI [2.98, 13.71], P = 0.002),decreasing postoperative infectious morbidity (OR = 0.24,95% CI [0.06, 0.93], P = 0.04), shortening the length of hospital stay (WMD= -3.55, 95% CI [-5.26, -1.84], P<0.00001). No serious adverse effects were found.CONCLUSION: Postoperative PN supplemented with glutamine dipeptide is effective and safe to decrease the infectious rate, reduce the length of hospital stay and improve nitrogen balance in patients undergoing abdominal surgery. Further high quality trials in children and severe patients are required, and mortality and hospital cost should be considered in future RCTs with sufficient size and rigorous design.

  10. Enzymatic Synthesis of Dipeptide Derivatives Containing Noncoded Amino Acids in Organic Solvents

    Institute of Scientific and Technical Information of China (English)

    YANG,Hong(杨洪); ZHOU,Chuang(周闯); TIAN,Gui-Ling(田桂玲); YE,Yun-Hua(叶蕴华)

    2002-01-01

    A series of dipeptide derivatives containing non-coded amino acis, N-Boc-4-X-Phe-Ala-NHNHNHPh (X= Cl, Br, I, NO2),were synthesized by using thermoase in organic solvents. The physical data were consistent with the same samples prepared by 3-( diethoxyphosphoryloxy)-1, 2, 3-benzotriazin-4 (3H)-one (DEPBT). Influence of different substituted groups of the non-coded amino acids and different organic solvents on the enzymatic peptide synthesis was studied.

  11. Correlation of electronic structures of three cyclic dipeptides with their photoemission spectra

    Science.gov (United States)

    Arachchilage, Anoja P. Wickrama; Wang, Feng; Feyer, Vitaliy; Plekan, Oksana; Prince, Kevin C.

    2010-11-01

    We have investigated the electronic structure of three cyclic dipeptides: cyclo(Glycyl-Glycyl) (cGG), cyclo(Leucyl-Prolyl) (cLP), and cyclo(Phenylalanyl-Prolyl) (cPP). These compounds are biologically active and cLP and cPP are derived from cGG (also known as diketopiperazine), by the addition of the respective functional groups of the amino acids, namely, phenyl, alkyl or a fused pyrrolidine ring (proline). Experimental valence and core level spectra have been interpreted in the light of theoretical calculations to identify the basic chemical properties associated with the central ring, and with the additional functional groups in cLP and cPP. The theoretically simulated spectra of all three cyclic dipeptides in both valence and core spaces agreed reasonably well with the experimental spectra. The three molecules displayed similarities in their core spectra, suggesting that the diketopiperazine structure plays an important role in determining the inner shell spectrum. The experimental C 1s spectra of cLP and cPP are analogous but differ from cGG due to the side chains attached to the diketopiperazine structure. Single spectral peaks in the N 1s (and O 1s) spectra of the dipeptides indicate that the chemical environment of the nitrogen atoms (and oxygen atoms) are very similar, although they show a small splitting in the simulated spectra of cPL and cPP, due to the reduction of their point group symmetry. Valence band spectra of the three dipeptides in the frontier orbital region of 9-11 eV exhibit similarities; however theoretical analysis shows that significant changes occur due to the involvement of the side chain in the frontier orbitals of cPP, while lesser changes are found for cLP.

  12. Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides.

    Science.gov (United States)

    Quistad, G B; Sparks, S E; Casida, J E

    2001-05-15

    Organophosphorus (OP) compound-induced inhibition of acetylcholinesterase (AChE) and neuropathy target esterase explains the rapid onset and delayed neurotoxic effects, respectively, for OP insecticides and related compounds but apparently not a third or intermediate syndrome with delayed onset and reduced limb mobility. This investigation tests the hypothesis that fatty acid amide hydrolase (FAAH), a modulator of endogenous signaling compounds affecting sleep (oleamide) and analgesia (anandamide), is a sensitive target for OP pesticides with possible secondary neurotoxicity. Chlorpyrifos oxon inhibits 50% of the FAAH activity (IC50 at 15 min, 25 degrees C, pH 9.0) in vitro at 40--56 nM for mouse brain and liver, whereas methyl arachidonyl phosphonofluoridate, ethyl octylphosphonofluoridate (EOPF), oleyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (oleyl-BDPO), and dodecyl-BDPO give IC50s of 0.08--1.1 nM. These BDPOs and EOPF inhibit mouse brain FAAH in vitro with > or =200-fold higher potency than for AChE. Five OP pesticides inhibit 50% of the brain FAAH activity (ED50) at diazinon, and methamidophos occurs near acutely toxic levels, profenofos and tribufos are effective at asymptomatic doses. Two BDPOs (dodecyl and phenyl) and EOPF are potent inhibitors of FAAH in vivo (ED50 0.5--6 mg/kg). FAAH inhibition of > or =76% in brain depresses movement of mice administered anandamide at 30 mg/kg ip, often leading to limb recumbency. Thus, OP pesticides and related inhibitors of FAAH potentiate the cannabinoid activity of anandamide in mice. More generally, OP compound-induced FAAH inhibition and the associated anandamide accumulation may lead to reduced limb mobility as a secondary neurotoxic effect.

  13. Reaction mechanism of the acidic hydrolysis of highly twisted amides: Rate acceleration caused by the twist of the amide bond.

    Science.gov (United States)

    Mujika, Jon I; Formoso, Elena; Mercero, Jose M; Lopez, Xabier

    2006-08-03

    We present an ab initio study of the acid hydrolysis of a highly twisted amide and a planar amide analogue. The aim of these studies is to investigate the effect that the twist of the amide bond has on the reaction barriers and mechanism of acid hydrolysis. Concerted and stepwise mechanisms were investigated using density functional theory and polarizable continuum model calculations. Remarkable differences were observed between the mechanism of twisted and planar amide, due mainly to the preference for N-protonation of the former and O-protonation of the latter. In addition, we were also able to determine that the hydrolytic mechanism of the twisted amide will be pH dependent. Thus, there is a preference for a stepwise mechanism with formation of an intermediate in the acid hydrolysis, whereas the neutral hydrolysis undergoes a concerted-type mechanism. There is a nice agreement between the characterized intermediate and available X-ray data and a good agreement with the kinetically estimated rate acceleration of hydrolysis with respect to analogous undistorted amide compounds. This work, along with previous ab initio calculations, describes a complex and rich chemistry for the hydrolysis of highly twisted amides as a function of pH. The theoretical data provided will allow for a better understanding of the available kinetic data of the rate acceleration of amides upon twisting and the relation of the observed rate acceleration with intrinsic differential reactivity upon loss of amide bond resonance.

  14. Extended solvent-contact model for protein solvation: test cases for dipeptides.

    Science.gov (United States)

    Choi, Hwanho; Kang, Hongsuk; Park, Hwangseo

    2013-05-01

    Solvation effects are critically important in the structural stabilization and functional optimization of proteins. Here, we propose a new solvation free energy function for proteins, and test its applicability in predicting the solvation free energies of dipeptides. The present solvation model involves the improvement of the previous solvent-contact model assuming that the molecular solvation free energy could be given by the sum over the individual atomic contributions. In addition to the existing solvent-contact term, the modified solvation free energy function includes the self-solvation term that reflects the effects of intramolecular interactions in the solute molecule on solute-solvent interactions. Four kinds of atomic parameters should be determined in this solvation model: atomic fragmental volume, maximum atomic occupancy, atomic solvation, and atomic self-solvation parameters. All of these parameters for 16 atom types are optimized with a standard genetic algorithm in such a way to minimize the difference between the solvation free energies of dipeptides obtained from high-level quantum chemical calculations and those predicted by the solvation free energy function. The solvation free energies of dipeptides estimated from the new solvation model are in good agreement with the quantum chemical results. Therefore, the optimized solvation free energy function is expected to be useful for examining the structural and energetic features of proteins in aqueous solution.

  15. 2, 5-diketopiperazines (cyclic dipeptides) in beef: identification, synthesis, and sensory evaluation.

    Science.gov (United States)

    Chen, M Z; Dewis, M L; Kraut, K; Merritt, D; Reiber, L; Trinnaman, L; Da Costa, N C

    2009-03-01

    Stewed beef and grilled dry aged beef were analyzed as part of an in-depth analytical program, with the aim of creating new flavors incorporating only compounds identified in the target foods and identifying new synthesis targets. In-house GC-MS analyses of several types of cooked beef have identified over 1000 volatile and semivolatile components; many for the 1st time. Among the semivolatiles detected were ten 2, 5-diketopiperazines (cyclic dipeptides) previously unreported in beef. These cyclic dipeptides are cis-cyclo(L-Ile-L-Pro), cis-cyclo(L-Leu-L-Pro), cis-cyclo(L-Pro-L-Pro), cis-cyclo(L-Pro-L-Val), cis-cyclo(L-Ala-L-Pro), cyclo(Gly-L-Pro), cyclo(Gly-L-Leu), cis-cyclo(L-Met-L-Pro), cis-cyclo(L-Phe-L-Pro), and cis-cyclo(L-Phe-L-Val). All 10 cyclic dipeptides were synthesized and evaluated organoleptically. Among them cis-cyclo(L-Leu-L-Pro), cis-cyclo(L-Met-L-Pro), and cis-cyclo(L-Phe-L-Pro) were found to be of particular organoleptic interest.

  16. Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist.

    Science.gov (United States)

    Hwang, Tsong-Long; Hung, Chih-Hao; Hsu, Ching-Yun; Huang, Yin-Ting; Tsai, Yu-Chi; Hsieh, Pei-Wen

    2013-06-14

    Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2˙(-)) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein.

  17. Dipeptides and Diketopiperazines in the Yamato-791198 and Murchison Carbonaceous Chondrites

    Science.gov (United States)

    Shimoyama, Akira; Ogasawara, Ryo

    2002-04-01

    The Yamato-791198 and Murchison carbonaceous chondrites were analyzed for dipeptides and diketopiperazines as well as amino acids and hydantoins by gas chromatography combined with mass spectrometry. Glycylglycine (gly-gly) and cyclo(gly-gly) were detected at the concentrations of 11 and 18 pmol g^-1, respectively, in Yamato-791198, and 4 and 23 pmol g^-1, respectively, in Murchison. No other dipeptide and diketopiperazine were detected. Five hydantoins were detected at 8 to 65 pmol g^-1 in Yamato-791198 and seven in Murchison at 6 to 104 pmol g^-1. Total concentration of the glycine (gly) dimers is approximately four orders of magnitude less than the concentration of free gly in Yamato-791198, and three orders of magnitude less than that in Murchison. The absence of L- and LL-stereoisomers of dipeptides consisting of protein amino acids indicates that gly-gly and cyclo(gly-gly) detected are native to the chondrites and not from terrestrial contaminants. A possibility was discussed that the gly dimers might have been formed by condensation of gly monomers but not formed through N-carboxyanhydrides of gly.

  18. Homology models guide discovery of diverse enzyme specificities among dipeptide epimerases in the enolase superfamily

    Science.gov (United States)

    Lukk, Tiit; Sakai, Ayano; Kalyanaraman, Chakrapani; Brown, Shoshana D.; Imker, Heidi J.; Song, Ling; Fedorov, Alexander A.; Fedorov, Elena V.; Toro, Rafael; Hillerich, Brandan; Seidel, Ronald; Patskovsky, Yury; Vetting, Matthew W.; Nair, Satish K.; Babbitt, Patricia C.; Almo, Steven C.; Gerlt, John A.; Jacobson, Matthew P.

    2012-01-01

    The rapid advance in genome sequencing presents substantial challenges for protein functional assignment, with half or more of new protein sequences inferred from these genomes having uncertain assignments. The assignment of enzyme function in functionally diverse superfamilies represents a particular challenge, which we address through a combination of computational predictions, enzymology, and structural biology. Here we describe the results of a focused investigation of a group of enzymes in the enolase superfamily that are involved in epimerizing dipeptides. The first members of this group to be functionally characterized were Ala-Glu epimerases in Eschericiha coli and Bacillus subtilis, based on the operon context and enzymological studies; these enzymes are presumed to be involved in peptidoglycan recycling. We have subsequently studied more than 65 related enzymes by computational methods, including homology modeling and metabolite docking, which suggested that many would have divergent specificities;, i.e., they are likely to have different (unknown) biological roles. In addition to the Ala-Phe epimerase specificity reported previously, we describe the prediction and experimental verification of: (i) a new group of presumed Ala-Glu epimerases; (ii) several enzymes with specificity for hydrophobic dipeptides, including one from Cytophaga hutchinsonii that epimerizes D-Ala-D-Ala; and (iii) a small group of enzymes that epimerize cationic dipeptides. Crystal structures for certain of these enzymes further elucidate the structural basis of the specificities. The results highlight the potential of computational methods to guide experimental characterization of enzymes in an automated, large-scale fashion. PMID:22392983

  19. Interconnection between the protein solubility and amino acid and dipeptide compositions.

    Science.gov (United States)

    Niu, Xiaohui; Li, Nana; Chen, Dinyan; Wang, Zengzhen

    2013-01-01

    Obtaining soluble proteins in sufficient concentrations helps increase the overall success rate in various experimental studies. Protein solubility is an individual trait ultimately determined by its primary protein sequence. Exploring the interconnection between the protein solubility and the compositions of protein sequence is instrumental for setting priorities on targets in large scale proteomics projects. In this paper, amino acid composition (20 dimensions) and the dipeptide composition (400 dimensions) were extracted to form the total candidate feature pool (420 dimensions), and each feature was selected into the feature vectors one by one, which were sorted by the absolute value of the correlation coefficient. Finally, we evaluated and recorded the 420 results of Support Vector Machine (SVM) as the prediction engine. According to the results of SVM, the first 208 features were chosen from the 420 dimensions, which were considered as the efficient ones. By analyzing the composition of the former 208 features, we found that the protein solubility was significantly influenced by the occurrence frequencies of the acidic amino acids, basic amino acids, non-polar hydrophobic amino acids and the two polar neutral amino acids(C, Q) in the protein sequences. Additionally, we detected that the dipeptides composed by the acidic amino acids (D, E) and basic amino acids (K, R and H), especially the dipeptide composed by the acidic amino acids (D, E), had strong interconnection with the protein solubility.

  20. Effect of dipeptide of glutamine and alanine on severe traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    YANG De-lin; XU Jun-fa

    2007-01-01

    Objective: To determine the effect of dipeptide of glutamine and alanine on patients with severe traumatic brain injury. Methods: A total of 46 patients (31 males and 15 females, aged 7-68 years, (47±9.6) years on average) with severe traumatic brain injury were randomized into two groups: Group G (n=23) and Group C (n=23). The patients in Group G received nutritional remedy with the dipeptide of glutamine and alanine, whereas the patients in Group C received routine nutritional therapy only. GCS changes, the length of stay in the neurosurgical intensive care unit (NICU), the mortality,the count of lymphocytes, related complications including lung infection and hemorrhage of alimentary tracts, etc, were examined and recorded. Results: The fatality rate and the length of stay in NICU in Group G was lower than these in Group C (P<0.05), but no obvious difference was found in GCS changes of the patients between the two groups (P>0.05). The patients with lung infection and alimentary tract hemorrhage in Group G were less than those in Group C (P<0.05). The count of lymphocytes in Group G was more than that in Group C (P<0.05), but no difference was found in other nutritional data. Conclusions: Dipeptide of glutamine and alanine can increase the resisting stress and anti-infection ability of patients with severe traumatic brain injury, which can also lower the mortality and shorten the NICU stay.

  1. Water-mediated conformations of the alanine dipeptide as revealed by distributed umbrella sampling simulations, quantum mechanics based calculations, and experimental data.

    Science.gov (United States)

    Cruz, Víctor; Ramos, Javier; Martínez-Salazar, Javier

    2011-04-28

    An exhaustive umbrella sampling simulation of the alanine dipeptide in solution is reported. The presence of stable Y conformations in solution is assessed by both quantum calculations and experimental data from X-ray and NMR protein-solved structures available in the protein coil library. The agreement between experimental and simulation Ramachandran plots of the dipeptide in solution is excellent. A suitable explanation of the stabilization of the Y conformation mediated by water for the alanine dipeptide is discussed on the basis of Car-Parrinello MD calculations of the dipeptide in water.

  2. Synthesis of Novel Extractants——Amide Podands

    Institute of Scientific and Technical Information of China (English)

    TANGHong-bin; ZHUWen-bin; YEGuo-an; ZHUZhi-xuan; CHENWen-jun

    2003-01-01

    Amide podands which are used as a novel extractants are widely concerned recently. In the early stage, the studies were focused on the amide potands substituted with short-chain alky group, and for avoiding the formation of the second organic phase, aromatic, halogenated or higher alcohol compound must be used as diluents.

  3. Hydrogen storage and ionic mobility in amide-halide systems.

    Science.gov (United States)

    Anderson, Paul A; Chater, Philip A; Hewett, David R; Slater, Peter R

    2011-01-01

    We report the results of a systematic study of the effect of halides on hydrogen release and uptake in lithium amide and lithium imide, respectively. The reaction of lithium amide and lithium imide with lithium or magnesium chloride, bromide and iodide resulted in a series of amide-halide and imide-halide phases, only two of which have been reported previously. On heating with LiH or MgH2, the amide-halides synthesised all released hydrogen more rapidly than lithium amide itself, accompanied by much reduced, or in some cases undetectable, release of ammonia by-product. The imide-halides produced were found to hydrogenate more rapidly than lithium imide, reforming related amide-halide phases. The work was initiated to test the hypothesis that the incorporation of halide anions might improve the lithium ion conductivity of lithium amide and help maintain high lithium ion mobility at all stages of the de/rehydrogenation process, enhancing the bulk hydrogen storage properties of the system. Preliminary ionic conductivity measurements indicated that the most conducting amide- and imide-halide phases were also the quickest to release hydrogen on heating and to hydrogenate. We conclude that ionic conductivity may be an important parameter in optimising the materials properties of this and other hydrogen storage systems.

  4. Synthesis and characterisation of uniform bisester tetra-amide segments

    NARCIS (Netherlands)

    Krijgsman, J.; Husken, D.; Gaymans, R.J.

    2003-01-01

    The synthesis and characterisation of a new type of high melting and fast crystallising amide units that can be used for copolymerisation have been studied. These bisester tetra-amide or TxTxT-dimethyl segments (T is a terephthalic unit and x=(CH2)n (n=2–8)) can be synthesised in a two-step reaction

  5. Picosecond thermometer in the amide I band of myoglobin

    DEFF Research Database (Denmark)

    Austin, R.H.; Xie, A.; Meer, L. van der;

    2005-01-01

    The amide I and II bands in myoglobin show a heterogeneous temperature dependence, with bands at 6.17 and 6.43 mu m which are more intense at low temperatures. The amide I band temperature dependence is on the long wavelength edge of the band, while the short wavelength side has almost no tempera...

  6. Understanding the Amide-II Vibrations in β-Peptides.

    Science.gov (United States)

    Zhao, Juan; Wang, Jianping

    2015-11-25

    In this work, the vibrational characteristics of the amide-II modes in β-peptides in five helical conformations, namely, 8-, 10-, 12-, 14-, and 10/12-helices, have been examined. Remarkable conformational dependence of the amide-II spectral profile is obtained by ab initio computations as well as modeling analysis. Intramolecular hydrogen-bonding interaction and its influence on backbone structure and on the amide-II local-mode transition frequencies and intensities are examined. Through-space and through-bond contributions of the amide-II vibrational couplings are analyzed, and it was found that hydrogen-bonding interaction is not a determining factor for the coupling strength. The results reported here provide useful benchmarks for understanding experimental amide-II infrared spectra of β-peptides and suggest the potential application of this mode on monitoring the structures and dynamics of β-peptides.

  7. Amidated and ibuprofen-conjugated kyotorphins promote neuronal rescue and memory recovery in cerebral hypoperfusion dementia model

    Directory of Open Access Journals (Sweden)

    Sónia eSá Santos

    2016-01-01

    Full Text Available Chronic brain ischemia is a prominent risk factor for neurological dysfunction and progression for dementias, including Alzheimer’s disease (AD. In rats, permanent bilateral common carotid artery occlusion (2VO causes a progressive neurodegeneration in the hippocampus, learning deficits and memory loss as it occurs in AD. Kyotorphin (KTP is an endogenous antinociceptive dipeptide whose role as neuromodulator/neuroprotector has been suggested. Recently, we designed two analgesic KTP-derivatives, KTP-amide (KTP-NH2 and KTP-NH2 linked to ibuprofen (IbKTP-NH2 to improve KTP brain targeting. This study investigated the effects of KTP-derivatives on cognitive/behavioral functions (motor/spatial memory/nociception and hippocampal pathology of female rats in chronic cerebral hypoperfusion (2VO-rat model. 2VO-animals were treated with KTP-NH2 or IbKTP-NH2 for 7 days at weeks 2 and 5 post-surgery. After behavioral testing (week 6, coronal sections of hippocampus were H&E-stained or immunolabeled for the cellular markers GFAP (astrocytes and NFL (neurons. Our findings show that KTP-derivatives, mainly IbKTP-NH2, enhanced cognitive impairment of 2VO-animals and prevented neuronal damage in hippocampal CA1 subfield, suggesting their potential usefulness for the treatment of dementia.

  8. Retinobenzoic acids. 4. Conformation of aromatic amides with retinoidal activity. Importance of trans-amide structure for the activity.

    Science.gov (United States)

    Kagechika, H; Himi, T; Kawachi, E; Shudo, K

    1989-10-01

    N-Methylation of two retinoidal amide compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (3, Am80) and 4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)carbonyl]amino]benzoic acid (5, Am580), resulted in the disappearance of their potent differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. Studies with 1H NMR and UV spectroscopy indicated that large conformational differences exist between the active secondary amides and the inactive N-methyl amides. From a comparison of the spectroscopic results of these amides with those of stilbene derivatives, the conformations of the active amides are expected to resemble that of (E)-stilbene, whereas the inactive amides resemble the Z isomer: 3 (Am80) and 5 (Am580) have a trans-amide bond and their whole structures are elongated, while the N-methylated compounds [4 (Am90) and 6 (Am590)] have a cis-amide bond, resulting in the folding of the two benzene rings. These structures in the crystals were related to those in solution by 13C NMR spectroscopic comparison between the two phases (solid and solution).

  9. Amide to Alkyne Interconversion via a Nickel/Copper-Catalyzed Deamidative Cross-Coupling of Aryl and Alkenyl Amides

    KAUST Repository

    Srimontree, Watchara

    2017-06-05

    A nickel-catalyzed deamidative cross-coupling reaction of amides with terminal alkynes as coupling partners was disclosed. This newly developed methodology allows the direct interconversion of amides to alkynes and enables a facile route for C(sp2)-C(sp) bond formation in a straightforward and mild fashion.

  10. Recognition of Streptococcus pneumoniae and muramyl dipeptide by NOD2 results in potent induction of MMP-9, which can be controlled by lipopolysaccharide stimulation.

    Science.gov (United States)

    Vissers, Marloes; Hartman, Yvonne; Groh, Laszlo; de Jong, Dirk J; de Jonge, Marien I; Ferwerda, Gerben

    2014-12-01

    Matrix metallopeptidase 9 (MMP-9) is a protease involved in the degradation of extracellular matrix collagen. Evidence suggests that MMP-9 is involved in pathogenesis during Streptococcus pneumoniae infection. However, not much is known about the induction of MMP-9 and the regulatory processes involved. We show here that the Gram-positive bacteria used in this study induced large amounts of MMP-9, in contrast to the Gram-negative bacteria that were used. An important pathogen-associated molecular pattern (PAMP) for Gram-positive bacteria is muramyl dipeptide (MDP). MDP is a very potent inducer of MMP-9 and showed a dose-dependent MMP-9 induction. Experiments using peripheral blood mononuclear cells (PBMCs) from Crohn's disease patients with nonfunctional NOD2 showed that MMP-9 induction by Streptococcus pneumoniae and MDP is NOD2 dependent. Increasing amounts of lipopolysaccharide (LPS), an important PAMP for Gram-negative bacteria, resulted in decreasing amounts of MMP-9. Moreover, the induction of MMP-9 by MDP could be counteracted by simultaneously adding LPS. The inhibition of MMP-9 expression by LPS was found to be regulated posttranscriptionally, independently of tissue inhibitor of metalloproteinase 1 (TIMP-1), an endogenous inhibitor of MMP-9. Collectively, these data show that Streptococcus pneumoniae is able to induce large amounts of MMP-9. These high MMP-9 levels are potentially involved in Streptococcus pneumoniae pathogenesis.

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

    Science.gov (United States)

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

    2010-10-01

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

  12. Synthesis of novel poly(aryl ether amide)s containing the phthalazinone moiety

    Institute of Scientific and Technical Information of China (English)

    CHENG, Lin(程琳); JIAN, Xi- Gao(蹇锡高)

    2000-01-01

    Two novel heterocyclic diamine monomers: 1,2-dihydro-2-(4-aminophenyl)-4- [ 4-( 4-aminophenoxy ) phenyl ]-( 2H )-phtha-lazin-1-one and 1, 2-dihydro-2-( 4-aminophenyl)-4-[ 4-( 4-aminophenoxy)-3, 5-dimethylphenyl]-(2H)-phthalazin-1-one were successfully synthesized using readily available heterocyclic bisphenol-like monomers through two steps in high yield. A series of novel poly(aryl ether amide)s containing the phthalazinone moiety with inherent viscosities of 1.16-1.67 dL/g were prepared by the direct polymerization of the novel diamines and aromatic dicarboxylic acids using triphenyl phosphite and pyridine as condensing agents. The polymers were readily soluble in a variety of solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc),dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), and pyridine. The polymers had high glass transition tenperatured(Tg) in the 291-329℃ range.

  13. Structural Characterization of N-Alkylated Twisted Amides: Consequences for Amide Bond Resonance and N-C Cleavage.

    Science.gov (United States)

    Hu, Feng; Lalancette, Roger; Szostak, Michal

    2016-04-11

    Herein, we describe the first structural characterization of N-alkylated twisted amides prepared directly by N-alkylation of the corresponding non-planar lactams. This study provides the first experimental evidence that N-alkylation results in a dramatic increase of non-planarity around the amide N-C(O) bond. Moreover, we report a rare example of a molecular wire supported by the same amide C=O-Ag bonds. Reactivity studies demonstrate rapid nucleophilic addition to the N-C(O) moiety of N-alkylated amides, indicating the lack of n(N) to π*(C=O) conjugation. Most crucially, we demonstrate that N-alkylation activates the otherwise unreactive amide bond towards σ N-C cleavage by switchable coordination.

  14. Hepatoprotective amide constituents from the fruit of Piper chaba: Structural requirements, mode of action, and new amides.

    Science.gov (United States)

    Matsuda, Hisashi; Ninomiya, Kiyofumi; Morikawa, Toshio; Yasuda, Daisuke; Yamaguchi, Itadaki; Yoshikawa, Masayuki

    2009-10-15

    The 80% aqueous acetone extract from the fruit of Piper chaba (Piperaceae) was found to have hepatoprotective effects on D-galactosamine (D-GalN)/lipopolysaccharide-induced liver injury in mice. From the ethyl acetate-soluble fraction, three new amides, piperchabamides E, G, and H, 33 amides, and four aromatic constituents were isolated. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: (i) the amide moiety is essential for potent activity; and (ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effects at doses of 5 and 10 mg/kg, po and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

  15. Trends for isolated amino acids and dipeptides: Conformation, divalent ion binding, and remarkable similarity of binding to calcium and lead

    Science.gov (United States)

    Ropo, M.; Blum, V.; Baldauf, C.

    2016-11-01

    We derive structural and binding energy trends for twenty amino acids, their dipeptides, and their interactions with the divalent cations Ca2+, Ba2+, Sr2+, Cd2+, Pb2+, and Hg2+. The underlying data set consists of more than 45,000 first-principles predicted conformers with relative energies up to ~4 eV (~400 kJ/mol). We show that only very few distinct backbone structures of isolated amino acids and their dipeptides emerge as lowest-energy conformers. The isolated amino acids predominantly adopt structures that involve an acidic proton shared between the carboxy and amino function. Dipeptides adopt one of two intramolecular-hydrogen bonded conformations C5 or . Upon complexation with a divalent cation, the accessible conformational space shrinks and intramolecular hydrogen bonding is prevented due to strong electrostatic interaction of backbone and side chain functional groups with cations. Clear correlations emerge from the binding energies of the six divalent ions with amino acids and dipeptides. Cd2+ and Hg2+ show the largest binding energies–a potential correlation with their known high acute toxicities. Ca2+ and Pb2+ reveal almost identical binding energies across the entire series of amino acids and dipeptides. This observation validates past indications that ion-mimicry of calcium and lead should play an important role in a toxicological context.

  16. Cinnamic acid amides from Tribulus terrestris displaying uncompetitive α-glucosidase inhibition.

    Science.gov (United States)

    Song, Yeong Hun; Kim, Dae Wook; Curtis-Long, Marcus J; Park, Chanin; Son, Minky; Kim, Jeong Yoon; Yuk, Heung Joo; Lee, Keun Woo; Park, Ki Hun

    2016-05-23

    The α-glucosidase inhibitory potential of Tribulus terrestris extracts has been reported but as yet the active ingredients are unknown. This study attempted to isolate the responsible metabolites and elucidate their inhibition mechanism of α-glucosidase. By fractionating T. terristris extracts, three cinnamic acid amide derivatives (1-3) were ascertained to be active components against α-glucosidase. The lead structure, N-trans-coumaroyltyramine 1, showed significant inhibition of α-glucosidase (IC50 = 0.42 μM). Moreover, all active compounds displayed uncompetitive inhibition mechanisms that have rarely been reported for α-glucosidase inhibitors. This kinetic behavior was fully demonstrated by showing a decrease of both Km and Vmax, and Kik/Kiv ratio ranging between 1.029 and 1.053. We progressed to study how chemical modifications to the lead structure 1 may impact inhibition. An α, β-unsaturation carbonyl group and hydroxyl group in A-ring of cinnamic acid amide emerged to be critical functionalities for α-glucosidase inhibition. The molecular modeling study revealed that the inhibitory activities are tightly related to π-π interaction as well as hydrogen bond interaction between enzyme and inhibitors.

  17. Benzoylureas as removable cis amide inducers: synthesis of cyclic amides via ring closing metathesis (RCM).

    Science.gov (United States)

    Brady, Ryan M; Khakham, Yelena; Lessene, Guillaume; Baell, Jonathan B

    2011-02-07

    Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.

  18. Poly(amide-graft-acrylate) interfacial compounds

    Science.gov (United States)

    Zamora, Michael Perez

    Graft copolymers with segments of dissimilar chemistries have been shown to be useful in a variety of applications as surfactants, compatibilizers, impact modifiers, and surface modifiers. The most common route to well defined graft copolymers is through the use of macromonomers, polymers containing a reactive functionality and thus capable of further polymerization. However, the majority of the studies thus far have focused on the synthesis of macromonomers capable of reacting with vinyl monomers to form graft copolymers. This study focused on the synthesis of macromonomers capable of participating in condensation polymerizations. A chain transfer functionalization method was utilized. Cysteine was evaluated as a chain transfer agent for the synthesis of amino acid functionalized poly(acrylate) and poly(methacrylate) macromonomers. Low molar mass, functionalized macromonomers were produced. These macromonomers were proven to be capable of reacting with amide precursors to form poly(amide-g-acrylate) graft copolymers. Macromonomers and graft copolymers were characterized by gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) spectroscopy, elemental analysis (EA), inductively coupled plasma (ICP), and differential scanning calorimetry (DSC). The second part of this research involved poly(dimethacrylate) dental restorative materials. Volumetric shrinkage during the cure of these resins results in a poor interface between the resin and the remaining tooth structure, limiting the lifetime of these materials. Cyclic anhydrides were incorporated into common monomer compositions used in dental applications. Volume expansion from the ring opening hydrolysis of these anhydrides was shown to be feasible. The modified dental resins were characterized by swelling, extraction and ultraviolet spectroscopy (UV), and density measurements. Linear poLymers designed to model the crosslinked dental resins were

  19. Ferrocenylaniline based amide analogs of methoxybenzoic acids: Synthesis, structural characterization and butyrylcholinesterase (BChE) inhibition studies

    Science.gov (United States)

    Altaf, Ataf Ali; Kausar, Samia; Hamayun, Muhammad; Lal, Bhajan; Tahir, Muhammad Nawaz; Badshah, Amin

    2017-10-01

    Three new ferrocene based amides were synthesized with slight structural difference. The general formula of the amides is C5H5FeC5H4C6H4NHCOC6H4(OCH3). The synthesized compounds were characterized by instrumental techniques like elemental analysis, FTIR and NMR spectroscopy. Structure of the two compounds was also studied by single crystal X-rays diffraction analysis. Structural studies provide the evidence that pMeO (one of the synthesized compounds) is an example of amides having no intermolecular hydrogen bonding in solid structure. In the BChE inhibition assay, compound (oMeO) having strong intermolecular force in the solid structure is less active than the compound (pMeO) with weak intermolecular forces in the solid structure. The docking studies proved that hydrogen bonding between inhibitor and BChE enzyme is of more importance for the activity, rather than intermolecular hydrogen bonding in the solid structure of inhibitor.

  20. Trends for isolated amino acids and dipeptides: Conformation, divalent ion binding, and remarkable similarity of binding to calcium and lead

    CERN Document Server

    Ropo, Matti; Baldauf, Carsten

    2016-01-01

    We derive structural and binding energy trends for twenty amino acids, their dipeptides, and their interactions with the divalent cations Ca$^{2+}$, Ba$^{2+}$, Sr$^{2+}$, Cd$^{2+}$, Pb$^{2+}$, and Hg$^{2+}$. The underlying data set consists of 45,892 first-principles predicted conformers with relative energies up to about 4 eV (about 400kJ/mol). We show that only very few distinct backbone structures of isolated amino acids and their dipeptides emerge as lowest-energy conformers. The isolated amino acids predominantly adopt structures that involve an acidic proton shared between the carboxy and amino function. Dipeptides adopt one of two intramolecular-hydrogen bonded conformations C$_5$ or equatorial C$_7$. Upon complexation with a divalent cation, the accessible conformational space shrinks and intramolecular hydrogen bonding is prevented due to strong electrostatic interaction of backbone and side chain functional groups with cations. Clear correlations emerge from the binding energies of the six divalent ...

  1. Effects of dipeptides containing the amino acid, proline on the chemotaxis of Tetrahymena pyriformis. Evolutionary conclusions on the formation of hormone receptors and hormones.

    Science.gov (United States)

    Köhidai, L; Soós, P; Csaba, G

    1997-06-01

    Our investigations demonstrate that proline-containing dipeptides can provoke a chemosensory response from the unicellular Tetrahymena pyriformis. The chemotactic effects of the dipeptides have a close relationship with the side chain and the lipophilicity of the amino-terminal amino acid. Comparison of 'mirror' variants of proline-containing dipeptides points to the fact that dipeptides with small side chain and non-polar character amino acids (Gly-Pro, Ala-Pro) are preferred on the amino-terminal end. In the case of amino acids with very variable side chains, small (Pro-Gly) and the large side chain and non-polar character amino acids (Pro-Leu, Pro-Phe) on the carboxyl-terminal end can induce significant chemotactic responses. With valine on any terminus the proline-containing dipeptide induced a weak repellent effect.

  2. Three bioactive cyclic dipeptides from the Bacillus sp. N strain associated with entomopathogenic nematode.

    Science.gov (United States)

    Nishanth, Sasidharan Kumar; Nambisan, Bala; Dileep, C

    2014-03-01

    In continuation of our search for new bioactive secondary metabolites from Bacillus cereus associated with entomopathogenic nematode (EPN), three cyclic dipeptides (CDPs), cyclo(L-Leu-D-Arg) (1), cyclo(2-hydroxy-Pro-L-Leu) (2), and cyclo(L-Val-L-Pro) (3) were purified from the ethyl acetate extract of B. cereus. The chemical structure of the compounds was identified by 1D, 2D NMR and HR-ESI-MS. Cyclo(L-Leu-D-Arg) recorded best antifungal activity and the highest activity was recorded against Cryptococcus neoformans (1 μg/mL), which is better than the standard antifungal agent amphotericin B. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used for finding cell proliferation inhibition and cyclo(L-Leu-D-Arg) recorded significant activity against breast cancer cell line (MDAM-B231) (IC50 value: 25 μM) and the three cyclic dipeptides recorded no toxicity against normal human cell (fore skin (FS) normal fibroblast) up to 50 μM except cyclo(L-Val-L-Pro). Cyclo(L-Leu-D-Arg) induced significant morphological changes and DNA fragmentation associated with apoptosis in MDAM-B231 cells by acridine orange/ethidium bromide staining and flow cytometry analysis. Out of three cyclic dipeptides tested only cyclo(2-hydroxy-Pro-L-Leu) recorded significant antioxidant activity. The hydroxyl radical scavenging activity of cyclo(2-hydroxy-Pro-L-Leu) is greater than BHA, the standard antioxidant agent. Cyclo(L-Leu-D-Arg) was isolated for the first time from a natural source with a d-arginine residue. To the best of our knowledge, this is the first time that the bioactivity of the isolated cyclic dipeptides is reported against medically important fungi and cancer cells. This study is a significant contribution to the knowledge of cyclo(L-Leu-D-Arg) from B. cereus as potential sources of new drugs in the pharmacological industry, especially as potent antifungal and anticancer agent. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Serine dipeptide lipids of Porphyromonas gingivalis inhibit osteoblast differentiation: Relationship to Toll-like receptor 2.

    Science.gov (United States)

    Wang, Yu-Hsiung; Nemati, Reza; Anstadt, Emily; Liu, Yaling; Son, Young; Zhu, Qiang; Yao, Xudong; Clark, Robert B; Rowe, David W; Nichols, Frank C

    2015-12-01

    Porphyromonas gingivalis is a periodontal pathogen strongly associated with loss of attachment and supporting bone for teeth. We have previously shown that the total lipid extract of P. gingivalis inhibits osteoblast differentiation through engagement of Toll-like receptor 2 (TLR2) and that serine dipeptide lipids of P. gingivalis engage both mouse and human TLR2. The purpose of the present investigation was to determine whether these serine lipids inhibit osteoblast differentiation in vitro and in vivo and whether TLR2 engagement is involved. Osteoblasts were obtained from calvaria of wild type or TLR2 knockout mouse pups that also express the Col2.3GFP transgene. Two classes of serine dipeptide lipids, termed Lipid 654 and Lipid 430, were tested. Osteoblast differentiation was monitored by cell GFP fluorescence and osteoblast gene expression and osteoblast function was monitored as von Kossa stained mineral deposits. Osteoblast differentiation and function were evaluated in calvarial cell cultures maintained for 21 days. Lipid 654 significantly inhibited GFP expression, osteoblast gene expression and mineral nodule formation and this inhibition was dependent on TLR2 engagement. Lipid 430 also significantly inhibited GFP expression, osteoblast gene expression and mineral nodule formation but these effects were only partially attributed to engagement of TLR2. More importantly, Lipid 430 stimulated TNF-α and RANKL gene expression in wild type cells but not in TLR2 knockout cells. Finally, osteoblast cultures were observed to hydrolyze Lipid 654 to Lipid 430 and this likely occurs through elevated PLA2 activity in the cultured cells. In conclusion, our results show that serine dipeptide lipids of P. gingivalis inhibit osteoblast differentiation and function at least in part through engagement of TLR2. The Lipid 430 serine class also increased the expression of genes that could increase osteoclast activity. We conclude that Lipid 654 and Lipid 430 have the potential

  4. Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells.

    Science.gov (United States)

    Kondratenko, Rodion V; Derevyagin, Vladimir I; Skrebitsky, Vladimir G

    2010-05-31

    Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion.

  5. In vitro antibacterial screening of six proline-based cyclic dipeptides in combination with β-lactam antibiotics against medically important bacteria.

    Science.gov (United States)

    Kumar, S Nishanth; Lankalapalli, Ravi S; Kumar, B S Dileep

    2014-05-01

    The in vitro synergistic antibacterial activity of six proline-based cyclic dipeptides [cyclo(D-Pro-L-Leu), cyclo(L-Pro-L-Met), cyclo(D-Pro-L-Phe), cyclo(L-Pro-L-Phe), cyclo(L-Pro-L-Tyr), and cyclo(L-Pro-D-Tyr)] in combination imipenem and ceftazidime was investigated in the present manuscript. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the cyclic dipeptides were compared with those of the standard antibiotics (imipenem and ceftazidime). The synergistic antibacterial activities of cyclic dipeptides with imipenem or ceftazidime were assessed using the checkerboard and time-kill methods. The results of the present study showed that the combined effect of six cyclic dipeptides with imipenem predominantly recorded synergistic interaction (FIC index bacteria was completely attenuated after 12-24 h of treatment with a 50:50 ratio of proline-based cyclic dipeptides and antibiotics. These synergistic effects have a potential role in delaying the development of resistance as the antibacterial activity is achieved with the very low concentrations of cyclic dipeptides and antibiotics. The cytotoxicity of cyclic dipeptides was tested against VERO cell line (African green monkey kidney cell line), and no cytotoxicity was recorded for cyclic dipeptides up to 100 μg/mL. These findings suggest that combination of cyclic dipeptides and antibiotics might be a good strategy for the individualization of novel templates for the development of new antimicrobial agents or combinations of drugs for antimicrobial chemotherapy. Moreover, these combinations may lead to the development of a new and vital antimicrobial combination against the infections caused by pathogenic bacteria. The in vitro synergistic activity of cyclic dipeptides with antibiotics against medically important bacteria is reported here for the first time.

  6. γ-Glutamyl-dipeptides: Easy tools to rapidly probe the stereoelectronic properties of ionotropic glutamate receptor binding pocket

    DEFF Research Database (Denmark)

    Tamborini, Lucia; Nicosia, Veronica; Conti, Paola

    2016-01-01

    γ-Glutamyl-dipeptides, built by condensing the distal carboxylate of L-Glu (or D-Glu) onto a series of differently functionalized amino acids, were prepared and used as tools for rapidly probing the stereoelectronic properties of iGluRs, searching for subtype-selective ligands.......γ-Glutamyl-dipeptides, built by condensing the distal carboxylate of L-Glu (or D-Glu) onto a series of differently functionalized amino acids, were prepared and used as tools for rapidly probing the stereoelectronic properties of iGluRs, searching for subtype-selective ligands....

  7. Copper/N,N-Dimethylglycine Catalyzed Goldberg Reactions Between Aryl Bromides and Amides, Aryl Iodides and Secondary Acyclic Amides

    Directory of Open Access Journals (Sweden)

    Liqin Jiang

    2014-08-01

    Full Text Available An efficient and general copper-catalyzed Goldberg reaction at 90–110 °C between aryl bromides and amides providing the desired products in good to excellent yields has been developed using N,N-dimethylglycine as the ligand. The reaction is tolerant toward a wide range of amides and a variety of functional group substituted aryl bromides. In addition, hindered, unreactive aromatic and aliphatic secondary acyclic amides, known to be poor nucleophiles, are efficiently coupled with aryl iodides through this simple and cheap copper/N,N-dimethylglycine catalytic system.

  8. SYNTHESIS AND BIOLOGICAL ACTIVITY OF AMIDE DERIVATIVES OF GINKGOLIDE A

    Institute of Scientific and Technical Information of China (English)

    LI-HONG HU; ZHONG-LIANG CHEN; YU-YUAN XIE

    2001-01-01

    Amide derivatives of ginkgolide A were prepared and evaluated for their in vitro ability to inhibit the PAF-induced aggregation of rabbit platelets. They showed less activities than their parent compound ginkgolide A.

  9. Silver-catalyzed synthesis of amides from amines and aldehydes

    Science.gov (United States)

    Madix, Robert J; Zhou, Ling; Xu, Bingjun; Friend, Cynthia M; Freyschlag, Cassandra G

    2014-11-18

    The invention provides a method for producing amides via the reaction of aldehydes and amines with oxygen adsorbed on a metallic silver or silver alloy catalyst. An exemplary reaction is shown in Scheme 1: (I), (II), (III). ##STR00001##

  10. MICROBIAL DEGRADATION OF SEVEN AMIDES BY SUSPENDED BACTERIAL POPULATIONS

    Science.gov (United States)

    Microbial transformation rate constants were determined for seven amides in natural pond water. A second-order mathematical rate expression served as the model for describing the microbial transformation. Also investigated was the relationship between the infrared spectra and the...

  11. AMIDE: A Free Software Tool for Multimodality Medical Image Analysis

    Directory of Open Access Journals (Sweden)

    Andreas Markus Loening

    2003-07-01

    Full Text Available Amide's a Medical Image Data Examiner (AMIDE has been developed as a user-friendly, open-source software tool for displaying and analyzing multimodality volumetric medical images. Central to the package's abilities to simultaneously display multiple data sets (e.g., PET, CT, MRI and regions of interest is the on-demand data reslicing implemented within the program. Data sets can be freely shifted, rotated, viewed, and analyzed with the program automatically handling interpolation as needed from the original data. Validation has been performed by comparing the output of AMIDE with that of several existing software packages. AMIDE runs on UNIX, Macintosh OS X, and Microsoft Windows platforms, and it is freely available with source code under the terms of the GNU General Public License.

  12. Amid the Economic Rubble,Shangkong will Rise

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    @@ Two years ago, bankers and policymakers were arguing heatedly over whether New York or London was the world's premier financial centre. Amid the post-crisis rubble that covers both cities, those arguments now look terribly passé.

  13. Phase space investigation of the lithium amide halides

    Energy Technology Data Exchange (ETDEWEB)

    Davies, Rosalind A. [Hydrogen Storage Chemistry Group, School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT (United Kingdom); Hydrogen and Fuel Cell Group, School of Chemical Engineering, University of Birmingham, Edgbaston B15 2TT (United Kingdom); Hewett, David R.; Korkiakoski, Emma [Hydrogen Storage Chemistry Group, School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT (United Kingdom); Thompson, Stephen P. [Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0QX (United Kingdom); Anderson, Paul A., E-mail: p.a.anderson@bham.ac.uk [Hydrogen Storage Chemistry Group, School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT (United Kingdom)

    2015-10-05

    Highlights: • The lower limits of halide incorporation in lithium amide have been investigated. • The only amide iodide stoichiometry observed was Li{sub 3}(NH{sub 2}){sub 2}I. • Solid solutions were observed in both the amide chloride and amide bromide systems. • A 46% reduction in chloride content resulted in a new phase: Li{sub 7}(NH{sub 2}){sub 6}Cl. • New low-chloride phase maintained improved H{sub 2} desorption properties of Li{sub 4}(NH{sub 2}){sub 3}Cl. - Abstract: An investigation has been carried out into the lower limits of halide incorporation in lithium amide (LiNH{sub 2}). It was found that the lithium amide iodide Li{sub 3}(NH{sub 2}){sub 2}I was unable to accommodate any variation in stoichiometry. In contrast, some variation in stoichiometry was accommodated in Li{sub 7}(NH{sub 2}){sub 6}Br, as shown by a decrease in unit cell volume when the bromide content was reduced. The amide chloride Li{sub 4}(NH{sub 2}){sub 3}Cl was found to adopt either a rhombohedral or a cubic structure depending on the reaction conditions. Reduction in chloride content generally resulted in a mixture of phases, but a new rhombohedral phase with the stoichiometry Li{sub 7}(NH{sub 2}){sub 6}Cl was observed. In comparison to LiNH{sub 2}, this new low-chloride phase exhibited similar improved hydrogen desorption properties as Li{sub 4}(NH{sub 2}){sub 3}Cl but with a much reduced weight penalty through addition of chloride. Attempts to dope lithium amide with fluoride ions have so far proved unsuccessful.

  14. Artists with Arthritis Create Beauty amid Pain

    Institute of Scientific and Technical Information of China (English)

    Alan; Mozes; 蔡峥伟

    2000-01-01

    得此来稿,我们曾犹豫再三,是否刊用此文。因为,其内容给人的第一印象颇有点离奇。Artists with Arthritis Create Beauty amid Pain,怎么可能呢?细读之下,你也许会觉得,此文虽是一家之言,但也并非荒唐。尤其是本文的收尾句,笔锋一转,抖出了妙言: ...in addition to the emotional support such stories can give RA patients,there are now new drug options that far surpass the treatment choices Renoir faced. 此句是否可译:除了此类故事能够给患风湿病者一种情感上的支持之外,现在可选的新药要比Renoir(雷诺阿,法国印象派画家。主要作品有《包厢》、《游船上的午餐》、《浴女》等。)时代强得多。

  15. Hydrogen Bonding Interaction between Atmospheric Gaseous Amides and Methanol.

    Science.gov (United States)

    Zhao, Hailiang; Tang, Shanshan; Xu, Xiang; Du, Lin

    2016-12-30

    Amides are important atmospheric organic-nitrogen compounds. Hydrogen bonded complexes of methanol (MeOH) with amides (formamide, N-methylformamide, N,N-dimethylformamide, acetamide, N-methylacetamide and N,N-dimethylacetamide) have been investigated. The carbonyl oxygen of the amides behaves as a hydrogen bond acceptor and the NH group of the amides acts as a hydrogen bond donor. The dominant hydrogen bonding interaction occurs between the carbonyl oxygen and the OH group of methanol as well as the interaction between the NH group of amides and the oxygen of methanol. However, the hydrogen bonds between the CH group and the carbonyl oxygen or the oxygen of methanol are also important for the overall stability of the complexes. Comparable red shifts of the C=O, NH- and OH-stretching transitions were found in these MeOH-amide complexes with considerable intensity enhancement. Topological analysis shows that the electron density at the bond critical points of the complexes fall in the range of hydrogen bonding criteria, and the Laplacian of charge density of the O-H∙∙∙O hydrogen bond slightly exceeds the upper value of the Laplacian criteria. The energy decomposition analysis further suggests that the hydrogen bonding interaction energies can be mainly attributed to the electrostatic, exchange and dispersion components.

  16. Effects of exercise on leukocyte death: prevention by hydrolyzed whey protein enriched with glutamine dipeptide.

    Science.gov (United States)

    Cury-Boaventura, Maria Fernanda; Levada-Pires, Adriana C; Folador, Alessandra; Gorjão, Renata; Alba-Loureiro, Tatiana C; Hirabara, Sandro M; Peres, Fabiano P; Silva, Paulo R S; Curi, Rui; Pithon-Curi, Tania C

    2008-06-01

    Lymphocyte and neutrophil death induced by exercise and the role of hydrolyzed whey protein enriched with glutamine dipeptide (Gln) supplementation was investigated. Nine triathletes performed two exhaustive exercise trials with a 1-week interval in a randomized, double blind, crossover protocol. Thirty minutes before treadmill exhaustive exercise at variable speeds in an inclination of 1% the subjects ingested 50 g of maltodextrin (placebo) or 50 g of maltodextrin plus 4 tablets of 700 mg of hydrolyzed whey protein enriched with 175 mg of glutamine dipeptide dissolved in 250 mL water. Cell viability, DNA fragmentation, mitochondrial transmembrane potential and production of reactive oxygen species (ROS) were determined in lymphocytes and neutrophils. Exhaustive exercise decreased viable lymphocytes but had no effect on neutrophils. A 2.2-fold increase in the proportion of lymphocytes and neutrophils with depolarized mitochondria was observed after exhaustive exercise. Supplementation of maltodextrin plus Gln (MGln) prevented the loss of lymphocyte membrane integrity and the mitochondrial membrane depolarization induced by exercise. Exercise caused an increase in ROS production by neutrophils, whereas supplementation of MGln had no additional effect. MGln supplementation partially prevented lymphocyte apoptosis induced by exhaustive exercise possibly by a protective effect on mitochondrial function.

  17. Some dipeptides reverse the inhibitory effect of GABA on /sup 35/S-TBPS binding

    Energy Technology Data Exchange (ETDEWEB)

    Squires, R.F.; Saederup, E.

    1987-05-01

    All known GABA-A receptor blocker reverse the inhibitory effect of GABA on /sup 35/S-t-butylphosphorothionate (TBPS) binding to rat brain membranes in vitro. This system has already been used to identify several novel GABA antagonists. The authors now report that 12 out of 52 dipeptides tested (all containing L-amino acids), at 1 mM, significantly reverse the inhibitory effect of 1 ..mu..M GABA, which inhibits specific /sup 35/S-TBPS binding about 60%. Most of the active dipeptides contain an aromatic and a basic amino acid. Tryptophan usually conferred greater activity than phe or tyr, while arg usually conferred greater activity than lys or his. Several larger peptides containing the HFRW sequence found in ACTH were also GABA antagonists; ACTH(1-24), ACTH(1-18), ACTH(1-13), ACTH(4-10) and ..gamma..-MSH while ACTH(11-24) was inactive. The excitatory effects of these later peptides may be in part due to blockade of GABA-A receptors.

  18. Fluorescence kinetics of Trp-Trp dipeptide and its derivatives in water via ultrafast fluorescence spectroscopy.

    Science.gov (United States)

    Jia, Menghui; Yi, Hua; Chang, Mengfang; Cao, Xiaodan; Li, Lei; Zhou, Zhongneng; Pan, Haifeng; Chen, Yan; Zhang, Sanjun; Xu, Jianhua

    2015-08-01

    Ultrafast fluorescence dynamics of Tryptophan-Tryptophan (Trp-Trp/Trp2) dipeptide and its derivatives in water have been investigated using a picosecond resolved time correlated single photon counting (TCSPC) apparatus together with a femtosecond resolved upconversion spectrophotofluorometer. The fluorescence decay profiles at multiple wavelengths were fitted by a global analysis technique. Nanosecond fluorescence kinetics of Trp2, N-tert-butyl carbonyl oxygen-N'-aldehyde group-l-tryptophan-l-tryptophan (NBTrp2), l-tryptophan-l-tryptophan methyl ester (Trp2Me), and N-acetyl-l-tryptophan-l-tryptophan methyl ester (NATrp2Me) exhibit multi-exponential decays with the average lifetimes of 1.99, 3.04, 0.72 and 1.22ns, respectively. Due to the intramolecular interaction between two Trp residues, the "water relaxation" lifetime was observed around 4ps, and it is noticed that Trp2 and its derivatives also exhibit a new decay with a lifetime of ∼100ps, while single-Trp fluorescence decay in dipeptides/proteins shows 20-30ps. The intramolecular interaction lifetime constants of Trp2, NBTrp2, Trp2Me and NATrp2Me were then calculated to be 3.64, 0.93, 11.52 and 2.40ns, respectively. Candidate mechanisms (including heterogeneity, solvent relaxation, quasi static self-quenching or ET/PT quenching) have been discussed.

  19. Electrocatalytic Oxidation of Formate with Nickel Diphosphane Dipeptide Complexes. Effect of Ligands Modified with Amino Acids

    Energy Technology Data Exchange (ETDEWEB)

    Galan, Brandon R. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Reback, Matthew L. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Jain, Avijita [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Appel, Aaron M. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Shaw, Wendy J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2013-09-03

    A series of nickel bis-diphosphine complexes with dipeptides appended to the ligands were investigated for the catalytic oxidation of formate. Typical rates of ~7 s-1 were found, similar to the parent complex (~8 s-1), with amino acid size and positioning contributing very little to rate or operating potential. Hydroxyl functionalities did result in lower rates, which were recovered by protecting the hydroxyl group. The results suggest that the overall dielectric introduced by the dipeptides does not play an important role in catalysis, but free hydroxyl groups do influence activity suggesting contributions from intra- or intermolecular interactions. These observations are important in developing a fundamental understanding of the affect that an enzyme-like outer coordination sphere can have upon molecular catalysts. This work was funded by the US DOE Basic Energy Sciences, Chemical Sciences, Geoscience and Biosciences Division (BRG, AJ, AMA, WJS), the US DOE Basic Energy Sciences, Physical Bioscience program (MLR). Pacific Northwest National Laboratory is operated by Battelle for the U.S. Department of Energy.

  20. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines.

    Science.gov (United States)

    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert

    2016-03-01

    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

  1. Dipeptide Aggregation in Aqueous Solution from Fixed Point-Charge Force Fields.

    Science.gov (United States)

    Götz, Andreas W; Bucher, Denis; Lindert, Steffen; McCammon, J Andrew

    2014-04-08

    The description of aggregation processes with molecular dynamics simulations is a playground for testing biomolecular force fields, including a new generation of force fields that explicitly describe electronic polarization. In this work, we study a system consisting of 50 glycyl-l-alanine (Gly-Ala) dipeptides in solution with 1001 water molecules. Neutron diffraction experiments have shown that at this concentration, Gly-Ala aggregates into large clusters. However, general-purpose force fields in combination with established water models can fail to correctly describe this aggregation process, highlighting important deficiencies in how solute-solute and solute-solvent interactions are parametrized in these force fields. We found that even for the fully polarizable AMOEBA force field, the degree of association is considerably underestimated. Instead, a fixed point-charge approach based on the newly developed IPolQ scheme [Cerutti et al. J. Phys. Chem.2013, 117, 2328] allows for the correct modeling of the dipeptide aggregation in aqueous solution. This result should stimulate interest in novel fitting schemes that aim to improve the description of the solvent polarization effect within both explicitly polarizable and fixed point-charge frameworks.

  2. Nonplanar tertiary amides in rigid chiral tricyclic dilactams. Peptide group distortions and vibrational optical activity.

    Science.gov (United States)

    Pazderková, Markéta; Profant, Václav; Hodačová, Jana; Sebestík, Jaroslav; Pazderka, Tomáš; Novotná, Pavlína; Urbanová, Marie; Safařík, Martin; Buděšínský, Miloš; Tichý, Miloš; Bednárová, Lucie; Baumruk, Vladimír; Maloň, Petr

    2013-08-22

    We investigate amide nonplanarity in vibrational optical activity (VOA) spectra of tricyclic spirodilactams 5,8-diazatricyclo[6,3,0,0(1,5)]undecan-4,9-dione (I) and its 6,6',7,7'-tetradeuterio derivative (II). These rigid molecules constrain amide groups to nonplanar geometries with twisted pyramidal arrangements of bonds to amide nitrogen atoms. We have collected a full range vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectra including signals of C-H and C-D stretching vibrations. We report normal-mode analysis and a comparison of calculated to experimental VCD and ROA. The data provide band-to-band assignment and offer a possibility to evaluate roles of constrained nonplanar tertiary amide groups and rigid chiral skeletons. Nonplanarity shows as single-signed VCD and ROA amide I signals, prevailing the couplets expected to arise from the amide-amide interaction. Amide-amide coupling dominates amide II (mainly C'-N stretching, modified in tertiary amides by the absence of a N-H bond) transitions (strong couplet in VCD, no significant ROA) probably due to the close proximity of amide nitrogen atoms. At lower wavenumbers, ROA spectra exhibit another likely manifestation of amide nonplanarity, showing signals of amide V (δ(oop)(N-C) at ~570 cm(-1)) and amide VI (δ(oop)(C'═O) at ~700 cm(-1) and ~650 cm(-1)) vibrations.

  3. Functional architectures based on self-assembly of bio-inspired dipeptides: Structure modulation and its photoelectronic applications.

    Science.gov (United States)

    Chen, Chengjun; Liu, Kai; Li, Junbai; Yan, Xuehai

    2015-11-01

    Getting inspiration from nature and further developing functional architectures provides an effective way to design innovative materials and systems. Among bio-inspired materials, dipeptides and its self-assembled architectures with functionalities have recently been the subject of intensive studies. However, there is still a great challenge to explore its applications likely due to the lack of effective adaptation of their self-assembled structures as well as a lack of understanding of the self-assembly mechanisms. In this context, taking diphenylalanine (FF, a core recognition motif for molecular self-assembly of the Alzheimer's β-amyloid polypeptides) as a model of bio-inspired dipeptides, recent strategies on modulation of dipeptide-based architectures were introduced with regard to both covalent (architectures modulation by coupling functional groups) and non-covalent ways (controlled architectures by different assembly pathways). Then, applications are highlighted in some newly emerging fields of innovative photoelectronic devices and materials, such as artificial photosynthetic systems for renewable solar energy storage and renewable optical waveguiding materials for optoelectronic devices. At last, the challenges and future perspectives of these bio-inspired dipeptides are also addressed.

  4. Computational Study of Environmental Effects on Torsional Free Energy Surface of N-Acetyl-N'-methyl-L-alanylamide Dipeptide

    Science.gov (United States)

    Carlotto, Silvia; Zerbetto, Mirco

    2014-01-01

    We propose an articulated computational experiment in which both quantum mechanics (QM) and molecular mechanics (MM) methods are employed to investigate environment effects on the free energy surface for the backbone dihedral angles rotation of the small dipeptide N-Acetyl-N'-methyl-L-alanylamide. This computation exercise is appropriate for an…

  5. HISTOCHEMICAL AND ELECTRON-MICROSCOPIC CHARACTERIZATION OF HEPATIC MACROPHAGE SUBFRACTIONS ISOLATED FROM NORMAL AND LIPOSOMAL MURAMYL DIPEPTIDE TREATED RATS

    NARCIS (Netherlands)

    HOEDEMAKERS, RMJ; ATMOSOERODJOBRIGGS, JE; MORSELT, HWM; DAEMEN, T; SCHERPHOF, GL; HARDONK, MJ

    1995-01-01

    Subfractions of the hepatic macrophage population, differing in cell size, were isolated from normal rats and rats treated with liposomal muramyl dipeptide (lipMDP) and analyzed histochemically and by ultrastructural peroxidase cytochemistry. The majority of cells in all subfractions of control rats

  6. Solution-Phase Synthesis of Dipeptides: A Capstone Project That Employs Key Techniques in an Organic Laboratory Course

    Science.gov (United States)

    Marchetti, Louis; DeBoef, Brenton

    2015-01-01

    A contemporary approach to the synthesis and purification of several UV-active dipeptides has been developed for the second-year organic laboratory. This experiment exposes students to the important technique of solution-phase peptide synthesis and allows an instructor to highlight the parallel between what they are accomplishing in the laboratory…

  7. Effects of glycyl-glutamine dipeptide supplementation on myocardial damage and cardiac function in rats after severe burn injury.

    Science.gov (United States)

    Zhang, Yong; Yan, Hong; Lv, Shang-Gun; Wang, Lin; Liang, Guang-Ping; Wan, Qian-Xue; Peng, Xi

    2013-01-01

    Glutamine decreases myocardial damage in ischemia/reperfusion injury. However, the cardioprotective effect of glutamine after burn injury remains unclear. Present study was to explore the protective effect of glycyl-glutamine dipeptide on myocardial damage in severe burn rats. Seventy-two Wistar rats were randomly divided into three groups: normal control (C), burned control (B) and glycyl-glutamine dipeptide-treated (GG) groups. B and GG groups were inflicted with 30% total body surface area of full thickness burn. The GG group was given 1.5 g/kg glycyl-glutamine dipeptide per day and the B group was given the same dose of alanine via intraperitoneal injection for 3 days. The serum CK, LDH, AST, and, blood lactic acid levels, as well as the myocardium ATP and GSH contents, were measured. The indices of cardiac contractile function and histopathological change were analyzed at 12, 24, 48, and 72 post-burn hours (PBH). The serum CK, LDH, AST and blood lactic acid levels increased, and the myocardium ATP and GSH content decreased in both burned groups. Compared with B group, the CK, LDH, AST and blood lactic acid levels reduced, myocardium ATP and GSH content increased in GG group. Moreover, the inhibition of cardiac contractile function and myocardial histopathological damage were reduced significantly in GG group. We conclude that myocardial histological structure and function were damaged significantly after burn injury, glycyl-glutamine dipeptide supplementation is beneficial to myocardial preservation by improving cardiocyte energy metabolism, increasing ATP and glutathione synthesis.

  8. Phenylalanine-containing cyclic dipeptides--the lowest molecular weight hydrogelators based on unmodified proteinogenic amino acids.

    Science.gov (United States)

    Kleinsmann, Alexander J; Nachtsheim, Boris J

    2013-09-14

    Cyclic dipeptides (diketopiperazines - DKPs) that are based on the proteinogenic amino acid phenylalanine in combination with serine, cysteine, glutamate, histidine and lysine are described as simple and remarkable low molecular weight hydrogelators. Blends of selected DKPs show remarkable pH-dependent properties and can be applied as easy to tune materials in drug delivery.

  9. Solution-Phase Synthesis of Dipeptides: A Capstone Project That Employs Key Techniques in an Organic Laboratory Course

    Science.gov (United States)

    Marchetti, Louis; DeBoef, Brenton

    2015-01-01

    A contemporary approach to the synthesis and purification of several UV-active dipeptides has been developed for the second-year organic laboratory. This experiment exposes students to the important technique of solution-phase peptide synthesis and allows an instructor to highlight the parallel between what they are accomplishing in the laboratory…

  10. Photoelectron spectra and structures of three cyclic dipeptides: PhePhe, TyrPro, and HisGly

    Science.gov (United States)

    Wickrama Arachchilage, Anoja P.; Wang, Feng; Feyer, Vitaliy; Plekan, Oksana; Prince, Kevin C.

    2012-03-01

    We have investigated the electronic structure of three cyclic dipeptides: cyclo(Histidyl-Glycyl) (cHisGly), cyclo(Tyrosyl-Prolyl) (cTyrPro), and cyclo(Phenylalanyl-Phenylalanyl) (cPhePhe) in the vapor phase, by means of photoemission spectroscopy and theoretical modeling. The last compound was evaporated from the solid linear dipeptide, but cyclised, losing water to form cPhePhe in the gas phase. The results are compared with our previous studies of three other cyclopeptides. Experimental valence and core level spectra have been interpreted in the light of calculations to identify the basic chemical properties associated with the central diketopiperazine ring, and with the additional functional groups. The valence spectra are generally characterized by a restricted set of outer valence orbitals separated by a gap from most other valence orbitals. The theoretically simulated core and valence spectra of all three cyclic dipeptides agree reasonably well with the experimental spectra. The central ring and the side chains act as independent chromophores whose spectra do not influence one another, except for prolyl dipeptides, where the pyrrole ring is fused with the central ring. In this case, significant changes in the valence and core level spectra were observed, and explained by stronger hybridization of the valence orbitals.

  11. The Feasibility of Enzyme Targeted Activation for Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine; Cathepsin D as a Potential Targeted Enzyme

    Directory of Open Access Journals (Sweden)

    Gordon L. Amidon

    2012-03-01

    Full Text Available The improvement of therapeutic efficacy for cancer agents has been a big challenge which includes the increase of tumor selectivity and the reduction of adverse effects at non-tumor sites. In order to achieve those goals, prodrug approaches have been extensively investigated. In this report, the potential activation enzymes for 5¢-amino acid/dipeptide monoester floxuridine prodrugs in pancreatic cancer cells were selected and the feasibility of enzyme specific activation of prodrugs was evaluated. All prodrugs exhibited the range of 3.0–105.7 min of half life in Capan-2 cell homogenate with the presence and the absence of selective enzyme inhibitors. 5¢-O-L-Phenylalanyl-L-tyrosyl-floxuridine exhibited longer half life only with the presence of pepstatin A. Human cathepsin B and D selectively hydrolized 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine and 5¢-O-L-phenylalanyl-L-glycylfloxuridine compared to the other tested prodrugs. The wide range of growth inhibitory effect by floxuridine prodrugs in Capan-2 cells was observed due to the different affinities of prodrug promoieties to enyzmes. In conclusion, it is feasible to design prodrugs which are activated by specific enzymes. Cathepsin D might be a good candidate as a target enzyme for prodrug activation and 5¢-O-L-phenylalanyl-L-tyrosylfloxuridine may be the best candidate among the tested floxuridine prodrugs.

  12. Preparation of platinum(IV) complexes with dipeptide and diimine. X-ray crystal structure and 195Pt NMR spectra.

    Science.gov (United States)

    Watabe, Masatoshi; Fukuda, Hiroto; Kitsukawa, Koichiro; Nakajima, Hiroshi; Yukawa, Yasuhiko; Igarashi, Satoshi; Fujii, Yuki; Takayama, Toshio

    2006-10-01

    We prepared platinum(IV) complexes containing dipeptide and diimine or diamine, the [PtCl(dipeptide-N,N,O)(diimine or diamine)]Cl complex, where -N,N,O means dipeptide coordinated as a tridentate chelate, dipeptide=glycylglycine (NH(2)CH(2)CON(-)CH(2)COO(-), digly, where two protons of dipeptide are detached when the dipeptide coordinates to metal ion as a tridentate chelate), glycyl-L-alanine (NH(2)CH(2)CON(-)CHCH(3)COO(-), gly-L-ala), L-alanylglycine (NH(2)CH CH(3)CON(-)CH(2)COO(-), L-alagly), or L-alanyl-L-alanine (NH(2)CHCH(3)CON(-)CHCH(3)COO(-), dil-ala), and diimine or diamine=bipyridine (bpy), ethylenediamine (en), N-methylethylenediamine (N-Me-en), or N,N'-dimethylethylenediamine (N,N'-diMe-en). In the complexes containing gly-L-ala or dil-ala, two separate peaks of the (195)Pt NMR spectra of the [PtCl(dipeptide-N,N,O)(diimine or diamine)]Cl complexes appeared in, but in the complexes containing digly or L-alagly, one peak which contained two overlapped signals appeared. One of the two complexes containing gly-L-ala and bpy, [PtCl(gly-L-ala-N,N,O)(bpy)]NO(3), crystallized and was analyzed. This complex has the monoclinic space group P2(1)2(1)2(1) with unit cell dimensions of a=9.7906(3)A, b=11.1847(2)A, c=16.6796(2)A, Z=4. The crystal data revealed that this [PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex has the near- (Cl, CH(3)) configuration of two possible isomers. Based on elemental analysis, the other complex must have the near- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) configuration. The (195)Pt NMR chemical shifts of the near- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex and the far- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex are 0 ppm and -19 ppm, respectively (0 ppm for the Na(2)[PtCl(6)] signal). The additive property of the (195)Pt NMR chemical shift is discussed. The (195)Pt NMR chemical shifts of [PtCl(dipeptide-N,N,O)(bpy)]Cl appeared at a higher field when the H attached to the dipeptide carbon atom was replaced with a

  13. Dipeptides in clinical nutrition%谷氨酰胺双肽在临床营养中的运用

    Institute of Scientific and Technical Information of China (English)

    PeterFuerstMD

    2001-01-01

    A)What should be known about supplemental glutamine-(dipeptides)?In numerous controlled clinical trials it could be convincingly demonstrated that supplemental glutamine-(dipeptide) nutrition was associated with improved nitrogen balance and mood;increased protein synthesis and lymphocyte count (total and subpopulation);maintained intestinal function,intracellular muscle free glutamine pool,gut permeability and function;reduced 3MeHis excretion,morbidity,length of hospital stay and sepsis frequency.A current European multi center study with ala-gln provides convincing evidence that the clinical use of glutamine dipeptide spares nitrogen and shortens length of hospital stay as compared with the controls.The infusion of the glutamine containing dipeptide solution was free of any side effects, and recovery was normal for each patient.Provision of glutamine-(dipeptide) should be considered as a replacement of a deficiency rather than a supplement.This implies that the beneficial effects observed are due to a correction of disadvantages produced by an inadequacy of conventional nutrition.B)What is new in glutamine(dipeptide)research?(1)It is purposed that tiessue glutathione synthesis is a crucial factor in causing reversal of the clinical,biochemical signs of critical illness,a condition associated with decreased glutathione status.Indeed,the decreased ratio GSH/GSSG suggests oxidative stress in the tissues.In the uture,glutamine containing dipeptides will certainly serve as a means to maintain and/or restore tissur glutathione concentrations.(2)Modification of the endogenous inflammatory response:attenuation of the elaboration of pro-inflammatory mediators,upregulation of antiinflammatory factors,improved immune response.Studies are in progress showing that supplemental glutamine containing dipeptides decrease cytotoxicity and the synthesis of TNFα and IL8 while they enhance the ability to express the anti-inflammatory IL10.An encouraging perspective is the novel

  14. Cations bind only weakly to amides in aqueous solutions.

    Science.gov (United States)

    Okur, Halil I; Kherb, Jaibir; Cremer, Paul S

    2013-04-01

    We investigated salt interactions with butyramide as a simple mimic of cation interactions with protein backbones. The experiments were performed in aqueous metal chloride solutions using two spectroscopic techniques. In the first, which provided information about contact pair formation, the response of the amide I band to the nature and concentration of salt was monitored in bulk aqueous solutions via attenuated total reflection Fourier transform infrared spectroscopy. It was found that molar concentrations of well-hydrated metal cations (Ca(2+), Mg(2+), Li(+)) led to the rise of a peak assigned to metal cation-bound amides (1645 cm(-1)) and a decrease in the peak associated with purely water-bound amides (1620 cm(-1)). In a complementary set of experiments, the effect of cation identity and concentration was investigated at the air/butyramide/water interface via vibrational sum frequency spectroscopy. In these studies, metal ion-amide binding led to the ordering of the adjacent water layer. Such experiments were sensitive to the interfacial partitioning of cations in either a contact pair with the amide or as a solvent separated pair. In both experiments, the ordering of the interactions of the cations was: Ca(2+) > Mg(2+) > Li(+) > Na(+) ≈ K(+). This is a direct cationic Hofmeister series. Even for Ca(2+), however, the apparent equilibrium dissociation constant of the cation with the amide carbonyl oxygen was no tighter than ∼8.5 M. For Na(+) and K(+), no evidence was found for any binding. As such, the interactions of metal cations with amides are far weaker than the analogous binding of weakly hydrated anions.

  15. Mechanistic Investigations of Oxidation of Some Dipeptides by Sodium N-chloro-p-toluenesulfonamide in Alkaline Medium: A Kinetic Study

    Institute of Scientific and Technical Information of China (English)

    PUTTASWAMY; VAZ Nirmala; RAJENAHALLY VGOWDA Jagadeesh

    2008-01-01

    The kinetics of oxidation of five dipeptides (DPP) viz., glycylglycine (Gly-Gly), L-alanyl-L-alanine (Ala-Ala),L-valyl-L-valine (Val-Val), L-leucyl-L-leucine (Leu-Leu) and phenylglycyl-phenylglycine (Phg-Phg) by sodium N-chloro-p-toluenesuifonamide or chloramine-T (CAT) in NaOH medium was studied at 308 K. The reactions follow identical kinetics for all the dipeptides, being first-order dependence each on [CAT]o, [DPP]o and fractional-order on [OH-]. Addition of p-toluenesulfonamide or halide ions (CI- or Br-) has no significant effect on the rate of reaction. The reaction rate was found to increase with increase in ionic strength of the medium. The solvent isotope effect was studied using D2O. The activation parameters for the reaction were computed from Arrhenius plots. Equilibrium and decomposition constants were evaluated. The oxidation products of the dipeptides were identiffed as their corresponding aldehydes. An isokinetic relationship was observed with β=352 K, indicating that enthalpy factors control the reaction rate. CH3C6H4SO2NCl- of the oxidant has been postulated as the reactive oxidizing species. Under comparable experimental conditions, the rate of oxidation of the dipeptides increases in the order: Phg-Phg>Ala-Ala>Val-Val>Leu-Leu>Gly-Gly. The kinetics of oxidation of the dipeptides have also been compared with those of their corresponding monomer amino acids. The observed results have been explained by a plausible mechanism and the related rate law has been deduced.

  16. Structural and spectroscopic investigation on antioxidant dipeptide, L-Methionyl-L-Serine: A combined experimental and DFT study

    Science.gov (United States)

    Kecel-Gunduz, Serda; Bicak, Bilge; Celik, Sefa; Akyuz, Sevim; Ozel, Aysen E.

    2017-06-01

    The focus of this study is to determine the conformational, structural and vibrational properties of Methionyl-Serine dipeptide (L-Methionyl-L-Serine, Met-Ser), a biological active molecule. To investigate their energetically preferred conformations, molecular mechanics methods were utilized to determine the optimal conformations of the 3402 different dihedral angle values of the backbone and side chains. It was found that the extended (e) backbone shape in the LB conformational range was the most stable L-Methionyl-L-Serine dipeptide conformation, with 3.12 kcal/mol of energy. Density Functional Theory (DFT) was used to determine the optimized geometry, the vibrational wavenumbers and modes of the title dipeptide values, with 6-31G (d,p) and 6-311++G (d,p) basis sets. The potential energy distribution data was used to carry out the assignment of the bands. In addition, the vibrational spectra of the most stable conformer and its dimer form were determined and the obtained results were compared with the experimental IR and Raman spectra in the solid phase. To determine the presence of intramolecular charge transfer, molecular dipole moment, polarizability and hyperpolarizability, the Natural Bond Orbital (NBO), HOMO-LUMO calculations, the linear polarizability (α) and the first order hyperpolarizability (β0) value analyses of the investigated molecule were carried out using the DFT with the B3LYP/6-31++G(d,p) basis set. This study aims to determine a relatively stable conformation of antioxidant dipeptide and to investigate the molecular geometry, molecular vibrations and hydrogen bonding interactions between monomeric and dimeric forms of Methiony-Serine dipeptide.

  17. Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders

    Science.gov (United States)

    Ahn, Kay; Johnson, Douglas S.; Cravatt, Benjamin F.

    2009-01-01

    Background Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes without showing the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. Objectives This review highlights advances in the development of FAAH inhibitors of different mechanistic classes and their in vivo efficacy. Also highlighted are advances in technology for the in vitro and in vivo selectivity assessment of FAAH inhibitors employing activity-based protein profiling (ABPP) and click chemistry-ABPP, respectively. Recent reports on structure-based drug design for human FAAH generated by protein engineering using interspecies active site conversion are also discussed. Methods: The literature searches of Medline and SciFinder databases were used. Conclusions There has been tremendous progress in our understanding in FAAH and development of FAAH inhibitors with in vivo efficacy, selectivity, and drug like pharmacokinetic properties. PMID:20544003

  18. MEDV-13 for QSAR Studies on the COX-2 Inhibition by In domethacin Amides and Esters

    Institute of Scientific and Technical Information of China (English)

    LIU,Shu-Shen (刘树深); YIN,Chun-Sheng(印春生); SHI,Yun-Yu(施蕴渝); CAI,Shao-Xi(蔡绍皙); LI,Zhi-Liang(李志良)

    2001-01-01

    A molecular electronegativity distance vector based on 13 atomic types (MEDV-13), is a descriptor for predicting the biological activities of molecules based on the quantitative structure-activity relationship (QSAR). The MEDV-13 with 91 descriptors is employed to describe the structures of a series of selective cydooxygenase-2 (COX-2) inhibitors inchuding 16 indomethacin and its amide and ester derivatives (ImAE). A principal component regression (PCR) is used to derive a QSAR model relating the biological activities expressed by pIC50 values to the MEDV-13. With the number of principal components of 6, the correlation coeffcient (R) and the root mean square error (RMS) are 0.9245 and 0.1682 in modeling stage, and 0.8417 and 0.2389 in leave-one-out prediction step, respectively.

  19. Comparative study to predict dipeptidyl peptidase IV inhibitory activity of β-amino amide scaffold

    Directory of Open Access Journals (Sweden)

    S Patil

    2015-01-01

    Full Text Available Comparative study was performed on 34 β-amino amide derivatives as dipeptidyl peptidase IV inhibitors in order to determine their structural requirement to enhance the antidiabetic activities. Hologram quantitative structure activity relationships models utilized specialized fragment fingerprints (hologram length 353 which showed good predictivity with cross-validated q 2 and conventional r 2 values of 0.971 and 0.971, respectively. Models were validated and optimized by a test set of eight compounds and gave satisfactory predictive ability. Hologram quantitative structure activity relationships maps were helpful in prediction of the structural features of the ligands to account for the activity in terms of positively and negatively contributing towards activity. The information obtained from maps could be effectively use as a guiding tool for further structure modifications and synthesis of new potent antidiabetic agents.

  20. Iron(III) Chloride mediated reduction of Bis(1-isoquinolylcarbonyl)amide to an Amide

    Indian Academy of Sciences (India)

    Rojalin Sahu; Papuli Chaliha; Vadivelu Manivannan

    2016-01-01

    In methanol, FeCl3 reacted readily with L1H (L1H = bis(1-isoquinolylcarbonyl)amide) and afforded a complex having the formula [Fe(L2)Cl2] (1) {L2− = -((1-isoquinolyl)(methoxy)methyl)isoquinoline-1-carboxamide ion}. This reaction involves reduction of one of the two carbonyl groups present in L1H to (methoxy)methyl group. A plausible mechanism for the conversion of L1H to L2− has been proposed. Determination of molecular structure of 1 confirmed this conversion. Fe(III) ion is surrounded by three nitrogen atoms of the ligand and two chloride ions, imparting a rare distorted trigonal bipyramidal N3Cl2 coordination environment.

  1. Asymmetric cyanation of imines via dipeptide-derived organophosphine dual-reagent catalysis

    Science.gov (United States)

    Wang, Hong-Yu; Zheng, Chang-Wu; Chai, Zhuo; Zhang, Jia-Xing; Zhao, Gang

    2016-09-01

    Over the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base.

  2. Studies on intestinal absorption of amino acids and a dipeptide in a case of Hartnup disease.

    Science.gov (United States)

    Navab, F; Asatoor, A M

    1970-05-01

    A severely affected case of Hartnup disease is reported, where the patient responded rapidly to nicotinamide. This supports the view that all the clinical features, except reduced stature from general nutritional defect, are secondary to tryptophan and nicotinamide deficiency rather than to an unknown toxic factor. Severe malabsorption of both tryptophan and phenylalanine was demonstrated. The dipeptide carnosine was absorbed normally whereas when the two constituent amino acids, beta-alanine and L-histidine, were ingested, absorption of the former was normal but that of the latter was grossly defective. The suggestion is advanced that in cases of Hartnup disease protein nutrition is maintained by intestinal uptake of amino acids as oligopeptides rather than as free amino acids. By contrast, both modes of absorption are probably important in normal subjects. Radiology of the small intestine is abnormal in Hartnup disease when a large amount of protein is admixed with the barium meal.

  3. Structure-Functional Study of Tyrosine and Methionine Dipeptides: An Approach to Antioxidant Activity Prediction

    Directory of Open Access Journals (Sweden)

    Anna Torkova

    2015-10-01

    Full Text Available Quantum chemical methods allow screening and prediction of peptide antioxidant activity on the basis of known experimental data. It can be used to design the selective proteolysis of protein sources in order to obtain products with antioxidant activity. Molecular geometry and electronic descriptors of redox-active amino acids, as well as tyrosine and methionine-containing dipeptides, were studied by Density Functional Theory method. The calculated data was used to reveal several descriptors responsible for the antioxidant capacities of the model compounds based on their experimentally obtained antioxidant capacities against ABTS (2,2′-Azino-bis-(3-ethyl-benzothiazoline-6-sulfonate and peroxyl radical. A formula to predict antioxidant activity of peptides was proposed.

  4. The amidation step of diphthamide biosynthesis in yeast requires DPH6, a gene identified through mining the DPH1-DPH5 interaction network.

    Directory of Open Access Journals (Sweden)

    Shanow Uthman

    Full Text Available Diphthamide is a highly modified histidine residue in eukaryal translation elongation factor 2 (eEF2 that is the target for irreversible ADP ribosylation by diphtheria toxin (DT. In Saccharomyces cerevisiae, the initial steps of diphthamide biosynthesis are well characterized and require the DPH1-DPH5 genes. However, the last pathway step-amidation of the intermediate diphthine to diphthamide-is ill-defined. Here we mine the genetic interaction landscapes of DPH1-DPH5 to identify a candidate gene for the elusive amidase (YLR143w/DPH6 and confirm involvement of a second gene (YBR246w/DPH7 in the amidation step. Like dph1-dph5, dph6 and dph7 mutants maintain eEF2 forms that evade inhibition by DT and sordarin, a diphthamide-dependent antifungal. Moreover, mass spectrometry shows that dph6 and dph7 mutants specifically accumulate diphthine-modified eEF2, demonstrating failure to complete the final amidation step. Consistent with an expected requirement for ATP in diphthine amidation, Dph6 contains an essential adenine nucleotide hydrolase domain and binds to eEF2. Dph6 is therefore a candidate for the elusive amidase, while Dph7 apparently couples diphthine synthase (Dph5 to diphthine amidation. The latter conclusion is based on our observation that dph7 mutants show drastically upregulated interaction between Dph5 and eEF2, indicating that their association is kept in check by Dph7. Physiologically, completion of diphthamide synthesis is required for optimal translational accuracy and cell growth, as indicated by shared traits among the dph mutants including increased ribosomal -1 frameshifting and altered responses to translation inhibitors. Through identification of Dph6 and Dph7 as components required for the amidation step of the diphthamide pathway, our work paves the way for a detailed mechanistic understanding of diphthamide formation.

  5. Intramolecular amide bonds stabilize pili on the surface of bacilli

    Energy Technology Data Exchange (ETDEWEB)

    Budzik, Jonathan M.; Poor, Catherine B.; Faull, Kym F.; Whitelegge, Julian P.; He, Chuan; Schneewind, Olaf; (UC); (UCLA-MED)

    2010-01-12

    Gram-positive bacteria elaborate pili and do so without the participation of folding chaperones or disulfide bond catalysts. Sortases, enzymes that cut pilin precursors, form covalent bonds that link pilin subunits and assemble pili on the bacterial surface. We determined the x-ray structure of BcpA, the major pilin subunit of Bacillus cereus. The BcpA precursor encompasses 2 Ig folds (CNA{sub 2} and CNA{sub 3}) and one jelly-roll domain (XNA) each of which synthesizes a single intramolecular amide bond. A fourth amide bond, derived from the Ig fold of CNA{sub 1}, is formed only after pilin subunits have been incorporated into pili. We report that the domains of pilin precursors have evolved to synthesize a discrete sequence of intramolecular amide bonds, thereby conferring structural stability and protease resistance to pili.

  6. Mechanism of fluorescence quenching of tyrosine derivatives by amide group

    Science.gov (United States)

    Wiczk, Wiesław; Rzeska, Alicja; Łukomska, Joanna; Stachowiak, Krystyna; Karolczak, Jerzy; Malicka, Joanna; Łankiewicz, Leszek

    2001-06-01

    The difference between fluorescence lifetimes of the following amino acids: phenylalanine (Phe), tyrosine (Tyr), ( O-methyl)tyrosine (Tyr(Me)), (3-hydroxy)tyrosine (Dopa), (3,4-dimethoxy)phenylalanine (Dopa(Me) 2) and their amides was used to testify the mechanism of fluorescence quenching of aromatic amino acids by the amide group. On the basis of the Marcus theory of photoinduced electron transfer parabolic relationships between ln kET and ionization potentials reduced by energy of excitation ( IP-E ∗0,0) for the above-mentioned amino acids were obtained. This finding indicates the occurrence of photoinduced electron transfer from the excited chromophore group to the amide group.

  7. VCD Robustness of the Amide-I and Amide-II Vibrational Modes of Small Peptide Models.

    Science.gov (United States)

    Góbi, Sándor; Magyarfalvi, Gábor; Tarczay, György

    2015-09-01

    The rotational strengths and the robustness values of amide-I and amide-II vibrational modes of For(AA)n NHMe (where AA is Val, Asn, Asp, or Cys, n = 1-5 for Val and Asn; n = 1 for Asp and Cys) model peptides with α-helix and β-sheet backbone conformations were computed by density functional methods. The robustness results verify empirical rules drawn from experiments and from computed rotational strengths linking amide-I and amide-II patterns in the vibrational circular dichroism (VCD) spectra of peptides with their backbone structures. For peptides with at least three residues (n ≥ 3) these characteristic patterns from coupled amide vibrational modes have robust signatures. For shorter peptide models many vibrational modes are nonrobust, and the robust modes can be dependent on the residues or on their side chain conformations in addition to backbone conformations. These robust VCD bands, however, provide information for the detailed structural analysis of these smaller systems.

  8. Chiral separation of amides using supercritical fluid chromatography.

    Science.gov (United States)

    Xiang, Yanqiao; Dunetz, Joshua R; Lovdahl, Michael

    2013-06-07

    Nine amide derivatives bearing α-stereocenters as well as different substitutions on the amide nitrogen were synthesized via an n-propanephosphonic acid cyclic anhydride (T3P)-mediated coupling, and their enantiomeric pairs were separated using supercritical fluid chromatography (SFC). Five polysaccharide-based chiral stationary phases (CSPs), Chiralcel OD-H, and OJ-H, and Chiralpak AD-H, AS-H and IC columns were explored for the chiral separation of these compounds. None of the compounds could be resolved on all five columns, and no single column could separate all nine pairs of enantiomers. Comparatively, the IC and OD-H columns showed the best results for this group of amides, yielding baseline separations for eight of nine pairs. The type of polar functional group and aromatic substitution in the CSPs and the substitutions on the amide nitrogen had a significant impact on the enantiomeric resolution of the compounds in the interaction between the analyte and the stationary phases. The potential separation mechanism and the effect of substitutions in the CSPs and amide solutes on the separation are discussed. The effects of the organic modifiers, modifier composition, mobile phase additives, and temperature were investigated for the separation of these amides on the IC or the OD-H column. Baseline resolution was achieved under optimized chromatographic conditions using an IC or an OD-H column. Linearity, reproducibility, and limit of quantitation were also demonstrated for the compound 9. Approximately three-fold improvement in signal-to-noise was observed using a SFC system with better instrument design.

  9. Evaluating the Reduced Hydrophobic Taste Sensor Response of Dipeptides by Theasinensin A by Using NMR and Quantum Mechanical Analyses.

    Directory of Open Access Journals (Sweden)

    Jian Guo

    Full Text Available The current study demonstrated that theasinensin A (TSA had a potential to form the complex with hydrophobic Trp-containing dipeptides, and to reduce their membrane potential by artificial-lipid membrane taste sensor. At a 1:3 molar ratio of the 6 Trp-containing dipeptides together with TSA, we observed a significant chemical shift of the protons of the dipeptides (Δδ to a high magnetic field, when analyzed using 1H-nuclear-magnetic resonance (NMR spectroscopy. The Δδ values were correlated with the hydrophobicity (log P of the dipeptides and significant correlations were obtained (P = 0.022, R2 = 0.77; e.g., Trp-Leu with the highest log P value of 1.623 among the tested dipeptides showed the highest Δδ value of 0.105 ppm for the H7 proton of Trp-Leu, while less chemical shifts were observed in theasinensin B and epigallocatechin-3-O-gallate. Diffusion-ordered NMR spectroscopy revealed that the diffusion coefficient of 3 mM of Trp-Leu (7.6 × 10-11 m2/s at a pulse field gradient in the range 0.05-0.3 T/m decreased in the presence of 3 mM TSA (6.6 × 10-11 m2/s, suggesting that Trp-Leu forms a complex with TSA. Quantum mechanical calculations and rotating frame nuclear Overhauser effect-NMR spectroscopy provided configuration information on the geometry of the complex that Trp-Leu formed with TSA (1:1 complex with a ΔG energy of -8.7 kJ/mol. A sensor analysis using artificial-lipid membranes demonstrated that the changes in membrane potential of 1 mM Trp-Leu (21.8 ± 1.3 mV and Leu-Trp (5.3 ± 0.9 mV were significantly (P < 0.001 reduced by 1 mM TSA (Trp-Leu, 13.1 ± 2.4 mV; Leu-Trp, 3.5 ± 0.5 mV; TSA alone, 0.2 ± 0.01 mV, indicating the effective suppression of hydrophobicity of dipeptides by TSA-formed complex.

  10. Studies on the amide compounds ofMirabilis. Jalapa. L

    Institute of Scientific and Technical Information of China (English)

    SHEN; XuWei

    2001-01-01

    Mirabilis himalaica(Edgew.)Heinerl Var. Chinensis Heimerl belonging to the genus Mirabilis are used in chinese medicine as a remedy for various diseases[1].Its chemical constituents,however, have not been reported so far. we have carried out a detailed chemical investigatigation of the seeds and have isolated two new amides along with three known compounds.  The known compounds were identified by comparing their spectral data with those of authentic samples or with those reported in literature as daucosterol[2], bsitoserol[2], boeravinone E[3], in the present note, the structural elucidation of two new amides is reported.  ……

  11. Study on Alternating Copolymerization of Polyester-amides

    Institute of Scientific and Technical Information of China (English)

    WEI Wen-liang; LI Jian-mei; ZHU Fang-liang

    2002-01-01

    The preparing methods, choice of catalysts and reaction kinetics of one of the monomers, diesteramide(DEA), of polyester-amides were investigated in details. The chemical structure of DEA was analyzed. And the Polyester-amides (PEA) were obtained by melt copolymerization with DEA. It is shown that DEA can be synthesized by DMT and hexamethylene diamine with the catalyst EX - 1 or EX - 2. The relationship between reaction rate of synthesizing monomer and concentration of hexamethylene diamine is first order kinetic relation.

  12. Studies on the amide compounds ofMirabilis. Jalapa. L

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@ Mirabilis himalaica(Edgew.)Heinerl Var. Chinensis Heimerl belonging to the genus Mirabilis are used in chinese medicine as a remedy for various diseases[1].Its chemical constituents,however, have not been reported so far. we have carried out a detailed chemical investigatigation of the seeds and have isolated two new amides along with three known compounds. The known compounds were identified by comparing their spectral data with those of authentic samples or with those reported in literature as daucosterol[2], bsitoserol[2], boeravinone E[3], in the present note, the structural elucidation of two new amides is reported.

  13. Oxidative peptide /and amide/ formation from Schiff base complexes

    Science.gov (United States)

    Strehler, B. L.; Li, M. P.; Martin, K.; Fliss, H.; Schmid, P.

    1982-01-01

    One hypothesis of the origin of pre-modern forms of life is that the original replicating molecules were specific polypeptides which acted as templates for the assembly of poly-Schiff bases complementary to the template, and that these polymers were then oxidized to peptide linkages, probably by photo-produced oxidants. A double cycle of such anti-parallel complementary replication would yield the original peptide polymer. If this model were valid, the Schiff base between an N-acyl alpha mino aldehyde and an amino acid should yield a dipeptide in aqueous solution in the presence of an appropriate oxidant. In the present study it is shown that the substituted dipeptide, N-acetyl-tyrosyl-tyrosine, is produced in high yield in aqueous solution at pH 9 through the action of H2O2 on the Schiff-base complex between N-acetyl-tyrosinal and tyrosine and that a great variety of N-acyl amino acids are formed from amino acids and aliphatic aldehydes under similar conditions.

  14. pH and reduction dual-responsive dipeptide cationic lipids with α-tocopherol hydrophobic tail for efficient gene delivery.

    Science.gov (United States)

    Liu, Qiang; Su, Rong-Chuan; Yi, Wen-Jing; Zheng, Li-Ting; Lu, Shan-Shan; Zhao, Zhi-Gang

    2017-03-31

    A series of tocopherol-based cationic lipid 3a-3f bearing a pH-sensitive imidazole moiety in the dipeptide headgroup and a reduction-responsive disulfide linkage were designed and synthesized. Acid-base titration of these lipids showed good buffering capacities. The liposomes formed from 3 and co-lipid 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) could efficiently bind and condense DNA into nanoparticles. Gel binding and HPLC assays confirmed the encapsulated DNA could release from lipoplexes 3 upon addition of 10 mM glutathione (GSH). MTT assays in HEK 293 cells demonstrated that lipoplexes 3 had low cytotoxicity. The in vitro gene transfection studies showed cationic dipeptide headgroups clearly affected the transfection efficiency (TE), and arginine-histidine based dipeptide lipid 3f give the best TE, which was 30.4 times higher than Lipofectamine 3000 in the presence of 10% serum. Cell-uptake assays indicated that basic amino acid containing dipeptide cationic lipids exhibited more efficient cell uptake than serine and aromatic amino acids based dipeptide lipids. Confocal laser scanning microscopy (CLSM) studies corroborated that 3 could efficiently deliver and release DNA into the nuclei of HeLa cells. These results suggest that tocopherol-based dipeptide cationic lipids with pH and reduction dual-sensitive characteristics might be promising non-viral gene delivery vectors.

  15. Thermal Stability, Sorption Properties and Morphology of Films of Dipeptide and Tripeptide Based on L-Glycine

    Directory of Open Access Journals (Sweden)

    Marat A. Ziganshin

    2015-12-01

    Full Text Available The effect of the number of amino acid residues in L-glycyl-L-glycine and L-glycyl-L-glycyl-L-glycine on thermal stability of powders, the sorption properties and surface morphology of thin films has been found. Dipeptide forms the film coated with disk-shaped nano-objects on the hydrophilic substrate, while tripeptide self-organizes to the film coated with nano-crystals on the hydrophobic substrate. Replacement of substrates (hydrophilic↔hydrophobic leads to the formation of smooth films of studied oligopeptides. Powders of oligopeptides do not form stable clathrates with water and organic compounds at room temperature. But their thin films are capable to bind organic or water vapors with high thermodynamic activity. Surprising difference in sorption selectivity of dipeptide and tripeptide has been observed. L-G

  16. Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers

    Science.gov (United States)

    Lin, Yi; Mori, Eiichiro; Kato, Masato; Xiang, Siheng; Wu, Leeju; Kwon, Ilmin; McKnight, Steven L.

    2016-01-01

    Summary Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRn targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRn binding, and that interaction between the PRn poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PRn-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein. PMID:27768897

  17. Toxic PR Poly-Dipeptides Encoded by the C9orf72 Repeat Expansion Target LC Domain Polymers.

    Science.gov (United States)

    Lin, Yi; Mori, Eiichiro; Kato, Masato; Xiang, Siheng; Wu, Leeju; Kwon, Ilmin; McKnight, Steven L

    2016-10-20

    Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRn targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRn binding and that interaction between the PRn poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PRn-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.

  18. 40 CFR 721.10176 - Amides, peanut-oil, N-[3-(dimethylamino)propyl].

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Amides, peanut-oil, N- . 721.10176... Substances § 721.10176 Amides, peanut-oil, N- . (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as amides, peanut-oil, N- (PMN P-04-144; CAS No....

  19. 40 CFR 721.720 - Alkoxylated fatty acid amide, alkylsulfate salt.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkoxylated fatty acid amide... Specific Chemical Substances § 721.720 Alkoxylated fatty acid amide, alkylsulfate salt. (a) Chemical... as an alkoxylated fatty acid amide, alkylsulfate salt (PMN P-97-136) is subject to reporting...

  20. 40 CFR 721.9075 - Quaternary ammonium salt of fluorinated alkylaryl amide.

    Science.gov (United States)

    2010-07-01

    ... fluorinated alkylaryl amide. 721.9075 Section 721.9075 Protection of Environment ENVIRONMENTAL PROTECTION... amide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as quaternary ammonium salt of fluorinated alkylaryl amide (PMN No. P-92-688)...

  1. 40 CFR 721.10063 - Halo substituted hydroxy nitrophenyl amide (generic).

    Science.gov (United States)

    2010-07-01

    ... amide (generic). 721.10063 Section 721.10063 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.10063 Halo substituted hydroxy nitrophenyl amide (generic). (a) Chemical... as halo substituted hydroxy nitrophenyl amide (PMN P-04-792) is subject to reporting under...

  2. 40 CFR 721.10191 - Amides, coco, N-[3-(dibutylamino)propyl].

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Amides, coco, N- . 721.10191 Section... Substances § 721.10191 Amides, coco, N- . (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as amides, coco, N- (PMN P-06-262; CAS No. 851544-20-2)...

  3. 40 CFR 721.10192 - Amides, coco, N-[3-(dibutylamino)propyl], acrylates.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Amides, coco, N- , acrylates. 721... Substances § 721.10192 Amides, coco, N- , acrylates. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as amides, coco, N- , acrylates (PMN...

  4. Use of triphenyl phosphate as risk mitigant for metal amide hydrogen storage materials

    Energy Technology Data Exchange (ETDEWEB)

    Cortes-Concepcion, Jose A.; Anton, Donald L.

    2016-04-26

    A process in a resulting product of the process in which a hydrogen storage metal amide is modified by a ball milling process using an additive of TPP. The resulting product provides for a hydrogen storage metal amide having a coating that renders the hydrogen storage metal amide resistant to air, ambient moisture, and liquid water while improving useful hydrogen storage and release kinetics.

  5. FMRF-amide-like immunoreactivity in brain and pituitary of the hagfish Eptatretus burgeri (Cyclostomata)

    DEFF Research Database (Denmark)

    Jirikowski, G; Erhart, G; Grimmelikhuijzen, C J

    1984-01-01

    the hypothalamus to the olfactory system and caudally to the medulla oblongata. FMRF-amide-like immunoreactivity was also found in cells of the adenohypophysis. These observations suggest that the hagfish possesses a brain FMRF-amide-like transmitter system and pituitary cells containing FMRF-amide-like material...

  6. Polyurethanes elastomers with amide chain extenders of uniform length

    NARCIS (Netherlands)

    van der Schuur, J.M.; Noordover, B.A.J.; Noordover, Bart; Gaymans, R.J.

    2006-01-01

    Toluene diisocyanate based polyurethanes with amide extenders were synthesized poly(propylene oxide) with a number average molecular weight of 2000 and endcapped with toluene diisocyanate was used as the polyether segment. The chain extenders were based on poly(hexamethylene terephthalamide):

  7. Modeling the amide I bands of small peptides

    NARCIS (Netherlands)

    Jansen, Thomas la Cour; Dijkstra, Arend G.; Watson, Tim M.; Hirst, Jonathan D.; Knoester, Jasper

    2006-01-01

    In this paper different floating oscillator models for describing the amide I band of peptides and proteins are compared with density functional theory (DFT) calculations. Models for the variation of the frequency shifts of the oscillators and the nearest-neighbor coupling between them with respect

  8. Polyurethane elastomers with amide chain extenders of uniform length

    NARCIS (Netherlands)

    Schuur, van der Martijn; Noordover, Bart; Gaymans, Reinoud J.

    2006-01-01

    Toluene diisocyanate based polyurethanes with amide extenders were synthesized poly(propylene oxide) with a number average molecular weight of 2000 and endcapped with toluene diisocyanate was used as the polyether segment. The chain extenders were based on poly(hexamethylene terephthalamide): hexame

  9. Intramolecular Amide Hydrolysis in N-Methylmaleamic Acid Revisited

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The intramolecular amide hydrolysis of N-methylmaleamic acid have been revisited by use of density functional theory and inclusion of solvent effects. The results indicate that concerted reaction mechanism is favored over stepwise reaction mechanism. This is in agreement with the previous theoretical study. Sovlent effects have significant influence on the reaction barrier.

  10. Preparation and characterization of amidated derivatives of alginic acid.

    Science.gov (United States)

    Taubner, Tomáš; Marounek, Milan; Synytsya, Andriy

    2017-10-01

    Alginic acid is a suitable material for modification to prepare new derivatives because of presence of its carboxyl groups. The high content of carboxyl groups over the entire length of its chain renders it an easily modifiable material with a possibility of achieving a high degree of substitution in the prepared derivatives. The salt of alginic acid (sodium alginate) is readily commercially available and is widely used in many branches of chemistry. Alginic acid was thus selected as the substrate for amidation. The amidation used two-steps: methyl esterification followed by amino-de-alkoxylation. The aim of this study was to prepare highly substituted derivatives with different polysaccharide chain characteristics. As such, the alginic acid was modified by the two-step amidation based on the esterification of the alginic acid carboxyl groups by reaction with methanol and further amino-de-alkoxylation (aminolysis) of the obtained methyl ester with amidation reagents (n-alkylamines, hydrazine and hydroxylamine). The purity and substitution degree of the prepared derivatives were monitored by vibration spectroscopic methods (FTIR and FT Raman) and organic elemental analysis. These analytical methods confirmed the preparation of highly or moderately substituted N-alkylamides, hydrazide and hydroxamic acid of alginic acid. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Method for enhancing amidohydrolase activity of fatty acid amide hydrolase

    Energy Technology Data Exchange (ETDEWEB)

    John, George; Nagarajan, Subbiah; Chapman, Kent; Faure, Lionel; Koulen, Peter

    2016-10-25

    A method for enhancing amidohydrolase activity of Fatty Acid Amide Hydrolase (FAAH) is disclosed. The method comprising administering a phenoxyacylethanolamide that causes the enhanced activity. The enhanced activity can have numerous effects on biological organisms including, for example, enhancing the growth of certain seedlings. The subject matter disclosed herein relates to enhancers of amidohydrolase activity.

  12. KNH2-KH: a metal amide-hydride solid solution.

    Science.gov (United States)

    Santoru, Antonio; Pistidda, Claudio; Sørby, Magnus H; Chierotti, Michele R; Garroni, Sebastiano; Pinatel, Eugenio; Karimi, Fahim; Cao, Hujun; Bergemann, Nils; Le, Thi T; Puszkiel, Julián; Gobetto, Roberto; Baricco, Marcello; Hauback, Bjørn C; Klassen, Thomas; Dornheim, Martin

    2016-09-27

    We report for the first time the formation of a metal amide-hydride solid solution. The dissolution of KH into KNH2 leads to an anionic substitution, which decreases the interaction among NH2(-) ions. The rotational properties of the high temperature polymorphs of KNH2 are thereby retained down to room temperature.

  13. Analogues of both Leu- and Met-enkephalin containing a constrained dipeptide isostere prepared from a Baylis-Hillman adduct.

    Science.gov (United States)

    Galeazzi, Roberta; Martelli, Gianluca; Marcucci, Eleonora; Orena, Mario; Rinaldi, Samuele; Lattanzi, Roberta; Negri, Lucia

    2010-04-01

    An efficient route was developed for the synthesis of the Fmoc-protected dipeptide 4, isostere of Gly-Gly containing an alpha-methylene beta-amino acid; the conformationally restricted analogues of Leu-enkephalin, 3a, and Met-enkephalin, 3b, respectively, were prepared by changing 4 for Gly(2)-Gly(3) in the native compounds 3a and 3b whose biological activities were significantly lower than the parent compounds.

  14. Changes of biological functions of dipeptide transporter (PepT1)and hormonal regulation in severe scald rats

    Institute of Scientific and Technical Information of China (English)

    Bing-Wei Sun; Xiao-Chen Zhao; Guang-Ji Wang; Ning Li; Jie-Shou Li

    2003-01-01

    AIM: To determine the regulatory effects of recombinant human growth hormone (rhGH) on dipeptide transport (PepT1) in normal and severe scald rats.METHODS: Male Sprague-Dawley rats with 30 % total body surface area (TBSA) Ⅲ degree scald were employed as the model. In this study rhGH was used at the dose of 2 IU.kg-1d-1. An everted sleeve of intestine 4 cm long obtained from mid-jejunum was securely incubated in Kreb's solution with radioactive dipeptide (3H-glycylsarcosine, 3H-Gly-Sar,10 μCi/ml) at 37 ℃ for 15 min to measure the effects of uptake and transport of PepT1 of small intestinal epithelial cells in normal and severe scald rats.RESULTS: Abundant blood supply to intestine and mesentery was observed in normal and scald rats administered rhGH,while less supply of blood to intestine and mesentery was observed in rats without rhGH. Compared with controls, the transport of dipeptide in normal rats with injection of rhGH was not significantly increased (P=0.1926), while the uptake was significantly increased (P=0.0253). The effects of transport and uptake of PepT1 in scald rats with injection of rhGH were significantly increased (P=0.0082, 0.0391).CONCLUSION: Blood supply to intestine and mesentery of rats was increased following injection of rhGH. The effects of uptake and transport of dipeptide transporters in small intestinal epithelial cells of rats with severe scald were markedly up-regulated by rhGH.

  15. Identify nature N-acylethanolamide-hydrolyzing acid amide(NAAA)inhibitor: effect of Angelicae Pubescentis Radix on anti-inflammation%独活挥发油对N-脂肪酰基乙醇胺水解酶的抑制作用及抗炎作用研究

    Institute of Scientific and Technical Information of China (English)

    孙文畅; 杨隆河; 邱彦; 任杰; 黄锐; 傅瑾

    2011-01-01

    oil which inhibited NAAA activity in a dose-dependent manner. On the LPS-induced RAW264. 7 cells, APR essential oil reversed LPS-suppressed N-palmitoylethanolamide(PEA) contents in a dose-dependent manner and reduced LPS-induced proinflammatory genes, TNF-α and IL-6. Moreover, APR essential oil reduced the mRNA expression of iNOS, subsequently reduced the release of NO, a classic inflammatory marker. Conclusion: The research demonstrated that the effect of APR on inflammation is mediated by the inhibition of NAAA activity , which increase the cellular endobioactor PEA levels and decrease proinflammatory factor. The results suggest that APR can serve as a nature NAAA inhibitor.

  16. Insecticidal, repellent and fungicidal properties of novel trifluoromethylphenyl amides.

    Science.gov (United States)

    Tsikolia, Maia; Bernier, Ulrich R; Coy, Monique R; Chalaire, Katelyn C; Becnel, James J; Agramonte, Natasha M; Tabanca, Nurhayat; Wedge, David E; Clark, Gary G; Linthicum, Kenneth J; Swale, Daniel R; Bloomquist, Jeffrey R

    2013-09-01

    Twenty trifluoromethylphenyl amides were synthesized and evaluated as fungicides and as mosquito toxicants and repellents. Against Aedes aegypti larvae, N-(2,6-dichloro-4-(trifluoromethyl)phenyl)-3,5-dinitrobenzamide (1e) was the most toxic compound (24 h LC50 1940 nM), while against adults N-(2,6-dichloro-4-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide (1c) was most active (24 h LD50 19.182 nM, 0.5 μL/insect). However, the 24 h LC50 and LD50 values of fipronil against Ae. aegypti larvae and adults were significantly lower: 13.55 nM and 0.787 × 10(-4) nM, respectively. Compound 1c was also active against Drosophila melanogaster adults with 24 h LC50 values of 5.6 and 4.9 μg/cm(2) for the Oregon-R and 1675 strains, respectively. Fipronil had LC50 values of 0.004 and 0.017 μg/cm(2) against the two strains of D. melanogaster, respectively. In repellency bioassays against female Ae. aegypti, 2,2,2-trifluoro-N-(2-(trifluoromethyl)phenyl)acetamide (4c) had the highest repellent potency with a minimum effective dosage (MED) of 0.039 μmol/cm(2) compared to DEET (MED of 0.091 μmol/cm(2)). Compound N-(2-(trifluoromethyl)phenyl)hexanamide (4a) had an MED of 0.091 μmol/cm(2) which was comparable to DEET. Compound 4c was the most potent fungicide against Phomopsis obscurans. Several trends were discerned between the structural configuration of these molecules and the effect of structural changes on toxicity and repellency. Para- or meta- trifluoromethylphenyl amides with an aromatic ring attached to the carbonyl carbon showed higher toxicity against Ae. aegypti larvae, than ortho- trifluoromethylphenyl amides. Ortho- trifluoromethylphenyl amides with trifluoromethyl or alkyl group attached to the carbonyl carbon produced higher repellent activity against female Ae. aegypti and Anopheles albimanus than meta- or para- trifluoromethylphenyl amides. The presence of 2,6-dichloro- substitution on the phenyl ring of the amide had an influence on larvicidal and repellent

  17. Alanylglutamine dipeptide and growth hormone maintain PepT1-mediated transport in oxidatively stressed Caco-2 cells.

    Science.gov (United States)

    Alteheld, B; Evans, M E; Gu, L H; Ganapathy, V; Leibach, F H; Jones, D P; Ziegler, T R

    2005-01-01

    Reactive oxygen species (ROS) produced by gut mucosal cells during conditions such as inflammatory bowel disease (IBD) may impair mucosal repair and nutrient transport/absorptive function. Absorption of di- and tripeptides in the small intestine and colon is mediated by the H(+)-dependent transporter PepT1, but effects of oxidative stress on di- and tripeptide transport are unknown. We assessed whether exposure to hydrogen peroxide (H(2)O(2)) influences dipeptide transport in human colonic epithelial (Caco-2) cells. Uptake of [(14)C]glycylsarcosine (Gly-Sar) was used to evaluate PepT1-mediated dipeptide transport. Exposure to 1-5 mmol/L H(2)O(2) for 24 h caused a dose-dependent decrease in Gly-Sar transport, which was associated with decreased PepT1 transport velocity (V(max)). Treatment with alanylglutamine (Ala-Gln) or growth hormone (GH) did not alter Caco-2 Gly-Sar transport in the absence of H(2)O(2). However, both Ala-Gln and GH prevented the decrease in dipeptide transport observed with 1 mmol/L H(2)O(2) treatment. Ala-Gln, but not GH, maintained cellular glutathione and prevented the decrease in PepT1 protein expression. Thus, these agents should be further investigated as potential therapies to improve absorption of small peptides in disorders associated with oxidative injury to the gut mucosa.

  18. Advances in simultaneous DSC-FTIR microspectroscopy for rapid solid-state chemical stability studies: some dipeptide drugs as examples.

    Science.gov (United States)

    Lin, Shan-Yang; Wang, Shun-Li

    2012-04-01

    The solid-state chemistry of drugs has seen growing importance in the pharmaceutical industry for the development of useful API (active pharmaceutical ingredients) of drugs and stable dosage forms. The stability of drugs in various solid dosage forms is an important issue because solid dosage forms are the most common pharmaceutical formulation in clinical use. In solid-state stability studies of drugs, an ideal accelerated method must not only be selected by different complicated methods, but must also detect the formation of degraded product. In this review article, an analytical technique combining differential scanning calorimetry and Fourier-transform infrared (DSC-FTIR) microspectroscopy simulates the accelerated stability test, and simultaneously detects the decomposed products in real time. The pharmaceutical dipeptides aspartame hemihydrate, lisinopril dihydrate, and enalapril maleate either with or without Eudragit E were used as testing examples. This one-step simultaneous DSC-FTIR technique for real-time detection of diketopiperazine (DKP) directly evidenced the dehydration process and DKP formation as an impurity common in pharmaceutical dipeptides. DKP formation in various dipeptides determined by different analytical methods had been collected and compiled. Although many analytical methods have been applied, the combined DSC-FTIR technique is an easy and fast analytical method which not only can simulate the accelerated drug stability testing but also at the same time enable to explore phase transformation as well as degradation due to thermal-related reactions. This technique offers quick and proper interpretations.

  19. Photochemical reaction of 2-(3-benzoylphenyl)propionic acid (ketoprofen) with basic amino acids and dipeptides.

    Science.gov (United States)

    Suzuki, Tadashi; Shinoda, Mio; Osanai, Yohei; Isozaki, Tasuku

    2013-08-22

    Photoreaction of 2-(3-benzoylphenyl)propionic acid (ketoprofen, KP) with basic amino acids (histidine, lysine, and arginine) and dipeptides (carnosine and anserine) including a histidine moiety in phosphate buffer solution (pH 7.4) has been investigated with transient absorption spectroscopy. With UV irradiation KP(-) gave rise to a carbanion through a decarboxylation reaction, and the carbanion easily abstracted a proton from the surrounding molecule to yield a 3-ethylbenzophenone ketyl biradical (EBPH). The dipeptides as well as the basic amino acids were found to accelerate the proton transfer reaction whereas alanine and glycine had no effect on the reaction, revealing that these amino acids having a protonated side chain act as a proton donor. The formation quantum yield of EBPH was estimated to be fairly large by means of an actinometrical method with benzophenone, and the bimolecular reaction rate constant for the proton transfer between the carbanion and the protonated basic amino acids or the protonated dipeptides was successfully determined. It has become apparent that the bimolecular reaction rate constant for the proton transfer depended on the acid dissociation constant for the side chain of the amino acids for the first time. This reaction mechanism was interpreted by difference of the heat of reaction for each basic amino acid based on the thermodynamical consideration. These results strongly suggest that the side chain of the basic amino acid residue in protein should play an important role for photochemistry of KP in vivo.

  20. Porphyrin amino acids-amide coupling, redox and photophysical properties of bis(porphyrin) amides.

    Science.gov (United States)

    Melomedov, Jascha; Wünsche von Leupoldt, Anica; Meister, Michael; Laquai, Frédéric; Heinze, Katja

    2013-07-14

    New trans-AB2C meso-substituted porphyrin amino acid esters with meso-substituents of tunable electron withdrawing power (B = mesityl, 4-C6H4F, 4-C6H4CF3, C6F5) were prepared as free amines 3a-3d, as N-acetylated derivatives Ac-3a-Ac-3d and corresponding zinc(II) complexes Zn-Ac-3a-Zn-Ac-3d. Several amide-linked bis(porphyrins) with a tunable electron density at each porphyrin site were obtained from the amino porphyrin precursors by condensation reactions (4a-4d) and mono- and bis(zinc(II)) complexes Zn(2)-4d and Zn(1)Zn(2)-4d were prepared. The electronic interaction between individual porphyrin units in bis(porphyrins) 4 is probed by electrochemical experiments (CV, EPR), electronic absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy in combination with DFT/PCM calculations on diamagnetic neutral bis(porphyrins) 4 and on respective charged mixed-valent radicals 4(+/-). The interaction via the -C6H4-NHCO-C6H4- bridge, the site of oxidation and reduction and the lowest excited singlet state S1, is tuned by the substituents on the individual porphyrins and the metalation state.

  1. Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide 18O-labeling.

    Science.gov (United States)

    Shackleford, Jessica P; Shen, Bo; Johnston, Jeffrey N

    2012-01-03

    The mechanism of umpolung amide synthesis was probed by interrogating potential sources for the oxygen of the product amide carbonyl that emanates from the α-bromo nitroalkane substrate. Using a series of (18)O-labeled substrates and reagents, evidence is gathered to advance two pathways from the putative tetrahedral intermediate. Under anaerobic conditions, a nitro-nitrite isomerization delivers the amide oxygen from nitro oxygen. The same homolytic nitro-carbon fragmentation can be diverted by capture of the carbon radical intermediate with oxygen gas (O(2)) to deliver the amide oxygen from O(2). This understanding was used to develop a straightforward protocol for the preparation of (18)O-labeled amides in peptides by simply performing the umpolung amide synthesis reaction under an atmosphere of 18O2.

  2. Synthesis, structure, and reactivity of tris(amidate) mono(amido) and tetrakis(amidate) complexes of group 4 transition metals.

    Science.gov (United States)

    Payne, Philippa R; Thomson, Robert K; Medeiros, Diane M; Wan, Geoff; Schafer, Laurel L

    2013-11-28

    The syntheses of a series of tris(amidate) mono(amido) titanium and zirconium complexes are reported. The binding motif of the amidate ligand has been determined to depend on the size of the metal centre for these sterically demanding N,O-chelating ligands; the larger zirconium metal centre supports three κ(2)-(N,O) bound amidate ligands while the titanium analogue has one ligand bound in a κ(1)-(O) fashion to alleviate steric strain. Reactivity studies indicate that, despite high steric crowding about the tris(amidate) mono(amido) zirconium metal centre, transamination of the reactive dimethylamido ligand can be achieved using aniline. This complex is also an active precatalyst for intramolecular alkene hydroamination, in which protonolysis of one amidate ligand in the presence of excess amine is observed as an initiation step prior to catalytic turnover. Eight-coordinate homoleptic κ(2)-amidate complexes of zirconium and hafnium have also been prepared.

  3. Semi-catalytic reduction of secondary amides to imines and aldehydes.

    Science.gov (United States)

    Lee, Sun-Hwa; Nikonov, Georgii I

    2014-06-21

    Secondary amides can be reduced by silane HSiMe2Ph into imines and aldehydes by a two-stage process involving prior conversion of amides into iminoyl chlorides followed by catalytic reduction mediated by the ruthenium complex [Cp(i-Pr3P)Ru(NCCH3)2]PF6 (1). Alkyl and aryl amides bearing halogen, ketone, and ester groups were converted with moderate to good yields under mild reaction conditions to the corresponding imines and aldehydes. This procedure does not work for substrates bearing the nitro-group and fails for heteroaromatic amides. In the case of cyano substituted amides, the cyano group is reduced to imine.

  4. Effect of the Unsaturation of the Hydrocarbon Chain of Fatty-Amides on the CO2 Corrosion of Carbon Steel Using EIS and Real-Time Corrosion Measurement

    Directory of Open Access Journals (Sweden)

    J. Porcayo-Calderon

    2015-01-01

    Full Text Available Fatty-amide derivatives were evaluated to study the effect of the double bonds into the hydrocarbon chain (C18 on the corrosion behavior of carbon steel. Electrochemical impedance spectroscopy (EIS and real-time corrosion measurements were used to evaluate the inhibition mechanism of the fatty-amides on carbon steel in CO2-saturated (3% NaCl + 10% diesel emulsion at 50°C. EIS results demonstrated that the unsaturation present into the hydrocarbon chain contributes to the efficiency of fatty-amides, because they can be adsorbed on the metal surface by a flat-adsorption process reducing the presence of active sites and blocking the corrosion process and preventing the diffusion of corrosive species, such as H2O, H+, Cl−, and HCO3-. Real-time corrosion measurements also indicated that the effectiveness of the inhibitors is dependent on the unsaturation into the hydrocarbon chain, being also a good technique to determine the stability of the adsorption process of the inhibitors.

  5. Hormonal regulation of dipeptide transporter (PepT1) in Caco-2 cells with normal and anoxia/reoxygenation management

    Institute of Scientific and Technical Information of China (English)

    Bing-Wei Sun; Xiao-Chen Zhao; Guang-Ji Wang; Ning Li; Jie-Shou Li

    2003-01-01

    AIM: To determine the regulation effects of recombinant human growth hormone (rhGH) on dipeptide transporter (PepT1) in Caco-2 cells with normal culture and anoxia/reoxygenation injury.METHODS: A human intestinal cell monolayer (Caco-2) was used as the in vitro model of human small intestine and cephalexin as the model substrate for dipeptide transporter (PepT1). Caco-2 cells grown on Transwell membrane filters were preincubated in the presence of rhGH in the culture medium for 4 d, serum was withdrawn from monolayers for 24 h before each experiment. The transport experiments of cephalexin across apical membromes were then conducted;Caco-2 cells grown on multiple well dishes (24 pore) with normal culture or anoxia/reoxygenation injury were preincubated with rhGH as above and uptake of cephalexin was then measured.RESULTS: The transport and uptake of cephelaxin across apical membranes of Caco-2 cells after preincubation with rhGH were significantly increased compared with controls (P=0.045, 0.0223). Also, addition of rhGH at physiological concentration (34 nM) to incubation medium greatly stimulates cephalexin uptake by anoxia/reoxygenation injuried Caco-2 cells (P=0.0116), while the biological functions of PepT1 in injured Caco-2 cells without rhGH were markedly downregulated. Northem blot analysis showed that the level of PepT1 mRNA of rhGH-treated injured Caco-2cells was greatly increased compared to controls.CONCLUSION: The present results of rhGH stimulating the uptake and transport of cephalexin indicated that rhGH greatly upregulates the physiological effects of dipeptide transporters of Caco-2 cells. The alteration in the gene expression may be a mechanism of regulation of PepT1. In addition, Caco-2 cells take up cephalexin by the Proton-dependent dipeptide transporters that closely resembles the transporters present in the intestine. Caco-2 cells represent an ideal cellular model for future studies of the dipeptide transporter.

  6. A new acylamidase from Rhodococcus erythropolis TA37 can hydrolyze N-substituted amides.

    Science.gov (United States)

    Lavrov, K V; Zalunin, I A; Kotlova, E K; Yanenko, A S

    2010-08-01

    A new acylamidase was isolated from Rhodococcus erythropolis TA37 and characterized. N-Substituted acrylamides (isopropyl acrylamide, N,N-dimethyl-aminopropyl acrylamide, and methylene-bis-acrylamide), acid para-nitroanilides (4'-nitroacetanilide, Gly-pNA, Ala-pNA, Leu-pNA), and N-acetyl derivatives of glycine, alanine, and leucine are good substrates for this enzyme. Aliphatic amides (acetamide, acrylamide, isobutyramide, n-butyramide, and valeramide) are also used as substrates but with less efficiency. The enzyme subunit mass by SDS-PAGE is 55 kDa. Maximal activity is exhibited at pH 7-8 and 55°C. The enzyme is stable for 15 h at 22°C and for 0.5 h at 45°C. The Michaelis constant (K(m)) is 0.25 mM with Gly-pNA and 0.55 mM with Ala-pNA. The acylamidase activity is suppressed by inhibitors of serine proteases (phenylmethylsulfonyl fluoride and diisopropyl fluorophosphate) but is not suppressed by inhibitors of aliphatic amidases (acetaldehyde and nitrophenyl disulfides). The N-terminal amino acid sequence of the acylamidase is highly homologous to those of two putative amidases detected from sequenced R. erythropolis genomes. It is suggested that the acylamidase together with the detected homologs forms a new class within the amidase signature family.

  7. Amide I'-II' 2D IR spectroscopy provides enhanced protein secondary structural sensitivity.

    Science.gov (United States)

    Deflores, Lauren P; Ganim, Ziad; Nicodemus, Rebecca A; Tokmakoff, Andrei

    2009-03-11

    We demonstrate how multimode 2D IR spectroscopy of the protein amide I' and II' vibrations can be used to distinguish protein secondary structure. Polarization-dependent amide I'-II' 2D IR experiments on poly-l-lysine in the beta-sheet, alpha-helix, and random coil conformations show that a combination of amide I' and II' diagonal and cross peaks can effectively distinguish between secondary structural content, where amide I' infrared spectroscopy alone cannot. The enhanced sensitivity arises from frequency and amplitude correlations between amide II' and amide I' spectra that reflect the symmetry of secondary structures. 2D IR surfaces are used to parametrize an excitonic model for the amide I'-II' manifold suitable to predict protein amide I'-II' spectra. This model reveals that the dominant vibrational interaction contributing to this sensitivity is a combination of negative amide II'-II' through-bond coupling and amide I'-II' coupling within the peptide unit. The empirically determined amide II'-II' couplings do not significantly vary with secondary structure: -8.5 cm(-1) for the beta sheet, -8.7 cm(-1) for the alpha helix, and -5 cm(-1) for the coil.

  8. Simultaneous determination of doxorubicin and its dipeptide prodrug in mice plasma by HPLC with fluorescence detection

    Directory of Open Access Journals (Sweden)

    Jing Han

    2016-06-01

    Full Text Available A simple and sensitive high performance liquid chromatography with fluorescence detection (HPLC–FD has been developed for simultaneous quantification of doxorubicin (DOX and its dipeptide conjugate prodrug (PDOX in mice plasma. The chromatographic separation was carried out on an Amethyst C18–H column with gradient mobile phase of 0.1% formic acid and 0.1% formic acid in acetonitrile at a flow rate of 1.0 mL/min. The excitation and emission wavelengths were set at 490 and 550 nm, respectively. The method was comprehensively validated. The limits of detection were low up to 5.0 ng/mL for DOX and 25.0 ng/mL for PDOX. And the limits of quantification were low up to 12.5 ng/mL for DOX and 50 ng/mL for PDOX, which were lower than those for most of the current methods. The calibration curves showed good linearity (R2>0.999 over the concentration ranges. The extraction recoveries ranged from 84.0% to 88.2% for DOX and from 85.4% to 89.2% for PDOX. Satisfactory intra-day and inter-day precisions were achieved with RSDs less than 9.1%. The results show that the developed HPLC–FD method is accurate, reliable and will be helpful for preclinical pharmacokinetic study of DOX and PDOX.

  9. Bacterial Muramyl Dipeptide (MDP) Restricts Human Cytomegalovirus Replication via an IFN-β-Dependent Pathway.

    Science.gov (United States)

    Kapoor, Arun; Fan, Yi-Hsin; Arav-Boger, Ravit

    2016-02-02

    We recently reported that induction of NOD2 by human Cytomegalovirus (HCMV) resulted in virus inhibition and upregulation of antiviral and inflammatory cytokines. Here we investigated the effects of muramyl dipeptide (MDP), a bacterial cell wall component that activates NOD2, on HCMV replication and antiviral responses. HCMV infection of human foreskin fibroblasts induced NOD2, the downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2), resulting in phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). MDP treatment following infection at low multiplicity (MOI = 0.1 PFU/cell) inhibited HCMV in a dose-dependent manner and further induced phosphorylation of TBK1, IRF3 and expression of IFN-β. None of these effects of MDP were observed following infection at multiplicity of 1. In infected NOD2 knocked-down cells MDP did not induce IFN-β, irrespective of MOI. Treatment with MDP before infection also inhibited HCMV, an effect augmented with treatment duration. Treatment with an IFN-β receptor blocking antibody or knockdown of IFN-β significantly attenuated the inhibitory effect of MDP on HCMV. MDP treatment before or after infection with herpesvirus 1 did not inhibit its replication. Summarized, NOD2 activation exerts anti-HCMV activities predominantly via IFN-β. Since MDP is a bacterial cell wall component, ongoing microbial exposure may influence HCMV replication.

  10. Simultaneous determination of doxorubicin and its dipeptide prodrug in mice plasma by HPLC with fluorescence detection$

    Institute of Scientific and Technical Information of China (English)

    Jing Han; Jue Zhang; Haiyan Zhao; Yan Li; Zilin Chen

    2016-01-01

    A simple and sensitive high performance liquid chromatography with fluorescence detection (HPLC–FD) has been developed for simultaneous quantification of doxorubicin (DOX) and its dipeptide conjugate prodrug (PDOX) in mice plasma. The chromatographic separation was carried out on an Amethyst C18–H column with gradient mobile phase of 0.1%formic acid and 0.1%formic acid in acetonitrile at a flow rate of 1.0 mL/min. The excitation and emission wavelengths were set at 490 and 550 nm, respectively. The method was comprehensively validated. The limits of detection were low up to 5.0 ng/mL for DOX and 25.0 ng/mL for PDOX. And the limits of quantification were low up to 12.5 ng/mL for DOX and 50 ng/mL for PDOX, which were lower than those for most of the current methods. The calibration curves showed good linearity (R2 4 0.999) over the concentration ranges. The extraction recoveries ranged from 84.0%to 88.2% for DOX and from 85.4% to 89.2% for PDOX. Satisfactory intra-day and inter-day precisions were achieved with RSDs less than 9.1%. The results show that the developed HPLC–FD method is accurate, reliable and will be helpful for preclinical pharmacokinetic study of DOX and PDOX.

  11. Modulation of natural killer cytotoxicity by muramyl dipeptide and trehalose dimycolate incorporated in squalane droplets.

    Science.gov (United States)

    Masihi, K N; Lange, W; Rohde-Schulz, B

    1987-01-01

    The effect on natural killer (NK) cytotoxicity of splenic cells from BALB/c mice pretreated i.v. with squalane-in-water preparations of muramyl dipeptide (MDP), trehalose dimycolate (TDM), or the combination of MDP-plus-TDM was investigated. MDP or TDM augmented the NK cytotoxicity which peaked 48 h after the pretreatment whereas the combination of MDP and TDM induced an inhibition of the NK activity. Infection with influenza virus, a potent stimulator of NK cells, after the pretreatment with biological response modifiers resulted in a markedly enhanced NK activity on day 2 in MDP and control groups. Mice pretreated with TDM or the combination of MDP and TDM showed only moderate NK activity which peaked on day 3 after influenza infection. The NK activity was susceptible to asialo GM1 and complement treatment. The cytotoxicity of MDP-plus-TDM cells could be significantly enhanced after treatment with anti-macrophage monoclonal antibody and complement. NK activity induced by MDP or TDM was reduced by mixing MDP-plus-TDM cells. Addition of adherent cell-depleted MDP-plus-TDM suspension to MDP or TDM cells had a NK restorative effect. Splenic cells from mice pretreated 2 days earlier with MDP or TDM, but not MDP-plus-TDM, generated enhanced levels of luminol-dependent chemiluminescence.

  12. Dipeptide Mimetic of the Brain-derived Neurotrophic Factor Prevents Impairments of Neurogenesis in Stressed Mice.

    Science.gov (United States)

    Gudasheva, T A; Povarnina, P Yu; Seredenin, S B

    2017-02-01

    Brain-derived neurotrophic factor (BDNF) plays the central role in the mechanisms of regulation of neurogenesis and neuroplasticity. Impairment of these mechanisms is considered as one of the main etiological factors of depression. Dimeric dipeptide mimetic of BDNF loop 4 bis-(N-monosuccinyl-l-seryl-l-lysine) hexamethylenediamide (GSB-106) was synthesized at the V. V. Zakusov Research Institute of Pharmacology. In vivo experiments revealed significant antidepressant properties of GSB-106 in doses of 0.1-10 mg/kg (intraperitoneally and orally). Effects of GSB-106 on hippocampal neurogenesis were studied in mice subjected to chronic predator stress. Proliferative activity in the subgranular zone of the dental gyrus was assessed immunohistochemically by Ki-67 expression (a marker of dividing cells). It was found that GSB-106 (10 mg/kg, intraperitoneally, 5 days) completely prevents neurogenesis disturbances in stressed mice. These findings suggest that GSB-106 is a promising candidate for the development of antidepressant agents with BDNF-like mechanism of action.

  13. A dipeptide transporter from the arbuscular mycorrhizal fungus Rhizophagus irregularis is upregulated in the intraradical phase

    Science.gov (United States)

    Belmondo, Simone; Fiorilli, Valentina; Pérez-Tienda, Jacob; Ferrol, Nuria; Marmeisse, Roland; Lanfranco, Luisa

    2014-01-01

    Arbuscular mycorrhizal fungi (AMF), which form an ancient and widespread mutualistic symbiosis with plants, are a crucial but still enigmatic component of the plant micro biome. Nutrient exchange has probably been at the heart of the success of this plant-fungus interaction since the earliest days of plants on land. To characterize genes from the fungal partner involved in nutrient exchange, and presumably important for the functioning of the AM symbiosis, genome-wide transcriptomic data obtained from the AMF Rhizophagus irregularis were exploited. A gene sequence, showing amino acid sequence and transmembrane domains profile similar to members of the PTR2 family of fungal oligopeptide transporters, was identified and called RiPTR2. The functional properties of RiPTR2 were investigated by means of heterologous expression in Saccharomyces cerevisiae mutants defective in either one or both of its di/tripeptide transporter genes PTR2 and DAL5. These assays showed that RiPTR2 can transport dipeptides such as Ala-Leu, Ala-Tyr or Tyr-Ala. From the gene expression analyses it seems that RiPTR2 responds to different environmental clues when the fungus grows inside the root and in the extraradical phase. PMID:25232358

  14. The discovery and potential of N-sulfonylated dipeptide VLA-4 antagonists.

    Science.gov (United States)

    Hagmann, William K

    2004-01-01

    Through a directed screening of a combinatorial library containing carboxylic acids, N-sulfonylated dipeptides were identified as leads in the Merck Research Laboratories VLA-4 antagonist program. Further optimization quickly identified subnanomolar compounds with varying degrees of specificity over the related integrin alpha4beta7. Various metabolic liabilities were identified and addressed. However, the pharmacokinetic properties of nearly all compounds in this class were unacceptable. Other leads were identified with apparent good oral bioavailability, but these were generally associated with very high plasma protein binding and a loss of potency. The mechanism of high plasma clearance was identified in the rat as the organic acid transporter, mrp-2. Compounds were identified that were not substrates of mrp-2, but they still suffered from poor oral bioavailability. Finally, a shift in strategy to identifying VLA-4 antagonists that would be suitable as candidates for inhalation therapy resulted in the preparation of compounds with exception tight binding properties. These compounds were superior to BIO-1211 in the ovalbumin-sensitized mouse model of eosinophil trafficking to the lung. One particular compound had an exceptionally long off-rate with a KD < or = 2 pM. The evolution of the structure activity relationships in our laboratories and strategies for improving potencies and pharmacokinetic profiles are the subject of this review.

  15. Enhanced transdermal delivery of 5-aminolevulinic acid and a dipeptide by iontophoresis.

    Science.gov (United States)

    Krishnan, Gayathri; Roberts, Michael S; Grice, Jeffrey; Anissimov, Yuri G; Benson, Heather A E

    2011-01-01

    Poor skin permeability limits the application of peptides to the skin. Enhanced skin permeation could facilitate the development of new therapies for dermatologic and cosmeceutical applications. The aim of this study was to investigate the application of iontophoresis to the delivery of small peptide model compounds (5-aminolevulinic acid and L-alanine-L-tryptophan) across human skin. Under the conditions tested, iontophoresis increased the in vitro permeability coefficient of ALA.HCl across human epidermis from 7 X 10(-5) cm/h with passive diffusion to 110 x 10(-5) cm/h with iontophoresis. D-Glucose permeation elucidated the iontophoretic electrotransport of ALA.HCl to have contributions of both electrorepulsion and electroosmosis. The L-alanine-L-tryptophan permeability coefficient was increased from 1.5 x 10(-5) cm/h to 35 x 10(-5) cm/h with iontophoretic application. Iontophoretic delivery of the dipeptide increased markedly at lower pH because of an increase in electrorepulsive transport. The study demonstrates that iontophoresis can enhance epidermal permeation of a small peptide and peptide-like drug by up to 15- and 22-fold under the conditions tested.

  16. In vivo behavior of hydrogel beads based on amidated pectins.

    Science.gov (United States)

    Munjeri, O; Collett, J H; Fell, J T; Sharma, H L; Smith, A M

    1998-01-01

    Radio-labeled hydrogel beads, based on amidated pectin, have been produced by adding droplets of an amidated pectin solution to calcium chloride. Incorporation of model drugs into the beads and measurement of the dissolution rate showed that the properties of the beads were unaffected by the incorporation of the radiolabel. The labeled beads were used to carry out an in vivo study of their behavior in the gastrointestinal tract using human volunteers. The volunteers were given the beads after an overnight fast and images were obtained at frequent intervals during transit through the upper gastrointestinal tract and the colon. The beads exhibited rapid gastric emptying and proceeded to pass through the small intestine individually before regrouping at the ileo-caecal junction. Once in the colon, the beads again proceeded as individuals and evidence of the degradation of the beads was observed.

  17. Simulations of the temperature dependence of amide I vibration.

    Science.gov (United States)

    Kaminský, Jakub; Bouř, Petr; Kubelka, Jan

    2011-01-13

    For spectroscopic studies of peptide and protein thermal denaturation it is important to single out the contribution of the solvent to the spectral changes from those originated in the molecular structure. To obtain insights into the origin and size of the temperature solvent effects on the amide I spectra, combined molecular dynamics and density functional simulations were performed with the model N-methylacetamide molecule (NMA). The computations well reproduced frequency and intensity changes previously observed in aqueous NMA solutions. An empirical correction of vacuum frequencies in single NMA molecule based on the electrostatic potential of the water molecules provided superior results to a direct density functional average obtained for a limited number of solute-solvent clusters. The results thus confirm that the all-atom quantum and molecular mechanics approach captures the overall influence of the temperature dependent solvent properties on the amide I spectra and can improve the accuracy and reliability of molecular structural studies.

  18. Cleavage of an amide bond by a ribozyme

    Science.gov (United States)

    Dai, X.; De Mesmaeker, A.; Joyce, G. F.; Miller, S. L. (Principal Investigator)

    1995-01-01

    A variant form of a group I ribozyme, optimized by in vitro evolution for its ability to catalyze magnesium-dependent phosphoester transfer reactions involving DNA substrates, also catalyzes the cleavage of an unactivated alkyl amide when that linkage is presented in the context of an oligodeoxynucleotide analog. Substrates containing an amide bond that joins either two DNA oligos, or a DNA oligo and a short peptide, are cleaved in a magnesium-dependent fashion to generate the expected products. The first-order rate constant, kcat, is 0.1 x 10(-5) min-1 to 1 x 10(-5) min-1 for the DNA-flanked substrates, which corresponds to a rate acceleration of more than 10(3) as compared with the uncatalyzed reaction.

  19. Neighboring amide participation in thioether oxidation: relevance to biological oxidation.

    Science.gov (United States)

    Glass, Richard S; Hug, Gordon L; Schöneich, Christian; Wilson, George S; Kuznetsova, Larisa; Lee, Tang-man; Ammam, Malika; Lorance, Edward; Nauser, Thomas; Nichol, Gary S; Yamamoto, Takuhei

    2009-09-30

    To investigate neighboring amide participation in thioether oxidation, which may be relevant to brain oxidative stress accompanying beta-amyloid peptide aggregation, conformationally constrained methylthionorbornyl derivatives with amido moieties were synthesized and characterized, including an X-ray crystallographic study of one of them. Electrochemical oxidation of these compounds, studied by cyclic voltammetry, revealed that their oxidation peak potentials were less positive for those compounds in which neighboring group participation was geometrically possible. Pulse radiolysis studies provided evidence for bond formation between the amide moiety and sulfur on one-electron oxidation in cases where the moieties are juxtaposed. Furthermore, molecular constraints in spiro analogues revealed that S-O bonds are formed on one-electron oxidation. DFT calculations suggest that isomeric sigma*(SO) radicals are formed in these systems.

  20. Halo substituent effects on intramolecular cycloadditions involving furanyl amides.

    Science.gov (United States)

    Padwa, Albert; Crawford, Kenneth R; Straub, Christopher S; Pieniazek, Susan N; Houk, K N

    2006-07-21

    Intramolecular Diels-Alder reactions involving a series of N-alkenyl-substituted furanyl amides were investigated. Stable functionalized oxanorbornenes were formed in high yield upon heating at 80-110 degrees C. The cycloaddition reactions include several bromo-substituted furanyl amides, and these systems were found to proceed at a much faster rate and in higher yield than without substitution. This effect was observed by incorporating a halogen in the 3- or 5-position of the furan ring and appears to be general. The origin of increased cycloaddition rates for halo-substituted furans has been investigated with quantum mechanical calculations. The success of these reactions is attributed to increases in reaction exothermicities; this both decreases activation enthalpies and increases barriers to retrocycloadditions. Halogen substitution on furan increases reactant energy and stabilizes the product, which is attributed to the preference of electronegative halogens to be attached to a more highly alkylated and therefore more electropositive framework.

  1. Coumarin amide derivatives as fluorescence chemosensors for cyanide anions

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Qianqian [School of Material Science and Engineering, Shandong Provincial Key Laboratory of Preparation and Measurement of Building Materials, University of Jinan, Jinan 250022, Shandong (China); Liu, Zhiqiang [State Key Laboratory of Crystal Materials, Shandong University, Jinan 250100, Shandong (China); Cao, Duxia, E-mail: duxiacao@ujn.edu.cn [School of Material Science and Engineering, Shandong Provincial Key Laboratory of Preparation and Measurement of Building Materials, University of Jinan, Jinan 250022, Shandong (China); Guan, Ruifang, E-mail: mse_guanrf@ujn.edu.cn [School of Material Science and Engineering, Shandong Provincial Key Laboratory of Preparation and Measurement of Building Materials, University of Jinan, Jinan 250022, Shandong (China); Wang, Kangnan; Shan, Yanyan; Xu, Yongxiao; Ma, Lin [School of Material Science and Engineering, Shandong Provincial Key Laboratory of Preparation and Measurement of Building Materials, University of Jinan, Jinan 250022, Shandong (China)

    2015-07-01

    Four coumarin amide derivatives with 4-methyl coumarin or pyrene as terminal group have been synthesized. Their photophysical properties and recognition properties for cyanide anions have been examined. The results indicate that the compounds can recognize cyanide anions with obvious absorption and fluorescence spectra change, at the same time, obvious color and fluorescence change can be observed by naked eye. The in situ hydrogen nuclear magnetic resonance spectra and photophysical properties change confirm that Michael additions between the chemosensors and cyanide anions take place at the 4-position of coumarin. - Highlights: • Four coumarin amide derivatives with 4-methyl coumarin or pyrene as terminal group were synthesized. • The compounds can recognize cyanide anions with obvious absorption and fluorescence spectra change. • Michael additions between the chemosensors and cyanide anions take place at the 4-position of coumarin.

  2. Enzymatic synthesis of fatty amides from palm olein.

    Science.gov (United States)

    Al-Mulla, Emad A Jaffar; Yunus, Wan Md Zin Wan; Ibrahim, Nor Azowa Bt; Rahman, Mohd Zaki A

    2010-01-01

    Fatty amides have been successfully synthesized from palm olein and urea by a one-step lipase catalyzed reaction. The use of immobilized lipase as the catalyst for the preparation reaction provides an easy isolation of the enzyme from the products and other components in the reaction mixture. The fatty amides were characterized using Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance ((1)H NMR) technique and elemental analysis. The highest conversion percentage (96%) was obtained when the process was carried out for 36 hours using urea to palm oil ratio of 5.2: 1.0 at 40 degrees C. The method employed offers several advantages such as renewable and abundant of the raw material, simple reaction procedure, environmentally friendly process and high yield of the product.

  3. Solution-phase submonomer diversification of aza-dipeptide building blocks and their application in aza-peptide and aza-DKP synthesis.

    Science.gov (United States)

    Bourguet, Carine B; Proulx, Caroline; Klocek, Sophie; Sabatino, David; Lubell, William D

    2010-06-01

    Aza-peptides have been used as tools for studying SARs in programs aimed at drug discovery and chemical biology. Protected aza-dipeptides were synthesized by a solution-phase submonomer approach featuring alkylation of N-terminal benzophenone semicarbazone aza-Gly-Xaa dipeptides using different alkyl halides in the presence of potassium tert-butoxide as base. Benzophenone protected aza-dipeptide tert-butyl ester 31c was selectively deprotected at the C-terminal ester or N-terminal hydrazone to afford, respectively, aza-dipeptide acid and amine building blocks 36c and 40c, which were introduced into longer aza-peptides. Alternatively, removal of the benzophenone semicarbazone protection from aza-dipeptide methyl esters 29a-c led to intramolecular cyclization to produce aza-DKPs 39a-c. In light of the importance of aza-peptides and DKPs as therapeutic agents and probes of biological processes, this diversity-oriented solution-phase approach may provide useful tools for studying peptide science. (c) 2010 European Peptide Society and John Wiley & Sons, Ltd.

  4. T. thermophila group I introns that cleave amide bonds

    Science.gov (United States)

    Joyce, Gerald F. (Inventor)

    1997-01-01

    The present invention relates to nucleic acid enzymes or enzymatic RNA molecules that are capable of cleaving a variety of bonds, including phosphodiester bonds and amide bonds, in a variety of substrates. Thus, the disclosed enzymatic RNA molecules are capable of functioning as nucleases and/or peptidases. The present invention also relates to compositions containing the disclosed enzymatic RNA molecule and to methods of making, selecting, and using such enzymes and compositions.

  5. Total chemical synthesis of lassomycin and lassomycin-amide.

    Science.gov (United States)

    Lear, S; Munshi, T; Hudson, A S; Hatton, C; Clardy, J; Mosely, J A; Bull, T J; Sit, C S; Cobb, S L

    2016-05-11

    Herein we report a practical synthetic route to the lasso peptide lassomycin () and C-terminal variant lassomycin-amide (). The biological evaluation of peptides and against Mycobacterium tuberculosis revealed that neither had any activity against this bacterium. This lack of biological activity has led us to propose that naturally occurring lassomycin may actually exhibit a standard lasso peptide threaded conformation rather than the previously reported unthreaded structure.

  6. Guidelines for Middle Managers for Thriving amid Continuous Change

    OpenAIRE

    2016-01-01

    This thesis suggests the much needed guidelines for middle managers for thriving amid continuous change. Middle managers, being an integral part of their organizations, needed a set of consolidated guidelines for thriving in the times of continuous change. Thriving requires high engagement, learning and growth as a response in stressful situations. The proposed guidelines include elements from literature and recommendations of the middle managers which came from co-creation sessions with midd...

  7. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

    Science.gov (United States)

    Besidski, Yevgeni; Brown, William; Bylund, Johan; Dabrowski, Michael; Dautrey, Sophie; Harter, Magali; Horoszok, Lucy; Hu, Yin; Johnson, Dean; Johnstone, Shawn; Jones, Paul; Leclerc, Sandrine; Kolmodin, Karin; Kers, Inger; Labarre, Maryse; Labrecque, Denis; Laird, Jennifer; Lundström, Therese; Martino, John; Maudet, Mickaël; Munro, Alexander; Nylöf, Martin; Penwell, Andrea; Rotticci, Didier; Slaitas, Andis; Sundgren-Andersson, Anna; Svensson, Mats; Terp, Gitte; Villanueva, Huascar; Walpole, Christopher; Zemribo, Ronald; Griffin, Andrew M

    2012-10-01

    Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.

  8. Yttrium alkyl complexes with triamino-amide ligands

    NARCIS (Netherlands)

    Bambirra, Sergio; Boot, Steven J.; Leusen, Daan van; Meetsma, Auke; Hessen, Bart

    2004-01-01

    Two new monoanionic tetradentate triamino-amide ligands, [(Me2NCH2CH2)(2)N-B-N(t-Bu)](-) (B = (CH2)(2), L-1; SiMe2, L-2) were prepared. Reaction of LIH with Y(CH2SiMe3)(3)(THF)(2) yielded (LY)-Y-1(CH2SiMe3)(2) (1), which was structurally characterized. Compound 1 decomposes at ambient temperature vi

  9. Accumulation of hydroxycinnamic acid amides in winter wheat under snow.

    Science.gov (United States)

    Jin, Shigeki; Yoshida, Midori; Nakajima, Takashi; Murai, Akio

    2003-06-01

    It was found that the content of antifungal compounds p-coumaroylagmatine [1-(trans-4'-hydroxycinnamoylamino)-4-guanidinobutane] and p-coumaroyl-3-hydroxyagmatine [1-(trans-4'-hydroxycinnamoylamino)-3-hydroxy-4-guanidinobutane] in the crown of winter wheat (Triticum aestivum L. cv Chihokukomugi) significantly increased under snow cover. This finding suggests that the accumulation of these hydroxycinnamic acid amides was caused by winter stress and related to protecting the plant against snow mold under snow cover.

  10. Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

    DEFF Research Database (Denmark)

    Cao, Jianjing; Slack, Rachel D.; Bakare, Oluyomi M.

    2016-01-01

    pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl...

  11. Synthesis, morphology and properties of segmented poly(ether ester amide)s comprising uniform glycine or β-alanine extended bisoxalamide hard segments

    NARCIS (Netherlands)

    Sijbrandi, N.J.; Kimenai, A.J.; Mes, E.P.C.; Broos, R.; Bar, G.; Rosenthal, M.; Odarchenko, Y.; Ivanov, D.A.; Feijen, J.; Dijkstra, P.J.

    2012-01-01

    Segmented poly(ether ester amide)s comprising glycine or β-alanine extended bisoxalamide hard segments are highly phase separated thermoplastic elastomers with a broad temperature independent rubber plateau. These materials with molecular weights, Mn, exceeding 30 × 103 g mol−1 are conveniently prep

  12. An efficient computational model to predict protonation at the amide nitrogen and reactivity along the C-N rotational pathway.

    Science.gov (United States)

    Szostak, Roman; Aubé, Jeffrey; Szostak, Michal

    2015-04-14

    N-Protonation of amides is critical in numerous biological processes, including amide bonds proteolysis and protein folding as well as in organic synthesis as a method to activate amide bonds towards unconventional reactivity. A computational model enabling prediction of protonation at the amide bond nitrogen atom along the C-N rotational pathway is reported. Notably, this study provides a blueprint for the rational design and application of amides with a controlled degree of rotation in synthetic chemistry and biology.

  13. Probing the bioactive conformation of an archetypal natural product HDAC inhibitor with conformationally homogeneous triazole-modified cyclic tetrapeptides.

    Science.gov (United States)

    Horne, W Seth; Olsen, Christian A; Beierle, John M; Montero, Ana; Ghadiri, M Reza

    2009-01-01

    Fooling enzymes with mock amides: Analogues of apicidin, a cyclic-tetrapeptide inhibitor of histone deacetylase (HDAC), were designed with a 1,4- or 1,5-disubstituted 1,2,3-triazole in place of a backbone amide bond to fix the bond in question in either a trans-like or a cis-like configuration. Thus, the binding affinity of distinct peptide conformations (see picture) could be probed. One analogue proved in some cases to be superior to apicidin as an HDAC inhibitor.

  14. The discovery of novel tartrate-based TNF-[alpha] converting enzyme (TACE) inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Rosner, Kristin E.; Guo, Zhuyan; Orth, Peter; Shipps, Jr., Gerald W.; Belanger, David B.; Chan, Tin Yau; Curran, Patrick J.; Dai, Chaoyang; Deng, Yongqi; Girijavallabhan, Vinay M.; Hong, Liwu; Lavey, Brian J.; Lee, Joe F.; Li, Dansu; Liu, Zhidan; Popovici-Muller, Janeta; Ting, Pauline C.; Vaccaro, Henry; Wang, Li; Wang, Tong; Yu, W.; Zhou, G.; Niu, X.; Sun, J.; Kozlowski, J.A.; Lundell, D.J.; Madison, V.; McKittrick, B.; Piwinski, J.J.; Shih, N.Y.; Siddiqui, M. Arshad; Strickland, Corey O. (SPRI)

    2010-09-17

    A novel series of TNF-{alpha} convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.

  15. Immobilization of chiral enzyme inhibitors on solid supports by amide-forming coupling and olefin metathesis

    NARCIS (Netherlands)

    Reetz, MT; Ruggeberg, CJ; Droge, MJ; Quax, WJ

    2002-01-01

    The question whether phage display can be used as a selection method in the directed evolution of enantioselective enzymes has not been answered satisfactorily to date. In order to be able to test this in a specific case, namely in the hydrolytic kinetic resolution of the acetate derived from alpha,

  16. Single-conformation infrared spectra of model peptides in the amide I and amide II regions: experiment-based determination of local mode frequencies and inter-mode coupling.

    Science.gov (United States)

    Buchanan, Evan G; James, William H; Choi, Soo Hyuk; Guo, Li; Gellman, Samuel H; Müller, Christian W; Zwier, Timothy S

    2012-09-07

    Single-conformation infrared spectra in the amide I and amide II regions have been recorded for a total of 34 conformations of three α-peptides, three β-peptides, four α/β-peptides, and one γ-peptide using resonant ion-dip infrared spectroscopy of the jet-cooled, isolated molecules. Assignments based on the amide NH stretch region were in hand, with the amide I/II data providing additional evidence in favor of the assignments. A set of 21 conformations that represent the full range of H-bonded structures were chosen to characterize the conformational dependence of the vibrational frequencies and infrared intensities of the local amide I and amide II modes and their amide I/I and amide II/II coupling constants. Scaled, harmonic calculations at the DFT M05-2X/6-31+G(d) level of theory accurately reproduce the experimental frequencies and infrared intensities in both the amide I and amide II regions. In the amide I region, Hessian reconstruction was used to extract local mode frequencies and amide I/I coupling constants for each conformation. These local amide I frequencies are in excellent agreement with those predicted by DFT calculations on the corresponding (13)C = (18)O isotopologues. In the amide II region, potential energy distribution analysis was combined with the Hessian reconstruction scheme to extract local amide II frequencies and amide II/II coupling constants. The agreement between these local amide II frequencies and those obtained from DFT calculations on the N-D isotopologues is slightly worse than for the corresponding comparison in the amide I region. The local mode frequencies in both regions are dictated by a combination of the direct H-bonding environment and indirect, "backside" H-bonds to the same amide group. More importantly, the sign and magnitude of the inter-amide coupling constants in both the amide I and amide II regions is shown to be characteristic of the size of the H-bonded ring linking the two amide groups. These amide I/I and

  17. Dipeptide Formation from Amino Acid Monomer Induced by keV Ion Irradiation: An Implication for Physicochemical Repair by Radiation Itself

    Institute of Scientific and Technical Information of China (English)

    WANG Wei; YUAN Hang; WANG Xiangqin; YU Zengliang

    2008-01-01

    An identification of Phe dipeptide from L-phenylalanine monomers after keV nitro-gen and argon ion implantation, by using the HPLC (high performance liquid chromatography) and LC-MS(liquid chromatography mass spectrometer) methods is reported. The results showed a similar yield behavior for both ion species, namely: 1) the yield of dipeptides under alkalescent conditions was distinctly higher than that under acidic or neutral conditions; 2) for different ion species, the dose-yield curves tracked a similar trend which was called a counter-saddle curve. The dipeptide formation may implicate a recombination repair mechanism of damaged biomolecules that energetic ions have left in their wake. Accordingly a physicochemical self-repair mechanism by radiation itself for the ion-beam radiobiological effects is proposed.

  18. Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept

    Science.gov (United States)

    Vakhitova, Y. V.; Sadovnikov, S. V.; Borisevich, S. S.; Ostrovskaya, R. U.; A.Gudasheva, T.; Seredenin, S. B.

    2016-01-01

    This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide. PMID:27099787

  19. Defective small intestinal anion secretion, dipeptide absorption, and intestinal failure in suckling NBCe1-deficient mice.

    Science.gov (United States)

    Yu, Qin; Liu, Xuemei; Liu, Yongjian; Riederer, Brigitte; Li, Taolang; Tian, De-An; Tuo, Biguang; Shull, Gary; Seidler, Ursula

    2016-08-01

    The electrogenic Na(+)HCO3 (-) cotransporter NBCe1 (Slc4a4) is strongly expressed in the basolateral enterocyte membrane in a villous/surface predominant fashion. In order to better understand its physiological function in the intestine, isolated mucosae in miniaturized Ussing chambers and microdissected intestinal villi or crypts loaded with the fluorescent pH-indicator BCECF were studied from the duodenum, jejunum, and colon of 14- to 17-days-old slc4a4-deficient (KO) and WT mice. NBCe1 was active in the basal state in all intestinal segments under study, most likely to compensate for acid loads imposed upon the enterocytes. Upregulation of other basolateral base uptake mechanism occurs, but in a segment-specific fashion. Loss of NBCe1 resulted in severely impaired Cl(-) and fluid secretory response, but not HCO3 (-) secretory response to agonist stimulation. In addition, NBCe1 was found to be active during transport processes that load the surface enterocytes with acid, such as Slc26a3 (DRA)-mediated luminal Cl(-)/HCO3 (-) exchange or PEPT1-mediated H(+)/dipeptide uptake. Possibly because of the high energy demand for hyperventilation in conjunction with the fluid secretory and nutrient absorptive defects and the relative scarcity of compensatory mechanisms, NBCe1-deficient mice developed progressive jejunal failure, worsening of metabolic acidosis, and death in the third week of life. Our data suggest that the electrogenic influx of base via NBCe1 maintains enterocyte anion homeostasis and pHi control. Its loss impairs small intestinal Cl(-) and fluid secretion as well as the neutralization of acid loads imposed on the enterocytes during nutrient and electrolyte absorption.

  20. Screening of soy protein-derived hypotriglyceridemic di-peptides in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Matsui Toshiro

    2011-05-01

    Full Text Available Abstract Background Soy protein and soy peptides have attracted considerable attention because of their potentially beneficial biological properties, including antihypertensive, anticarcinogenic, and hypolipidemic effects. Although soy protein isolate contains several bioactive peptides that have distinct physiological activities in lipid metabolism, it is not clear which peptide sequences are responsible for the triglyceride (TG-lowering effects. In the present study, we investigated the effects of soy protein-derived peptides on lipid metabolism, especially TG metabolism, in HepG2 cells and obese Otsuka Long-Evans Tokushima fatty (OLETF rats. Results In the first experiment, we found that soy crude peptide (SCP-LD3, which was prepared by hydrolyze of soy protein isolate with endo-type protease, showed hypolipidemic effects in HepG2 cells and OLETF rats. In the second experiment, we found that hydrophilic fraction, separated from SCP-LD3 with hydrophobic synthetic absorbent, revealed lipid-lowering effects in HepG2 cells and OLETF rats. In the third experiment, we found that Fraction-C (Frc-C peptides, fractionated from hydrophilic peptides by gel permeation chromatography-high performance liquid chromatography, significantly reduced TG synthesis and apolipoprotein B (apoB secretion in HepG2 cells. In the fourth experiment, we found that the fraction with 0.1% trifluoroacetic acid, isolated from Frc-C peptides by octadecylsilyl column chromatography, showed hypolipidemic effects in HepG2 cells. In the final experiment, we found that 3 di-peptides, Lys-Ala, Val-Lys, and Ser-Tyr, reduced TG synthesis, and Ser-Tyr additionally reduced apoB secretion in HepG2 cells. Conclusion Novel active peptides with TG-lowering effects from soy protein have been isolated.

  1. Conformational analysis of XA and AX dipeptides in water by electronic circular dichroism and 1H NMR spectroscopy.

    Science.gov (United States)

    Hagarman, Andrew; Measey, Thomas; Doddasomayajula, Ravi S; Dragomir, Isabelle; Eker, Fatma; Griebenow, Kai; Schweitzer-Stenner, Reinhard

    2006-04-06

    We measured the temperature-dependent electronic circular dichroism (ECD) spectra of AX, XA, and XG dipeptides in D2O. The spectra of all XA and AX peptides indicate a substantial population of the polyproline II (PPII) conformation, while the ECD spectra of LG, KG, PG, and AG were found to be quantitatively different from the alanine-based dipeptides. Additional UV absorption data indicate that the ECD spectra of the XG peptides stem from electronic coupling between the peptide and the C-terminal group, and that spectral differences reflect different orientations of the latter. We also measured the 1H NMR spectra of the investigated dipeptides to determine the 3JHalphaNH coupling constants for the C-terminal residue. The observed temperature dependence of the ECD spectra and the respective room-temperature 3JHalphaNH coupling constants were analyzed by a two-state model encompassing PPII and a beta-like conformation. The PPII propensity of alanine in the XA series is only slightly modulated by the N-terminal side chain, and is larger than 50%. As compared to AA, XA peptides containing L, P, S, K V, E, T, and I all cause a relative stabilization of the extended beta-strand conformation. The PPII fractions of XA peptides varied between 0.64 for AA and 0.58 for DA, whereas the PPII fractions of AX peptides were much lower. From the investigated AX peptides, only AL and AQ showed the expected PPII propensity. We found that AT, AI, and AV clearly prefer an extended beta-strand conformation. A quantitative comparison of AA, AAA, and AAAA revealed a hierarchy AAAA > AAA approximately AA for the PPII population, in agreement with predictions from MD calculations and results from Raman optical activity studies (McColl et al. J. Am. Chem. Soc. 2004, 126, 5076).

  2. The clinical and economic value of the dipeptide alanyl-glutamine in total parenteral nutrition of critically ill patients treated in intensive care units in Italy

    Directory of Open Access Journals (Sweden)

    Maurizio Muscaritoli

    2009-06-01

    Full Text Available Introduction: the supplementation of alanyl-glutamine dipeptide in critically ill patients necessitating total parenteral nutrition (TPN improves clinical outcomes, reducing mortality, infection rate, and shortening ICU hospital lengths of stay (LOS, as compared to standard TPN regimens. Here we present a pharmacoeconomic evaluation of alanyl-glutamine dipeptide in critically ill patients admitted to Italian Intensive Care Units (ICUs. Methods: a Discrete Event Simulation model that incorporates outcomes rates from 200 Italian ICUs for over 60,000 patients, alanyl-glutamine dipeptide efficacy data synthesized by means of a Bayesian Random-Effects meta-analysis, and national cost data has been developed to evaluated the alternatives from the point of view of the hospital. Simulated clinical outcomes are death and infection rates in ICU, death rate in general ward, and hospital LOSs. One-way and probabilistic sensitivity analyses are performed by varying all uncertain parameter values in a plausible range. Results: alanyl-glutamine dipeptide results more effective and less costly than standard TPN: reduced mortality rate (23.55% ± 15.2% vs 34.50% ± 2.06%, infection rate (15.91% ± 3.95% vs 18.97% ± 3.94%, and hospital LOS (25.47 ± 0.26 vs 26.00 ± 0.27 days come at a lower total cost per patient (23,922 ± 3,249 vs 24,145 ± 3,361 Euro. Treatment cost is completely offset by savings on ICU and antibiotic costs. The cost/effectiveness acceptability curve indicates an estimated 78% probability of alanyl-glutamine dipeptide resulting dominant and a 90% probability of resulting cost/effective for a willingness to pay up to 1,500 Euro for one patient death avoided. Conclusions: alanyl-glutamine dipeptide is expected to improve clinical outcomes and to do so with a concurrent saving for the hospital.

  3. The effects of the EW dipeptide optical and chemical isomers on the CFU-S population in intact and irradiated mice.

    Science.gov (United States)

    Deigin, V I; Semenets, T N; Zamulaeva, I A; Maliutina, Ya V; Selivanova, E I; Saenko, A S; Semina, O V

    2007-03-01

    The influence of Glu-Trp (EW) synthetic dipeptide isomers on hemopoietic progenitor cells and certain immune response reactions is determined by their optical and chemical properties. Thus, the all L-amino acid containing dipeptides L-Glu-L-Trp and L-gammaGlu-L-Trp have no effect on proliferation of committed and pluripotent CFU-S in intact bone marrow. The optical isomers of the Glu residue are an essential determinant of the EW dipeptide biological activity. The inversion of the amino acid optical form imparts suppressor properties: D-Glu-D-Trp,D--gammaGlu-D-Trp, D-Glu-L-Trp and D-gammaGlu-L-Trp inhibit proliferation of hemopoietic progenitors in intact bone marrow. The type of the peptide bond between L-Glu and Trp is another important factor for the biological activity of the L-Glu-containing peptides. Unlike L-Glu-D-Trp with alpha-peptide bond, the dipeptide L-gammaGlu-D-Trp with gamma-peptide bond stimulates CFU-S-8 proliferation in intact bone marrow. The diverse effects of the EW optical isomers on hemopoietic progenitors underlie the radioprotective properties of the D-Glu-containing dipeptides and the radiotherapeutic ones of the L-Glu dipeptides. In animals, pre-irradiation injection of D-Glu-D-Trp, D-gammaGlu-D-Trp, D-Glu-L-Trp, D-gammaGlu-L-Trp, or post-irradiation injection of L-Glu-L-Trp, L-gammaGlu-L-Trp promoted regeneration of the hemopoietic progenitor population.

  4. Hamiltonian replica-permutation method and its applications to an alanine dipeptide and amyloid-β(29-42) peptides.

    Science.gov (United States)

    Itoh, Satoru G; Okumura, Hisashi

    2013-11-05

    We propose the Hamiltonian replica-permutation method (RPM) (or multidimensional RPM) for molecular dynamics and Monte Carlo simulations, in which parameters in the Hamiltonian are permuted among more than two replicas with the Suwa-Todo algorithm. We apply the Coulomb RPM, which is one of realization of the Hamiltonian RPM, to an alanine dipeptide and to two amyloid-β(29-42) molecules. The Hamiltonian RPM realizes more efficient sampling than the Hamiltonian replica-exchange method. We illustrate the protein misfolding funnel of amyloid-β(29-42) and reveal its dimerization pathways.

  5. Partial purification and characterization of an enzyme involved in the formation of beta-aspartyl dipeptides in rat kidney.

    Science.gov (United States)

    Tanaka, T; Hirai, M; Nakajima, T

    1978-11-01

    The formation of beta-aspartyl-glycine from asparagine and glycine was demonstrated in the supernatant of rat kidney. The enzyme involved in this process was partially purified. Based on the properties of the enzyme reaction and the coincidence of purification rates of this activity and asparaginase, it can be speculated that the enzyme is a kind of asparaginase. Examination of the preference for beta-aspartyl donors and acceptors showed that asparagine and glycine were the preferred donor and acceptor, respectively. beta-Aspartyl dipeptides also transferred their aspartyl residues to amino acids. Amino acids other than glycine also accepted the aspartyl moiety from the donors.

  6. Simplified captopril analogues as NDM-1 inhibitors.

    Science.gov (United States)

    Li, Ningning; Xu, Yintong; Xia, Qiang; Bai, Cuigai; Wang, Taiyi; Wang, Lei; He, Dingdi; Xie, Nannan; Li, Lixin; Wang, Jing; Zhou, Hong-Gang; Xu, Feng; Yang, Cheng; Zhang, Quan; Yin, Zheng; Guo, Yu; Chen, Yue

    2014-01-01

    Captopril is a New Delhi metallo-β-lactamase-1 (NDM-1) inhibitor with an IC50 value of 7.9μM. It is composed of two units: a 3-mercapto-2-methylpropanoyl fragment and a proline residue. In this study, we synthesized simple amide derivatives of 3-mercapto-2-methylpropanoic acid, and then tested them as NDM-1 inhibitors in order to identify the pharmacophore for NDM-1 inhibition. We found that the lead compound 22 had an IC50 value of 1.0μM. Further structure simplification provided compounds 31 and 32, which had IC50 values of 15 and 10μM, respectively. As compound 32 is a clinically used antidote for metal poisoning, it has great potential to be repurposed to treat bacterial infections. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Intracellular Self-Assembly of Cyclic d-Luciferin Nanoparticles for Persistent Bioluminescence Imaging of Fatty Acid Amide Hydrolase.

    Science.gov (United States)

    Yuan, Yue; Wang, Fuqiang; Tang, Wei; Ding, Zhanling; Wang, Lin; Liang, Lili; Zheng, Zhen; Zhang, Huafeng; Liang, Gaolin

    2016-07-26

    Fatty acid amide hydrolase (FAAH) overexpression induces several disorder symptoms in nerve systems, and therefore long-term tracing of FAAH activity in vivo is of high importance but remains challenging. Current bioluminescence (BL) methods are limited in detecting FAAH activity within 5 h. Herein, by rational design of a latent BL probe (d-Cys-Lys-CBT)2 (1), we developed a "smart" method of intracellular reduction-controlled self-assembly and FAAH-directed disassembly of its cyclic d-luciferin-based nanoparticles (i.e., 1-NPs) for persistent BL imaging of FAAH activity in vitro, in cells, and in vivo. Using aminoluciferin methyl amide (AMA), Lys-amino-d-luciferin (Lys-Luc), and amino-d-luciferin (NH2-Luc) as control BL probes, we validated that the persistent BL of 1 from luciferase-expressing cells or tumors was controlled by the activity of intracellular FAAH. With the property of long-term tracing of FAAH activity in vivo of 1, we envision that our BL precursor 1 could probably be applied for in vivo screening of FAAH inhibitors and the diagnosis of their related diseases (or disorders) in the future.

  8. Novel Synthesis of N-Substituted p-Hydroxybenzoic Amides on Soluble Polymer-Support

    Institute of Scientific and Technical Information of China (English)

    胡春玲; 陈祖兴; 杨桂春

    2003-01-01

    The synthesis of N-substituted p-hydroxybenzoic amides using a liquid phase approach is described. Poly(ethylene glycol)(PEG) and p-hydroxybenzoic acid were linked by oxalyl chloride to give compound 1, which was chlorinated by thionyl chloride, followed by amidation with NHR1R2 to yield compound 3. Hydrolysis of compound 3 gave the title amide 4.These crude library members were obtained in good yields with high purities.

  9. BODIPY catalyzed amide synthesis promoted by BHT and air under visible light.

    Science.gov (United States)

    Wang, Xiao-Fei; Yu, Shu-Sheng; Wang, Chao; Xue, Dong; Xiao, Jianliang

    2016-08-07

    A novel and efficient protocol for the synthesis of amides is reported which employs a BODIPY catalyzed oxidative amidation reaction between aromatic aldehydes and amines under visible light. Compared with the known Ru or Ir molecular catalysts and other organic dyes, the BODIPY catalyst showed higher reactivity toward this reaction. Mechanistic studies reveal that dioxygen could be activated through an ET and a SET pathway, forming active peroxides in situ, which are vital for the key step of the reaction, i.e. the oxidation of hemiaminal to amide. The broad substrate scope and mild reaction conditions make this reaction practically useful and environmentally friendly for the synthesis of amide compounds.

  10. Fabrication and characterization of poly(amide-imides)/TiO₂ nanocomposite gas separation membranes

    OpenAIRE

    1996-01-01

    Nanosized Ti02 rich domains were generated in-situ within poly(amide-imide) (PAl) and 6F-poly(amide-imide) (6FPAl) by a sol-gel process. The composite films showed a high optical transparency. The morphology of the Ti02 rich domains was observed by transmission electron microscopy (TEM). The Ti02 rich domains were well dispersed within the poly(amide-imide) and 6F-poly(amide-imide) matrices and were 5 nm to 50 nm in size. Limited study was also carried out for the fabrication o...

  11. Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.

    Science.gov (United States)

    Young, Wendy B; Barbosa, James; Blomgren, Peter; Bremer, Meire C; Crawford, James J; Dambach, Donna; Eigenbrot, Charles; Gallion, Steve; Johnson, Adam R; Kropf, Jeffrey E; Lee, Seung H; Liu, Lichuan; Lubach, Joseph W; Macaluso, Jen; Maciejewski, Pat; Mitchell, Scott A; Ortwine, Daniel F; Di Paolo, Julie; Reif, Karin; Scheerens, Heleen; Schmitt, Aaron; Wang, Xiaojing; Wong, Harvey; Xiong, Jin-Ming; Xu, Jianjun; Yu, Christine; Zhao, Zhongdong; Currie, Kevin S

    2016-01-15

    BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Refined homology model of monoacylglycerol lipase: toward a selective inhibitor

    Science.gov (United States)

    Bowman, Anna L.; Makriyannis, Alexandros

    2009-11-01

    Monoacylglycerol lipase (MGL) is primarily responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), an endocannabinoid with full agonist activity at both cannabinoid receptors. Increased tissue 2-AG levels consequent to MGL inhibition are considered therapeutic against pain, inflammation, and neurodegenerative disorders. However, the lack of MGL structural information has hindered the development of MGL-selective inhibitors. Here, we detail a fully refined homology model of MGL which preferentially identifies MGL inhibitors over druglike noninhibitors. We include for the first time insight into the active-site geometry and potential hydrogen-bonding interactions along with molecular dynamics simulations describing the opening and closing of the MGL helical-domain lid. Docked poses of both the natural substrate and known inhibitors are detailed. A comparison of the MGL active-site to that of the other principal endocannabinoid metabolizing enzyme, fatty acid amide hydrolase, demonstrates key differences which provide crucial insight toward the design of selective MGL inhibitors as potential drugs.

  13. Synthesis and structures of new helical,nanoscale ferrocenylphenyl amides

    Institute of Scientific and Technical Information of China (English)

    XU Yan; RAN Chunling; WANG Haixian; SONG Maoping

    2007-01-01

    Two novel ferrocenylphenyl-containing amides have been synthesized by reaction of ferrocenylbencarboxylchloride and 1,2-di-(o-aminophenoxy)ethane.A single crystal X-ray analysis shows that compound 3 crystallizes in the triclinic system,space group P-1,and compound 4 crystallizes in orthorhombic system,space group Pca21.There areintramolecular H-bonds in both the compounds,two H-bonds in compound 3 and one in compound 4.The dihedral angels of Cp-ring and phenyl ring range from 3.8° to 20.8°.

  14. Antifungal activity of natural and synthetic amides from Piper species

    Energy Technology Data Exchange (ETDEWEB)

    Marques, Joaquim V.; Oliveira, Alberto de; Kato, Massuo J., E-mail: majokato@iq.usp.b [Universidade de Sao Paulo (IQ/USP), SP (Brazil). Inst. de Quimica; Raggi, Ludmila; Young, Maria C. [Instituto de Botanica, Sao Paulo, SP (Brazil). Secao de Fisiologia e Bioquimica de Plantas

    2010-07-01

    The antifungal leaves extract from Piper scutifolium was submitted to bioactivity-guided chromatographic separation against Cladosporium cladosporioides and C. sphaerospermum yielding piperine, piperlonguminine and corcovadine as the active principles which displayed a detection limit of 1 {mu}g. Structure-activity relationships were investigated with the preparation of twelve analogs having differences in the number of unsaturations, aromatic ring substituents and in the amide moiety. Analogs having a single double-bond and no substituent in the aromatic ring displayed higher activity, while N,N,-diethyl analogs displayed higher dose-dependent activity. (author)

  15. Antiproliferative activity of synthetic fatty acid amides from renewable resources.

    Science.gov (United States)

    dos Santos, Daiane S; Piovesan, Luciana A; D'Oca, Caroline R Montes; Hack, Carolina R Lopes; Treptow, Tamara G M; Rodrigues, Marieli O; Vendramini-Costa, Débora B; Ruiz, Ana Lucia T G; de Carvalho, João Ernesto; D'Oca, Marcelo G Montes

    2015-01-15

    In the work, the in vitro antiproliferative activity of a series of synthetic fatty acid amides were investigated in seven cancer cell lines. The study revealed that most of the compounds showed antiproliferative activity against tested tumor cell lines, mainly on human glioma cells (U251) and human ovarian cancer cells with a multiple drug-resistant phenotype (NCI-ADR/RES). In addition, the fatty methyl benzylamide derived from ricinoleic acid (with the fatty acid obtained from castor oil, a renewable resource) showed a high selectivity with potent growth inhibition and cell death for the glioma cell line-the most aggressive CNS cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Three new amides from Streptomyces sp. H7372

    OpenAIRE

    Cheenpracha, Sarot; Borris,Robert P; Tran,Tammy T.; Jee,Jap Meng; Seow, Heng Fong; Cheah,Hwen-Yee; Ho,Coy Choke; Chang, Leng Chee

    2011-01-01

    Three new amides, methyl phenatate A (1), actiphenamide (2) and actiphenol 1-β-D-glucopyranoside (3), along with thirteen known compounds, were isolated from the organic extract of a fermentation culture of Streptomyces sp. H7372. The structures were elucidated by spectroscopic methods including 1D- and 2D-NMR techniques, and MS analyses. Cycloheximide (6) and cyclo(ΔAla-L-Val) (8) gave a clear zone of inhibition of Ras-Raf-1 interaction in the yeast two-hybrid assay which showed hi...

  17. N-Hydroxyimide Ugi Reaction toward α-Hydrazino Amides

    Science.gov (United States)

    2017-01-01

    The Ugi four-component reaction (U-4CR) with N-hydroxyimides as a novel carboxylic acid isostere has been reported. This reaction provides straightforward access to α-hydrazino amides. A broad range of aldehydes, amines, isocyanides and N-hydroxyimides were employed to give products in moderate to high yields. This reaction displays N–N bond formation by cyclic imide migration in the Ugi reaction. Thus, N-hydroxyimide is added as a new acid component in the Ugi reaction and broadens the scaffold diversity. PMID:28220702

  18. Identification of nitrogen compounds and amides from spent hydroprocessing catalyst

    Energy Technology Data Exchange (ETDEWEB)

    Choi, J.H.K.; Gray, M.R. (University of Alberta, Edmonton, AB (Canada). Dept. of Chemical Engineering)

    1991-06-01

    A spent commercial naphtha hydrotreating catalyst was analyzed to identify compounds which had accumulated on the catalyst surface during its active life. The catalyst was extracted with methylene chloride, methanol and pyridine to remove adsorbed organic material, which was rich in nitrogen and oxygen. A series of quinolones were identified in the methanol extract after enrichment with HCl-modified silica gel adsorption and subsequent silica gel chromatography. Tetra- and hexahydroquinolones with alkyl substituents up to C{sub 3} were identified. Similar amides have been identified in asphaltenes, and are very resistant to hydrogenation. Tetrahydroquinolines and piperidines were detected in the pyridine extract. 36 refs., 8 figs., 2 tabs.

  19. Synthesis and Crystal Structure of Conformationally Constrained Dipeptide with 1-Aminocyclopropanecarboxylic Acid Residue%含环丙烷氨基酸残基的构象限制二肽的合成及其晶体结构研究

    Institute of Scientific and Technical Information of China (English)

    张刘生; 潘成学; 李丽; 苏桂发; 黄婉云; 覃江克; 唐煌

    2011-01-01

    以(L)-苯丙氨酸甲酯盐酸盐、N-叔丁氧羰基-(L)-丙氨酸和2,3-二苯基-1-叔丁氧酰氨基环丙烷酸甲酯为原料,采用混酐法合成了两个含2,3-二苯基取代环丙烷氨基酸残基的构象限制二肽,并用IR、NMR、MS和单晶X-射线衍射对这两个二肽的结构进行了研究.%Two conformationally constrained dipeptides with a trans-2,3-diaryl-1-aminocyclo-propanecar-boxylic acid residue were synthesized from boc-(L)-phenylalanine,boc-(L)-alanine and 2,3-diphenyl-1-tert-butyl-cyclopropane carboxylic acid amide with the mixed anhydride methodology. The structures of two target compounds were studied by means of X-ray single crystal diffraction analysis.

  20. Thermodynamics of mixed-ligand complex formation of zinc nitrilotriacetate with amino acids and dipeptides in solution

    Energy Technology Data Exchange (ETDEWEB)

    Pyreu, Dmitrii, E-mail: pyreu@mail.ru [Department of Inorganic and Analytic Chemistry, Ivanovo State UniversityErmak 39, Ivanovo 153025 (Russian Federation); Gruzdev, Matvey; Kumeev, Roman [G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, Ivanovo (Russian Federation); Gridchin, Sergei [Ivanovo State University of Chemistry and Technology, Ivanovo (Russian Federation)

    2014-10-20

    Highlights: • Stable mixed ligand complexes of ZnNta with amino acids and dipeptides. • Histamine-like coordination mode of His in the complex ZnNtaHis. • Glycine-like coordination of Lys and Orn in the complexes ZnNtaL and ZnNtaHL • NH{sub 2}, CO-coordination mode of GlyGly in the complex ZnNtaGG. • NH{sub 2}, N{sup −} or NH2, N{sup −}, COO-coordination modes of GlyGly in the complex ZnNtaGGH{sub −1}. - Abstract: The isothermal calorimetry, pH-potentiometric titration and {sup 1}H and {sup 13}C NMR methods has been used to study the mixed-ligand complex formation in the systems Zn{sup 2+}–Nta{sup 3–}–L{sup −} (L = His, Orn, Lys, GlyGly, AlaAla) in aqueous solution at 298.15 K and the ionic strength of I = 0.5 (KNO{sub 3}). The thermodynamic parameters of formation of the mixed complexes have been determined. The relationship between the probable coordination modes of the complexone and amino acid or dipeptide molecules in the mixed-ligand complex and the thermodynamic parameters has been discussed.

  1. Hydrophobic dipeptide crystals: a promising Ag-free class of ultramicroporous materials showing argon/oxygen adsorption selectivity.

    Science.gov (United States)

    Afonso, R; Mendes, A; Gales, L

    2014-09-28

    The adsorption isotherms of nitrogen, oxygen and argon in four VA-class hydrophobic dipeptides are presented. Isotherms were determined at 5, 20 and 35 °C, for a pressure range of 0-6 bar. Under these conditions, adsorption is still in the Henry region. For all materials and temperatures, the sequence of preferential adsorption is Ar > O2 > N2, a highly abnormal result. At 5 °C, the dipeptide with the smallest pores, VI, has Ar/O2 adsorption equilibrium selectivities up to 1.30, the highest ever measured in Ag-free adsorbents. Gas uptakes, at 1 bar and 20 °C, are ∼0.05 mol kg(-1), very low relative values that are partially explained by the low porosity of the solids (materials for the process of O2 generation by pressure swing adsorption (PSA) is discussed. The results indicate some of the structural and chemical properties that prospective Ag-free adsorbents should have in order to have Ar/O2 selectivity, hydrophobic pores, less than 0.5 nm-wide, and porosity of, at least, 20%.

  2. Expression and purification of L-asparaginase from Escherichia coli and the inhibitory effects of cyclic dipeptides.

    Science.gov (United States)

    Zhang, Yanan; Li, Dan; Li, Yan

    2017-09-01

    L-asparaginase, a key enzyme involved in nitrogen metabolism, is an effective anti-tumour agent. Cyclic dipeptides, a group of compounds, contain several important biological functions. In this paper, we proposed a novel method for L-asparaginase expression and purification from Echerichia coli and determined the effect of cyclic dipeptides on the enzymatic activity of recombinant L-asparaginase. The gene ansB encoding L-asparaginase was amplified from the genome of E. coli BL21 (DE3) by polymerase chain reaction and sub-cloned into pET-15b vector to construct expressing plasmid pET-15b-ansB. The expression of recombinant protein was purified by affinity chromatography using a nickel resin followed by anion exchange chromatography. The purity and quality of the recombinant L-asparaginase were optimised. The results indicated that km for the recombinant L-asparaginase was 3.02 × 10(-4) mol/L. Both cyclo-(Pro-Tyr) and cyclo-(Pro-Phe) could inhibit the activity of recombinant L-asparaginase at the level of 10(-5) mol/L.

  3. Methylation of C9orf72 expansion reduces RNA foci formation and dipeptide-repeat proteins expression in cells.

    Science.gov (United States)

    Bauer, Peter O

    2016-01-26

    A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), together referred to as c9FTD/ALS. It has been suggested that a loss of C9orf72 protein expression, the formation of toxic RNA foci and dipeptide-repeat proteins contribute to C9orf72-related diseases. Interestingly, it has been shown that trimethylation of histones and methylation of CpG islands near the repeat expansion may play a role in the pathogenesis c9FTD/ALS. Recently, methylation of expanded repeat itself has been reported. To further elucidate the mechanisms underlying these diseases, the influence of epigenetic modification in the repeat expansion on its pathogenic effect was assessed. Here, a reduced formation of toxic RNA foci and dipeptide-repeat proteins upon methylation of the GGGGCC repeat in a cellular model of c9FTD/ALS is shown. Additionally, a novel methylcytosine-capture DNA hybridization immunoassay for semi-quantitative detection of the repeat methylation levels is presented, potentially usable for methylation analysis in patients carrying C9orf72 repeat expansion carriers as a diagnostic tool. Presented results suggest that increased level of pathogenic GGGGCC expansion methylation may be sufficient to alleviate the molecular pathology of the C9orf72-related diseases.

  4. Solvation and hydrogen bonding in alanine- and glycine-containing dipeptides probed using solution- and solid-state NMR spectroscopy.

    Science.gov (United States)

    Bhate, Manasi P; Woodard, Jaie C; Mehta, Manish A

    2009-07-15

    The NMR chemical shift is a sensitive reporter of peptide secondary structure and its solvation environment, and it is potentially rich with information about both backbone dihedral angles and hydrogen bonding. We report results from solution- and solid-state (13)C and (15)N NMR studies of four zwitterionic model dipeptides, L-alanyl-L-alanine, L-alanyl-glycine, glycyl-L-alanine, and glycyl-glycine, in which we attempt to isolate structural and environmental contributions to the chemical shift. We have mapped hydrogen-bonding patterns in the crystalline states of these dipeptides using the published crystal structures and correlated them with (13)C and (15)N magic angle spinning chemical shift data. To aid in the interpretation of the solvated chemical shifts, we performed ab initio quantum chemical calculations to determine the low-energy conformers and their chemical shifts. Assuming low energy barriers to interconversion between thermally accessible conformers, we compare the Boltzmann-averaged chemical shifts with the experimentally determined solvated-state shifts. The results allow us to correlate the observed differences in chemical shifts between the crystalline and solvated states to changes in conformation and hydrogen bonding that occur upon solvation.

  5. Synthesis and conformational analysis of hybrid α/β-dipeptides incorporating S-glycosyl-β(2,2)-amino acids.

    Science.gov (United States)

    García-González, Iván; Mata, Lara; Corzana, Francisco; Jiménez-Osés, Gonzalo; Avenoza, Alberto; Busto, Jesús H; Peregrina, Jesús M

    2015-01-12

    We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α-amino acid attached to a quaternary glyco-β-amino acid. In particular, we combined a S-glycosylated β(2,2)-amino acid and two different types of α-amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β-dipeptides. The key step in the synthesis involved the ring-opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur-containing nucleophile by using 1-thio-β-D-glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time-averaged restraints (MD-tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β-amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α-amino acids due to the presence of CH-π interactions between the phenyl or indole ring and the methyl groups of the β-amino acid unit.

  6. A genetic algorithm encoded with the structural information of amino acids and dipeptides for efficient conformational searches of oligopeptides.

    Science.gov (United States)

    Ru, Xiao; Song, Ce; Lin, Zijing

    2016-05-15

    The genetic algorithm (GA) is an intelligent approach for finding minima in a highly dimensional parametric space. However, the success of GA searches for low energy conformations of biomolecules is rather limited so far. Herein an improved GA scheme is proposed for the conformational search of oligopeptides. A systematic analysis of the backbone dihedral angles of conformations of amino acids (AAs) and dipeptides is performed. The structural information is used to design a new encoding scheme to improve the efficiency of GA search. Local geometry optimizations based on the energy calculations by the density functional theory are employed to safeguard the quality and reliability of the GA structures. The GA scheme is applied to the conformational searches of Lys, Arg, Met-Gly, Lys-Gly, and Phe-Gly-Gly representative of AAs, dipeptides, and tripeptides with complicated side chains. Comparison with the best literature results shows that the new GA method is both highly efficient and reliable by providing the most complete set of the low energy conformations. Moreover, the computational cost of the GA method increases only moderately with the complexity of the molecule. The GA scheme is valuable for the study of the conformations and properties of oligopeptides. © 2016 Wiley Periodicals, Inc.

  7. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain.

    Science.gov (United States)

    Jhaveri, Maulik D; Richardson, Denise; Kendall, David A; Barrett, David A; Chapman, Victoria

    2006-12-20

    Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic in models of acute and inflammatory pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve ligation model of neuropathic pain. Electrophysiological studies were performed 14-18 d after spinal nerve ligation or sham surgery, and the effects of the FAAH inhibitor cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597) on mechanically evoked responses of spinal neurons and levels of endocannabinoids were determined. Intraplantar URB597 (25 microg in 50 microl) significantly (p < 0.01) attenuated mechanically evoked responses of spinal neurons in sham-operated rats. Effects of URB597 were blocked by the cannabinoid 1 receptor (CB1) antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (30 microg in 50 microl) and the opioid receptor antagonist naloxone. URB597 treatment increased levels of anandamide, 2-arachidonyl glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of sham-operated rats. Intraplantar URB597 (25 microg in 50 microl) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of endocannabinoids. Intraplantar injection of a higher dose of URB597 (100 microg in 50 microl) significantly (p < 0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of endocannabinoids. Spinal administration of URB597 attenuated evoked responses of spinal neurons and elevated levels of endocannabinoids in sham-operated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats.

  8. Cyclic dipeptides from rhabditid entomopathogenic nematode-associated Bacillus cereus have antimicrobial activities.

    Science.gov (United States)

    Nishanth Kumar, S; Nath, Vishnu Sukumari; Pratap Chandran, R; Nambisan, Bala

    2014-02-01

    The cell free culture filtrate of Bacillus cereus associated with an entomopathogenic nematode, Rhabditis (Oscheius) sp. exhibited strong antimicrobial activity. The ethyl acetate extract of the bacterial culture filtrate was purified by silica gel column chromatography to obtain four bioactive compounds. The structure and absolute stereochemistry of these compounds were determined based on extensive spectroscopic analyses (FABMS, (1)H NMR, (13)C NMR, (1)H-(1)H COSY, (1)H-(13)C HMBC) and Marfey's method. The compounds were identified as cyclic dipeptides (CDPs): cyclo(L-Pro-L-Trp), cyclo(L-Leu-L-Val), cyclo(D-Pro-D-Met), and cyclo(D-Pro-D-Phe), respectively. Compounds recorded significant antibacterial activity against all the test bacteria (Staphylococcus epidermidis, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and methicillin-resistant S. aureus) except cyclo(L-Leu-L-Val). Cyclo(L-Leu-L-Val) recorded activity only against Gram positive bacteria. Best antibacterial activity was recorded by cyclo(L-Pro-L-Trp) against S. aureus (4 μg/ml). The four compounds were active against all the five fungi tested (Trichophyton rubrum, Aspergillus flavus, Candida albicans, Candida tropicalis and Cryptococcus neoformans) and the activity was compared with amphotericin B, the standard fungicide. The highest activity of 1 μg/ml by cyclo(L-Pro-L-Trp) was recorded against T. rubrum, a human pathogen responsible for causing athlete's foot, jock itch, and ringworm. The activity of cyclo(L-Pro-L-Trp) against T. rubrum, C. neoformans and C. albicans were better than amphotericin B, the standard antifungal agent. To our knowledge, this is the first report of antifungal activity of CDPs against the human pathogenic fungi T. rubrum and C. neoformans. The four CDPs are nontoxic to healthy human cell line up to 200 μg/ml. We conclude that the bacterium associated with entomopathogenic nematode is promising sources of natural antimicrobial

  9. Poly(ester amide)s from Poly(ethylene terephthalate) Waste for Enhancing Bone Regeneration and Controlled Release.

    Science.gov (United States)

    Natarajan, Janeni; Madras, Giridhar; Chatterjee, Kaushik

    2017-08-30

    The present study elucidates the facile synthesis and exceptional properties of a family of novel poly(ester amide)s (PEAs) based on bis(2-hydroxy ethylene) terephthalamide that was obtained from the poly(ethylene terephthalate) waste. Fourier transform infrared and (1)H NMR were used to verify the presence of ester and amide in the polymer backbone. Differential scanning calorimetry data showed that the glass transition temperature decreased with as the chain length of dicarboxylic acids increased. Dynamic mechanical analysis and contact angle studies proved that the modulus values and hydrophobicity increased with as the chain lengths of dicarboxylic acids increased. In vitro hydrolytic degradation and dye release studies demonstrated that the degradation and release decreased with as the chain lengths of dicarboxylic acids increased. Modeling these data illustrated that degradation and release follow first-order degradation and zero-order release, respectively. The in vitro cytocompatibility studies confirmed the minimal toxicity characteristic of these polymers. Osteogenic studies proved that these polymers can be highly influential in diverting the cells toward osteogenic lineage. Alizarin red staining evinced the presence of twice the amount of calcium phosphate deposits by the cells on these polymers when compared to the control. The observed result was also corroborated by the increased expression of alkaline phosphatase. These findings were further validated by the markedly higher mRNA expressions for known osteogenic markers using real time polymerase chain reaction. Therefore, these polymers efficiently promoted osteogenesis. This study demonstrates that the physical properties, degradation, and release kinetics can be altered to meet the specific requirements in organ regeneration as well as facilitate simultaneous polymer resorption through control of the chain length of the monomers. The findings of this study have significant implications for

  10. Aromatic inhibitors derived from ammonia-pretreated lignocellulose hinder bacterial ethanologenesis by activating regulatory circuits controlling inhibitor efflux and detoxification

    Directory of Open Access Journals (Sweden)

    David H. Keating

    2014-08-01

    Full Text Available Efficient microbial conversion of lignocellulosic hydrolysates to biofuels is a key barrier to the economically viable deployment of lignocellulosic biofuels. A chief contributor to this barrier is the impact on microbial processes and energy metabolism of lignocellulose-derived inhibitors, including phenolic carboxylates, phenolic amides (for ammonia-pretreated biomass, phenolic aldehydes, and furfurals. To understand the bacterial pathways induced by inhibitors present in ammonia-pretreated biomass hydrolysates, which are less well studied than acid-pretreated biomass hydrolysates, we developed and exploited synthetic mimics of ammonia-pretreated corn stover hydrolysate (ACSH. To determine regulatory responses to the inhibitors normally present in ACSH, we measured transcript and protein levels in an Escherichia coli ethanologen using RNA-seq and quantitative proteomics during fermentation to ethanol of synthetic hydrolysates containing or lacking the inhibitors. Our study identified four major regulators mediating these responses, the MarA/SoxS/Rob network, AaeR, FrmR, and YqhC. Induction of these regulons was correlated with a reduced rate of ethanol production, buildup of pyruvate, depletion of ATP and NAD(PH, and an inhibition of xylose conversion. The aromatic aldehyde inhibitor 5-hydroxymethylfurfural appeared to be reduced to its alcohol form by the ethanologen during fermentation whereas phenolic acid and amide inhibitors were not metabolized. Together, our findings establish that the major regulatory responses to lignocellulose-derived inhibitors are mediated by transcriptional rather than translational regulators, suggest that energy consumed for inhibitor efflux and detoxification may limit biofuel production, and identify a network of regulators for future synthetic biology efforts.

  11. Aromatic inhibitors derived from ammonia-pretreated lignocellulose hinder bacterial ethanologenesis by activating regulatory circuits controlling inhibitor efflux and detoxification

    Directory of Open Access Journals (Sweden)

    David H. Keating

    2014-08-01

    Full Text Available Efficient microbial conversion of lignocellulosic hydrolysates to biofuels is a key barrier to the economically viable deployment of lignocellulosic biofuels. A chief contributor to this barrier is the impact on microbial processes and energy metabolism of lignocellulose-derived inhibitors, including phenolic carboxylates, phenolic amides (for ammonia-pretreated biomass, phenolic aldehydes, and furfurals. To understand the bacterial pathways induced by inhibitors present in ammonia-pretreated biomass hydrolysates, which are less well studied than acid-pretreated biomass hydrolysates, we developed and exploited synthetic mimics of ammonia-pretreated corn stover hydrolysate (ACSH. To determine regulatory responses to the inhibitors normally present in ACSH, we measured transcript and protein levels in an Escherichia coli ethanologen using RNA-seq and quantitative proteomics during fermentation to ethanol of synthetic hydrolysates containing or lacking the inhibitors. Our study identified four major regulators mediating these responses, the MarA/SoxS/Rob network, AaeR, FrmR, and YqhC. Induction of these regulons was correlated with a reduced rate of ethanol production, buildup of pyruvate, depletion of ATP and NAD(PH, and an inhibition of xylose conversion. The aromatic aldehyde inhibitor 5-hydroxymethylfurfural appeared to be reduced to its alcohol form by the ethanologen during fermentation, whereas phenolic acid and amide inhibitors were not metabolized. Together, our findings establish that the major regulatory responses to lignocellulose-derived inhibitors are mediated by transcriptional rather than translational regulators, suggest that energy consumed for inhibitor efflux and detoxification may limit biofuel production, and identify a network of regulators for future synthetic biology efforts.

  12. Amidated pectin based hydrogels: synthesis, characterization and cytocompatibility study.

    Science.gov (United States)

    Mishra, R K; Singhal, J P; Datt, M; Banthia, A K

    2007-01-01

    The design and development of pectin-based hydrogels were attempted through the chemical modification of pectin with diethanolamine (DA). Diethanolamine modified pectin (DAMP) was synthesized by the chemical modification of pectin with varying concentrations of DA (1:1,1:2,1:3 and 1:4) at 5 oC in methanol. The modified product was used for the preparation of the hydrogel with glutaraldehyde (GA) reagent. The prepared hydrogels were characterized by Fourier transform infrared (FTIR) spectroscopy; organic elemental analysis, and X-ray diffraction (XRD), and swelling, hemocompatibility and cytocompatibility studies of the prepared hydrogels were also done. FTIR spectroscopy indicated the presence of primary and secondary amide absorption bands. The XRD pattern of the DAMP hydrogel clearly indicated that there was a considerable increase in crystallinity as compared to parent pectin. The degree of amidation (DA) and molar and mass reaction yields (Ym and Yn) was calculated based on the results of organic elemental analysis. Drug release studies from the hydrogel membranes were also evaluated in a Franz's diffusion cell. The hydrogels demonstrated good water holding properties and were found to be compatible with B-16 melanoma cells and human blood.

  13. Synthesis and Crystal Structure of a New Adamantane Amide Derivative

    Institute of Scientific and Technical Information of China (English)

    ZHOU Ying-Hua; LV Qi-Chun; ZHANG Qian; CHENG Yong; SHENG En-Hong

    2012-01-01

    A novel adamantane acyl amide derivative containing two phthalimido pendant groups(C31H31N3O5) has been synthesized,and its structure was characterized by elemental analysis,IR,1 H NMR spectra,and single-crystal X-ray diffraction.The crystal belongs to triclinic,space group P1 with a=7.3158(10),b=13.2405(18),c=14.378(2),α=72.419(2),β=84.496(2),γ=81.799(2)o,V=1312.0(3)3,Z=2,Dc=1.330 g/cm 3,μ=0.09 mm-1,Mr=525.59,F(000)=556,S=1.001,R=0.0523 and wR=0.0707 for 5901 unique reflections with 2363 observed ones(I〉2σ(I)).π-π stacking interactions(offset face-to-face) exist between the two rings of phthalimides from the neighboring molecules in the title crystal structure.The intermolecular dihedral angle between the two rings of neighboring phthalic amides is 6.26° and the distance is 4.008.

  14. Poly(ester amide)s based on (L)-lactic acid oligomers and α-amino acids: influence of the α-amino acid side chain in the poly(ester amide)s properties.

    Science.gov (United States)

    Fonseca, Ana C; Coelho, Jorge F J; Valente, Joana F A; Correia, Tiago R; Correia, Ilídio J; Gil, Maria H; Simões, Pedro N

    2013-01-01

    Novel biodegradable and low cytotoxic poly(ester amide)s (PEAs) based on α-amino acids and (L)-lactic acid (L-LA) oligomers were successfully synthesized by interfacial polymerization. The chemical structure of the new polymers was confirmed by spectroscopic analyses. Further characterization suggests that the α-amino acid plays a critical role on the final properties of the PEA. L-phenylalanine provides PEAs with higher glass transition temperature, whereas glycine enhances the crystallinity. The hydrolytic degradation in PBS (pH = 7.4) at 37 °C also depends on the α-amino acid, being faster for glycine-based PEAs. The cytotoxic profiles using fibroblast human cells indicate that the PEAs did not elicit an acute cytotoxic effect. The strategy presented in this work opens the possibility of synthesizing biodegradable PEAs with low citotoxicity by an easy and fast method. It is worth to mention also that the properties of these materials can be fine-tuned only by changing the α-amino acid.

  15. Stability of caffeic acid phenethyl amide (CAPA) in rat plasma.

    Science.gov (United States)

    Yang, John; Kerwin, Sean M; Bowman, Phillip D; Stavchansky, Salomon

    2012-05-01

    A validated C₁₈ reverse-phase HPLC method with UV detection at 320 nm was developed and used for the stability evaluation of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) in rat plasma. CAPA is the amide derivative of CAPE, a naturally occurring polyphenolic compound that has been found to be active in a variety of biological pathways. CAPA has been shown to protect endothelial cells against hydrogen peroxide-induced oxidative stress to a similar degree to CAPE. CAPE has been reported to be rapidly hydrolyzed in rat plasma via esterase enzymes. CAPA is expected to display a longer half-life than CAPE by avoiding hydrolysis via plasma esterases. The stability of CAPA and CAPE in rat plasma was investigated at three temperatures. The half-lives for CAPA were found to be 41.5, 10 and 0.82 h at 25, 37 and 60 °C, respectively. The half-lives for CAPE were found to be 1.95, 0.35 and 0.13 h at 4, 25 and 37 °C, respectively. The energy of activation was found to be 22.1 kcal/mol for CAPA and 14.1 kcal/mol for CAPE. A more stable compound could potentially extend the beneficial effects of CAPE.

  16. Collagen and component polypeptides: Low frequency and amide vibrations

    Science.gov (United States)

    Fontaine-Vive, F.; Merzel, F.; Johnson, M. R.; Kearley, G. J.

    2009-01-01

    Collagen is a fibrous protein, which exists widely in the human body. The biomechanical properties of collagen depend on its triple helix structure and the corresponding low frequency vibrations. We use first-principles, density functional theory methods and analytical force fields to investigate the molecular vibrations of a model collagen compound, the results being validated by comparison with published, inelastic neutron scattering data. The results from these atomistic simulations are used at higher frequency to study the Amide I and V vibrations and therefore the vibrational signature of secondary and tertiary structure formation. In addition to collagen, its component homopolymers, poly-glycine and poly-proline are also studied. The Amide V vibration of glycine is strongly modified in going from the single helix of poly-glycine II to the triple helix of collagen. The collagen models are hydrated and this work allows us to discuss the relative merits of density functional theory and force field methods when tackling complex, partially crystalline systems.

  17. PREPARATION AND CHARACTERIZATION OF AMIDATED PECTIN BASED POLYMER ELECTROLYTE MEMBRANES

    Institute of Scientific and Technical Information of China (English)

    R.K.Mishra; A.Anis; S.Mondal; M.Dutt; A.K.Banthia

    2009-01-01

    The work presents the synthesis and characterization of ami dated pectin(AP)based polymer electrolyte membranes(PEM)crosslinked with glutaraldehyde(GA).The prepared membranes are characterized by Fourier transform infrared spectroscopy(FTIR),organic elemental analysis,X-ray diffraction studies(XRD),thermogravimetric analysis (TGA)and impedance spectroscopy.Mechanical properties of the membranes are evaluated by tensile tests.The degree of amidation(DA),molar and mass reaction yields(YM and YN)are calculated based on the results of organic elemental analysis.FTIR spectroscopy indicated the presence of primary and secondary amide absorption bands.XRD pattern of membranes clearly indicates that there is a considerable increase in crystallinity as compared to parent pectin.TGA studies indicate that AP is less thermally stable than reference pectin.A maximum room temperature conductivity of 1.098×10-3 Scm-1 is obtained in the membrane,which is designated as AP-3.These properties make them good candidates for low cost biopolymer electrolyte membranes for fuel cell applications.

  18. Protolytic properties and complexation of DL-alpha-alanine and DL-alpha-valine and their dipeptides in aqueous and micellar solutions of surfactants

    NARCIS (Netherlands)

    Chernyshova, O. S.; Boychenko, Oleksandr; Abdulrahman, H.; Loginova, L. P.

    2013-01-01

    In this work we investigated the effect of the micellar media of anionic (sodium dodecylsulfate, SDS), cationic (cetylpiridinium chloride, CPC) and non-ionic (Brij-35) surfactants on the protolytic properties of amino acids DL-alpha-alanine, DL-alpha-valine and dipeptides L-alpha-alanyl-L-alpha-alan

  19. Chemo-immunotherapy of liver metastases; the in vitro and in vivo effects of 5-Fluo-rouracil combi¬ned with liposome-encapsulated muramyl dipeptide.

    NARCIS (Netherlands)

    Daemen, Toos; Dontje, BHJ; Regts, Djoeke; Morselt, Henriette; Scherphof, Gerrit

    1994-01-01

    While investigating the effects of 5-fluorouracil (5FU) on the tumoricidal state of rat liver macrophages activated in vitro by means of liposome-encapsulated muramyl dipeptide (MDP), we observed that 5FU in combination with macrophages produced substantially higher extents of cytolytic activity on

  20. Kinetic studies on substitution of cis-diaqua-chloro-tris-(dimethyl sulphoxide)-ruthenium(II) complex with some dipeptides in aqueous medium

    Indian Academy of Sciences (India)

    Arup Mandal; Parnajyoti Karmakar; Subhasis Mallick; Biplab K Bera; Subala Mondal; Sumon Ray; Alak K Ghosh

    2012-07-01

    The kinetics of interaction between cis-[RuCl(Me2SO)3(H2O)2]+ and some selected dipeptides such as glycyl glycine(gly gly), glycyl alanine(Gly-L-ala) and glycyl-L-leucine(gly leu) has been studied spectrophotometrically as a function of [RuCl(Me2SO)3(H2O)$^{+}_{2}$], [dipeptide] and temperature at a particular pH(5.0), where the substrate complex exists predominantly as a diaqua species (in aqueous solution) and dipeptides as the zwitter ions. The reaction has been found to proceed via two distinct consecutive steps i.e., it shows a non-linear dependence on the concentration of dipeptide: first process is dependent and the second step is independent of ligand concentration respectively. The rate constants for the processes are: k1 ∼ 10−3s-1 and k2 ∼ 10−5 s-1. The activation parameters were calculated from Eyring plots suggests an associative mechanism for the interaction process. From the temperature dependence of the outer sphere association equilibrium constants, the thermodynamic parameters were also calculated, which gives a negative G0 value at all temperatures studied, supporting the spontaneous formation of an outer sphere association complex.

  1. Comparison of Growth Performance and Whole-body Amino Acid Composition in Red Seabream (Pagrus major) Fed Free or Dipeptide Form of Phenylalanine.

    Science.gov (United States)

    Kim, Sung-Sam; Rahimnejad, Samad; Song, Jin-Woo; Lee, Kyeong-Jun

    2012-08-01

    This study was conducted to evaluate the efficacy of the dipeptide form of phenylalanine as a new source of amino acid in terms of growth performance and whole-body amino acid composition in comparison to the free form for red seabream (Pagrus major). Fish (1.46±0.001 g) were fed four isonitrogenous and isocaloric experimental diets containing 0.7 or 1.4% phenylalanine either in free or dipeptide form. A feeding trial was carried out in three replicates and the fish were fed to apparent satiation for six weeks. At the end of the feeding trial, feed intake of fish was influenced by both phenylalanine form and level and significantly higher values were obtained at an inclusion level of 0.7% and by the use of dipeptide form. However, the other growth parameters did not significantly differ among treatments. Whole-body amino acid compositions revealed no significant changes in concentrations of both essential and non-essential amino acids regardless of the increase in phenylalanine levels or the use of its different forms. The finding in this study indicates that juvenile red seabream can utilize dipeptide phenylalanine as efficiently as free form without any undesirable effects on growth performance or whole-body amino acid composition.

  2. Two enzymes which catalyze the amidation of peptide C-terminals are synthesized by a single mRNA. Peptide C mattan amid ka hanno wo shokubaisuru futatsu no koso wa ippon no mRNA yori goseisareru

    Energy Technology Data Exchange (ETDEWEB)

    Kato, I.; Yonekura, H.; Okamoto, H. (Tohoku Univ., Sendai (Japan))

    1991-10-25

    Recent findings by the authors are reviewed on the amidation that forms amid structure essential to physiological activities in C-terminals of peptide hormones such as oxytocin,VIP,PP. It is noted that the amidation had been considered to be catalyzed by peptidylglycine{alpha} -amidating monooxyganase ( PAM ) and that the authors investigated the PAM function by expression of PAM cDNA isolated from rat pituitary and its deletion mutant into COS-7 cells, reaching to the important findings of a singl PMA mRNA encoding two enzymes, namely one at 5 {prime} side, peptidylglicine {alpha} hydroxylase which catalyses the conversion of C-termianl glycine on peptide to the hydroxylated form ( the first step of amidation ),and another at 3{prime} side, {alpha}- hydroxylglycine amidating dealkylase which catalyzes the conversion of hydroxylated glycine to the amidated form ( the second step of amidation). 19 refs., 4 figs.

  3. 1H NMR spectra. Part 30(+): 1H chemical shifts in amides and the magnetic anisotropy, electric field and steric effects of the amide group.

    Science.gov (United States)

    Abraham, Raymond J; Griffiths, Lee; Perez, Manuel

    2013-03-01

    The (1)H spectra of 37 amides in CDCl(3) solvent were analysed and the chemical shifts obtained. The molecular geometries and conformational analysis of these amides were considered in detail. The NMR spectral assignments are of interest, e.g. the assignments of the formamide NH(2) protons reverse in going from CDCl(3) to more polar solvents. The substituent chemical shifts of the amide group in both aliphatic and aromatic amides were analysed using an approach based on neural network data for near (≤3 bonds removed) protons and the electric field, magnetic anisotropy, steric and for aromatic systems π effects of the amide group for more distant protons. The electric field is calculated from the partial atomic charges on the N.C═O atoms of the amide group. The magnetic anisotropy of the carbonyl group was reproduced with the asymmetric magnetic anisotropy acting at the midpoint of the carbonyl bond. The values of the anisotropies Δχ(parl) and Δχ(perp) were for the aliphatic amides 10.53 and -23.67 (×10(-6) Å(3)/molecule) and for the aromatic amides 2.12 and -10.43 (×10(-6) Å(3)/molecule). The nitrogen anisotropy was 7.62 (×10(-6) Å(3)/molecule). These values are compared with previous literature values. The (1)H chemical shifts were calculated from the semi-empirical approach and also by gauge-independent atomic orbital calculations with the density functional theory method and B3LYP/6-31G(++) (d,p) basis set. The semi-empirical approach gave good agreement with root mean square error of 0.081 ppm for the data set of 280 entries. The gauge-independent atomic orbital approach was generally acceptable, but significant errors (ca. 1 ppm) were found for the NH and CHO protons and also for some other protons.

  4. On the temperature dependence of amide I frequencies of peptides in solution.

    Science.gov (United States)

    Amunson, Krista E; Kubelka, Jan

    2007-08-23

    The temperature dependence of the amide I vibrational frequencies of peptides in solution was investigated. In D2O, the amide I' bands of both an alpha-helical oligopeptide, the random-coil poly(L-lysine), and the simplest amide, N-methyl acetamide (NMA), exhibit linear frequency shifts of approximately 0.07 cm(-1)/degrees C with increasing temperature. Similar amide I frequency shifts are also observed for NMA in both polar (acetonitrile and DMSO) and nonpolar (1,4-dioxane) organic solvents, thus ruling out hydrogen-bonding strength as the cause of these effects. The experimental NMA amide I frequencies in the organic solvents can be accurately described by a simple theory based on the Onsager reaction field with temperature-dependent solvent dielectric properties and a solute molecular cavity. DFT-level calculations (BPW91/cc-pVDZ) for NMA with an Onsager reaction field confirm the significant contribution of the molecular cavity to the predicted amide I frequencies. Comparison of the computations to experimental data shows that the frequency-dependent response of the reaction field, taken into account by the index of refraction, is crucial for describing the amide I frequencies in polar solvents. The poor predictions of the model for the NMA amide I band in D2O might be due, in part, to the unknown temperature dependence of the refractive index of D2O in the mid-IR range, which was approximated by the available values in the visible region.

  5. Palladium-catalyzed Substitution of Ketone or Aldehyde Bearing Aryl Triflates by Amines or Amides

    Institute of Scientific and Technical Information of China (English)

    TAO Xiaochun; DAI Chunya; CAO Xiongjie; CAI Lisheng; PIKE Victor W

    2009-01-01

    Various aryl triflates, bearing ketone or aldehyde groups, were evaluated for palladium-mediated introduction of an amino group at the triflate position in the presence of various phosphine ligands. BINAP was best for secondary amines, MOP-type ligand for primary or small secondary amines and Xantphos for primary or cyclic secondary amides. No ligand was found effective for acyclic secondary amides.

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

    Science.gov (United States)

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

    2016-09-16

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

  7. A case study on the myth of emission from aliphatic amides

    Science.gov (United States)

    Singh, Avinash Kumar; Das, Sreyashi; Datta, Anindya

    2016-12-01

    For several decades, aliphatic amidic compounds have been believed to be emissive. We report that this contention is incorrect and that the anomalous emission from amides originates in fluorescent impurities generated during their synthesis. In order to make this point, we have synthesized fluorescent compounds and have compared the absorption spectra with excitation spectra.

  8. Dynamics of urokinase receptor interaction with Peptide antagonists studied by amide hydrogen exchange and mass spectrometry

    DEFF Research Database (Denmark)

    Jørgensen, Thomas J D; Gårdsvoll, Henrik; Danø, Keld

    2004-01-01

    Using amide hydrogen exchange combined with electrospray ionization mass spectrometry, we have in this study determined the number of amide hydrogens on several peptides that become solvent-inaccessible as a result of their high-affinity interaction with the urokinase-type plasminogen activator r...

  9. Assessing Spectral Simulation Protocols for the Amide I Band of Proteins

    NARCIS (Netherlands)

    Cunha, Ana V.; Bondarenko, Anna S.; Jansen, Thomas L. C.

    2016-01-01

    We present a benchmark study of spectral simulation protocols for the amide I band of proteins. The amide I band is widely used in infrared spectroscopy of proteins due to the large signal intensity, high sensitivity to hydrogen bonding, and secondary structural motifs. This band has, thus, proven v

  10. An azole, an amide and a limonoid from Vepris uguenensis (Rutaceae).

    Science.gov (United States)

    Cheplogoi, Peter K; Mulholland, Dulcie A; Coombes, Philip H; Randrianarivelojosia, Milijaona

    2008-04-01

    The limonoid derivative, methyl uguenenoate, the azole, uguenenazole, and the amide, uguenenonamide, together with the known furoquinoline alkaloids flindersiamine and maculosidine, and syringaldehyde have been isolated from the root of the East African Rutaceae Vepris uguenensis. While methyl uguenenoate and the furoquinoline alkaloids displayed mild antimalarial activity, the azole and amide were completely inactive.

  11. Alpha-amidated peptides derived from pro-opiomelanocortin in normal human pituitary

    DEFF Research Database (Denmark)

    Fenger, M; Johnsen, A H

    1988-01-01

    Normal human pituitaries were extracted in boiling water and acetic acid, and the alpha-amidated peptide products of pro-opiomelanocortin (POMC), alpha-melanocyte-stimulating hormone (alpha MSH), gamma-melanocyte-stimulating hormone (gamma 1MSH), and amidated hinge peptide (HP-N), as well...

  12. A nordehydroabietyl amide-containing chiral diene for rhodium-catalysed asymmetric arylation to nitroolefins.

    Science.gov (United States)

    Li, Ruikun; Wen, Zhongqing; Wu, Na

    2016-11-29

    A highly enantioselective rhodium catalysed asymmetric arylation (RCAA) of nitroolefins with arylboronic acids is presented using a newly developed, C1-symmetric, non-covalent interacted, phellandrene derived, nordehydroabietyl amide-containing chiral diene under mild conditions. Stereoelectronic effects were studied, suggesting an activation of the bound substrate through the secondary amide as a hydrogen-bond donor.

  13. A General and Efficient CuBr2-Catalyzed N-Arylation of Secondary Acyclic Amides

    Institute of Scientific and Technical Information of China (English)

    王满刚; 于华; 尤心稳; 吴军; 商志才

    2012-01-01

    A general and efficient Cu(II)-catalyzed cross-coupling method is reported for the preparation of acyclic tertiary amides. Generally moderate to excellent yields and functional group tolerance were obtained with secondary acyclic amides and aryl halides as substrates in toluene.

  14. Polycarbonate modified with crystallisable bis-ester tetra-amide units in a reaction extrusion process

    NARCIS (Netherlands)

    Zuiderduin, W.C.J.; Gaymans, R.J.

    2008-01-01

    Dry blends of polycarbonate (PC) and a bis-ester tetra-amide were extruded at 305 °C with a mini twin screw extruder. The bis-ester tetra-amide diamide (T6T6T-dimethyl) was composed of two and a half repeat units of Nylon 6,T and had methyl ester endgroups. During the extrusion, a

  15. Optimizing production of Fc-amidated peptides by Chinese hamster ovary cells.

    Science.gov (United States)

    Carlson, Kristina; Pomerantz, Steven C; Vafa, Omid; Naso, Michael; Strohl, William; Mains, Richard E; Eipper, Betty A

    2015-10-16

    Amidation of the carboxyl terminal of many peptides is essential for full biological potency, often increasing receptor binding and stability. The single enzyme responsible for this reaction is peptidylglycine α-amidating monooxygenase (PAM: EC 1.14.17.3), a copper- and ascorbate-dependent Type I membrane protein. To make large amounts of high molecular weight amidated product, Chinese hamster ovary (CHO) cells were engineered to express exogenous PAM. To vary access of the enzyme to its substrate, exogenous PAM was targeted to the endoplasmic reticulum, trans-Golgi network, endosomes and lysosomes or to the lumen of the secretory pathway. PAM was equally active when targeted to each intracellular location and assayed in homogenates. Immunocytochemical analyses of CHO cells and a pituitary cell line demonstrated that targeting of exogenous PAM was partially successful. PAM substrates generated by expressing peptidylglycine substrates (glucagon-like peptide 1-Gly, peptide YY-Gly and neuromedin U-Gly) fused to the C-terminus of immunoglobulin Fc in CHO cell lines producing targeted PAM. The extent of amidation of the Fc-peptides was determined by mass spectrometry and amidation-specific enzyme immunoassays. Amidation was inhibited by copper chelation, but was not enhanced by the addition of additional copper or ascorbate. Peptide amidation was increased over endogenous levels by exogenous PAM, and targeting PAM to the endoplasmic reticulum or trans-Golgi network increased peptide amidation compared to endogenous CHO PAM.

  16. A structure-activity relationship study of small-molecule inhibitors of GLI1-mediated transcription.

    Science.gov (United States)

    Actis, Marcelo; Connelly, Michele C; Mayasundari, Anand; Punchihewa, Chandanamali; Fujii, Naoaki

    2011-01-01

    We have previously reported ketoprofen amide compounds as inhibitors of GLI1-mediated transcription, an essential down-stream element of the Hedgehog (Hh) pathway. These compounds inhibited Gli-luciferase reporter in C3H10T1/2 cells that were exogenously transfected with GLI1 and in Rh30 cells that endogenously overexpress GLI1. Here we have designed new derivatives of these compounds aiming to explore the structure-activation relationship (SAR). By replacing the ketone carbonyl group of the ketoprofen moiety with an ether, amide, sulfonamide, or sulfone, we found several new compounds that are equipotent to the ketoprofen amide compounds. Among them, sulfone 30 inhibited Gli-luciferase reporter in C3H10T1/2 cells that were exogenously transfected with GLI1 and in Rh30 cells that endogenously overexpress GLI1.

  17. Simulating the covalent modification of Fe(Ⅲ)-salophen with amino acid histidine or dipeptide Cys-His%氨基酸His或二肽Cys-His共价修饰Fe(Ⅲ)-salophen的计算机模拟

    Institute of Scientific and Technical Information of China (English)

    林英武

    2007-01-01

    Comparing with the structure of heme group that covalently linked to the polypeptide chain in natural heme proteins, we simulated the covalent modification of artificial Fe(Ⅲ)-salophen complex with amino acid histidine (His) or dipeptide cysteinyl-histidine (Cys-His), with the intention of providing useful information for design of metalloproteins containing nonnatural prosthetic group. By using molecular mechanics MM+ method, the molecular geometries were optimized, and then the single point calculation was carried out on the obtained structure with minimum energy by using semi-empirical ZINDO/1 method. Results illustrate that, with His serving as the fifth ligand of Fe(Ⅲ)-salophen, the molecule would be more stable when it was modified covalently, through forming an amide bond with His, by introducing a propionic group rather than a formic group. At the same time,the molecule would be more stable as modification occurred at position a rather than b of Fe(Ⅲ)-salophen, for both cases of His and Cys-His modification. In addition, of all these modified complexes, the most stable molecule was that being modified with dipeptide Cys-His at position a through a thioether bond that formed between the cysteine residue and an introduced vinyl group. This conformation consists with that found in natural c-type cytochromes. The current study presents the initial theoretical results, which could instruct the successful construction of functional Fe(Ⅲ)-salophen complex, and also direct its application in artificial metalloproteins design.%通过比较天然血红素蛋白中血红素与多肽链进行共价连接的结构,我们对组氨酸(His)或二肽半胱氨酰-组氨酸(Cys-His)共价修饰人工配合物Fe(Ⅲ)-salophen进行了计算机模拟,旨在为设计包含非天然辅基的金属蛋白分子提供有用的信息.修饰物采用分子力学MM+方法进行了分子构型优化,而且在最低能量构型的基础上,采用半经验量子化学ZINDO/1方

  18. Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain.

    Science.gov (United States)

    Chobanian, Harry R; Guo, Yan; Liu, Ping; Chioda, Marc D; Fung, Selena; Lanza, Thomas J; Chang, Linda; Bakshi, Raman K; Dellureficio, James P; Hong, Qingmei; McLaughlin, Mark; Belyk, Kevin M; Krska, Shane W; Makarewicz, Amanda K; Martel, Elliot J; Leone, Joseph F; Frey, Lisa; Karanam, Bindhu; Madeira, Maria; Alvaro, Raul; Shuman, Joyce; Salituro, Gino; Terebetski, Jenna L; Jochnowitz, Nina; Mistry, Shruti; McGowan, Erin; Hajdu, Richard; Rosenbach, Mark; Abbadie, Catherine; Alexander, Jessica P; Shiao, Lin-Lin; Sullivan, Kathleen M; Nargund, Ravi P; Wyvratt, Matthew J; Lin, Linus S; DeVita, Robert J

    2014-06-12

    We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

  19. Robust trans-amide helical structure of oligomers of bicyclic mimics of β-proline: impact of positional switching of bridgehead substituent on amide cis-trans equilibrium.

    Science.gov (United States)

    Wang, Siyuan; Otani, Yuko; Liu, Xin; Kawahata, Masatoshi; Yamaguchi, Kentaro; Ohwada, Tomohiko

    2014-06-06

    Because homooligomers of 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acid, a bridged β-proline analogue with a substituent installed at the remote C4-bridgehead position, completely biased the amide cis-trans equilibrium to the cis-amide structure, we expected that introduction of a substituent at the C1-bridgehead position adjacent to the carboxylic acid moiety, rather than the remote C4-bridgehead position, would tip the cis-trans amide equilibrium toward trans-amide structure without the aid of hydrogen bonding. Thus, in this work we established an efficient synthetic route to an optically active bicyclic analogue of 1,1-disubstituted β-proline, bearing a substituent at the C1-bridgehead position. Crystallographic, spectroscopic, and computational studies showed that indeed oligomers of this analogue take a consistent helical structure involving all-trans-amide linkages, independently of the number of residues, from the dimer up to the octamer. Oligomers composed of (R)-β-amino acid units form an extended left-handed helix with about 2.7 residues per turn and an approximately 4.0 Å rise per residue, characterized by complete lack of main-chain hydrogen bonding. This unique helical structure shows some similarity in shape to the trans-amide-based polyproline II (PPII) helix. The present helix was stable in various kinds of solvents such as alcohols. The present work provided a fundamental structural basis for future applications.

  20. Fast acquisition of high resolution 4-D amide-amide NOESY with diagonal suppression, sparse sampling and FFT-CLEAN.

    Science.gov (United States)

    Werner-Allen, Jon W; Coggins, Brian E; Zhou, Pei

    2010-05-01

    Amide-amide NOESY provides important distance constraints for calculating global folds of large proteins, especially integral membrane proteins with beta-barrel folds. Here, we describe a diagonal-suppressed 4-D NH-NH TROSY-NOESY-TROSY (ds-TNT) experiment for NMR studies of large proteins. The ds-TNT experiment employs a spin state selective transfer scheme that suppresses diagonal signals while providing TROSY optimization in all four dimensions. Active suppression of the strong diagonal peaks greatly reduces the dynamic range of observable signals, making this experiment particularly suitable for use with sparse sampling techniques. To demonstrate the utility of this method, we collected a high resolution 4-D ds-TNT spectrum of a 23kDa protein using randomized concentric shell sampling (RCSS), and we used FFT-CLEAN processing for further reduction of aliasing artifacts - the first application of these techniques to a NOESY experiment. A comparison of peak parameters in the high resolution 4-D dataset with those from a conventionally-sampled 3-D control spectrum shows an accurate reproduction of NOE crosspeaks in addition to a significant reduction in resonance overlap, which largely eliminates assignment ambiguity. Likewise, a comparison of 4-D peak intensities and volumes before and after application of the CLEAN procedure demonstrates that the reduction of aliasing artifacts by CLEAN does not systematically distort NMR signals.

  1. Structure-activity studies on the C-terminal amide of substance P.

    Science.gov (United States)

    Escher, E; Couture, R; Poulos, C; Pinas, N; Mizrahi, J; Theodoropoulos, D; Regoli, D

    1982-11-01

    Twelve C-terminal heptapeptide analogues of substance P have been synthesized by solid phase and by the classical solution method. The modifications concerned all the C-terminal primary amide of SP and should therefore help to understand the biological significance of this carboxamide, as evaluated by in vivo and in vitro bioassays. From the results it can be seen that not the slightest change of the two amide protons is tolerated without an important loss of activity: replacement of one or two amide protons with alkyl groups, extension of the amide to the hydrazide and its alkyl analogues, and exchange of the amide with an ester or a carboxylic acid all reduce the relative activity/affinity at least by 2-fold. It is not clear for what reason all these modifications produce such a drastic activity reduction.

  2. Synthesis of amide-functionalized cellulose esters by olefin cross-metathesis.

    Science.gov (United States)

    Meng, Xiangtao; Edgar, Kevin J

    2015-11-05

    Cellulose esters with amide functionalities were synthesized by cross-metathesis (CM) reaction of terminally olefinic esters with different acrylamides, catalyzed by Hoveyda-Grubbs 2nd generation catalyst. Chelation by amides of the catalyst ruthenium center caused low conversions using conventional solvents. The effects of both solvent and structure of acrylamide on reaction conversion were investigated. While the inherent tendency of acrylamides to chelate Ru is governed by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides, from 50% to up to 99%. Homogeneous hydrogenation using p-toluenesulfonyl hydrazide successfully eliminated the α,β-unsaturation of the CM products to give stable amide-functionalized cellulose esters. The amide-functionalized product showed higher Tg than its starting terminally olefinic counterpart, which may have resulted from strong hydrogen bonding interactions of the amide functional groups.

  3. Pyrrolic Amide: A New Hydrogen Bond Building Block for Self-assembly

    Institute of Scientific and Technical Information of China (English)

    YIN Zhen-Ming; LI Jian-Feng; HE Jia-Qi; ZHU Xiao-Qing; CHENG Jin-Pei

    2003-01-01

    @@ Molecular self-assembly has emerged as a powerful technology for the synthesis of nanostructured materials. In design of various molecular assemblies, hydrogen bonding is a preferably selected intra- or inter-molecular weak interaction in recent research by virtue of the directionality and specificity. The research for novel hydrogen bond building blocks that self-assembly into well defined structures is great important not only for gaining an understanding of the concepts of self-assembly but also for the design of new molecular materials. Pyrrolic amide moiety has one hydrogen bond acceptor (C =O) and two hydrogen bond donors (pyrrole NH and amide NH). By deliberately design, pyrrolic amide compounds would be new kinds hydrogen bond building blocks. So, pyrrolic amide compounds 1 ~ 6, which bear one, two or three pyrrolic amide moieties respectively, were designed and synthesized.

  4. Synthesis and antimicrobial activity of amide derivatives of polyether antibiotic-salinomycin.

    Science.gov (United States)

    Huczyński, Adam; Janczak, Jan; Stefańska, Joanna; Antoszczak, Michał; Brzezinski, Bogumil

    2012-07-15

    For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic-salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical gram-positive cocci, gram-negative rods and yeast-like organisms, as well as against a series of clinical isolates of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256 μg/mL to active with MIC of 2 μg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against gram-positive bacteria, MRSA and MSSA.

  5. Cu-catalyzed arylation of phosphinic amide facilitated by (±)-trans-cyclohexane-1,2-diamine

    Institute of Scientific and Technical Information of China (English)

    Juan Li; Song Lin Zhang; Chuan Zhou Tao; Yao Fu; Qing Xiang Guo

    2007-01-01

    Cu-catalyzed cross coupling between phosphinic amides and aryl halides was accomplished for the first time by using (±)-transcyclohexane-1,2-diamine as the ligand. This reaction provided a novel approach for synthesizing arylated phosphinic amides. Both kinetic measurement and theoretical calculation indicated that phosphinic amides were much less reactive than amides by about 10times in Cu-catalyzed cross coupling.

  6. Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).

    Science.gov (United States)

    MacKinnon, Colin H; Lau, Kevin; Burch, Jason D; Chen, Yuan; Dines, Jonathon; Ding, Xiao; Eigenbrot, Charles; Heifetz, Alexander; Jaochico, Allan; Johnson, Adam; Kraemer, Joachim; Kruger, Susanne; Krülle, Thomas M; Liimatta, Marya; Ly, Justin; Maghames, Rosemary; Montalbetti, Christian A G N; Ortwine, Daniel F; Pérez-Fuertes, Yolanda; Shia, Steven; Stein, Daniel B; Trani, Giancarlo; Vaidya, Darshan G; Wang, Xiaolu; Bromidge, Steven M; Wu, Lawren C; Pei, Zhonghua

    2013-12-01

    Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.

  7. Measurement and Correlation for Solubility of (S)-(+)-2,2-Dimethyl-cyclopropane Carbox Amide in Different Solvents%(S)-(+)-2,2-二甲基环丙烷甲酰胺在不同溶剂中溶解度的测定与关联

    Institute of Scientific and Technical Information of China (English)

    石晓华; 周彩荣; 高玉国; 陈新志

    2006-01-01

    (S)-(+)-2,2-dimethylcyclopropane carbox amide is a key intermediate of Cilastatin, an inhibitor of dehydropeptidase-I. Its corresponding solid-liquid equilibrium data will provide essential support for industrial design and further theoretical studies. The solubilities of (S)-(+)-2,2-dimethylcyclopropane carbox amide in toluene, dichloromethane, trichloromethane, ethyl acetate, ethanol and pure water at different temperature were measured using the synthetic method by a laser monitoring observation technique. The solubility data were correlated with the modified Apelblat equation. The calculated values were good in agreement with the experimental values.

  8. Mammalian peptidylglycine alpha-amidating monooxygenase mRNA expression can be modulated by the La autoantigen

    DEFF Research Database (Denmark)

    Brenet, Fabienne; Dussault, Nadège; Borch, Jonas

    2005-01-01

    Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the COOH-terminal alpha-amidation of peptidylglycine substrates, yielding amidated products. We have previously reported a putative regulatory RNA binding protein (PAM mRNA-BP) that binds specifically to the 3' untranslat...

  9. Lead optimization studies of cinnamic amide EP2 antagonists.

    Science.gov (United States)

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.

  10. Two benzoyl coumarin amide fluorescence chemosensors for cyanide anions

    Science.gov (United States)

    Wang, Zian; Wu, Qianqian; Li, Jiale; Qiu, Shuang; Cao, Duxia; Xu, Yongxiao; Liu, Zhiqiang; Yu, Xueying; Sun, Yatong

    2017-08-01

    Two new benzoyl coumarin amide derivatives with ortho hydroxyl benzoyl as terminal group have been synthesized. Their photophysical properties and recognition properties for cyanide anions in acetonitrile have also been examined. The influence of electron donating diethylamino group in coumarin ring and hydroxyl in benzoyl group on recognition properties was explored. The results indicate that the compounds can recognize cyanide anions with obvious absorption and fluorescence spectral change and high sensitivity. The import of diethylamine group increases smartly the absorption ability and fluorescence intensity of the compound, which allows the recognition for cyanide anions can be observed by naked eyes. The in situ hydrogen nuclear magnetic resonance spectra combining photophysical properties change and job's plot data confirm that Michael addition between the chemosensors and cyanide anions occurs. Molecular conjugation is interrupted, which leads to fluorescence quenching. At the same time, there is a certain extent hydrogen bond reaction between cyanide and hydroxyl group in the compounds, which is beneficial to the recognition.

  11. SYNTHESIS AND MORPHOLOGICAL STRUCTURE OF POLY(PHENYLENE SULFIDE AMIDE)

    Institute of Scientific and Technical Information of China (English)

    WU Qixian; CHEN Yongrong; ZHOU Zuowan

    1995-01-01

    Poly(phenylene sulfide amide) (PPSA) has been synthesized by using sulfur as Ssource which reacts with dichlorobenzamide (DCBA) and alkali in polar organic solvent atthe atmospheric pressure. The polymer structures were determined by elemental analysis,FT-IR and 1H-NMR. It is shown that the yielded polymer has linear structure and itsstructure unit is -p-C6H4-CONH -p-C6H4-S-. The polymer morphology was studied byX-ray diffraction and polarized microscopy. The results show that PPSA is a crystallinepolymer and its spherulites are the aggregation of nontwisting lamella or micro-threadstructure. Under shearing force, these crystals are dispersed to form micro-fibrillarstructure. The decomposition kinetics of PPSA was also studied at different heating rates.The decomposition energy of PPSA is higher than that of PPS.

  12. Catalysis of a Flavoenzyme-Mediated Amide Hydrolysis

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Tathagata; Zhang, Yang; Abdelwahed, Sameh; Ealick, Steven E.; Begley, Tadhg P. (Cornell); (TAM)

    2010-09-13

    A new pyrimidine catabolic pathway (the Rut pathway) was recently discovered in Escherichia coli K12. In this pathway, uracil is converted to 3-hydroxypropionate, ammonia, and carbon dioxide. The seven-gene Rut operon is required for this conversion. Here we demonstrate that the flavoenzyme RutA catalyzes the initial uracil ring-opening reaction to give 3-ureidoacrylate. This reaction, while formally a hydrolysis reaction, proceeds by an oxidative mechanism initiated by the addition of a flavin hydroperoxide to the C4 carbonyl. While peroxide-catalyzed amide hydrolysis has chemical precedent, we are not aware of a prior example of analogous chemistry catalyzed by flavin hydroperoxides. This study further illustrates the extraordinary catalytic versatility of the flavin cofactor.

  13. Interacting Blends of Novel Unsaturated Polyester Amide Resin with Styrene

    Directory of Open Access Journals (Sweden)

    Hasmukh S. Patel

    2004-01-01

    Full Text Available Novel unsaturated poly (ester-amide resins (UPEAs were prepared by the reaction between an epoxy resin, namely diglycidyl ether of bisphenol–A (DGEBA and unsaturated aliphatic bisamic acids using a base catalyst. These UPEAs were then blended with a vinyl monomer namely, Styrene (STY. to produce a homogeneous resin syrup. The curing of these UPEAs-STY. resin blends was carried out by using benzoyl peroxide (BPO as a catalyst and was monitored by using a differential scanning calorimeter (DSC. The glass fibre reinforced composites (i.e. laminates of these UPEA-STY. resin blends were fabricated using the DSC data. The chemical, mechanical and electrical properties of the glass fibre composites have also been evaluated. The unreinforced cured samples of the UPEA-STY. resin blends were also analyzed by thermogravimetry (TGA.

  14. Amides and neolignans from the aerial parts of Piper bonii.

    Science.gov (United States)

    Ding, Duo-Duo; Wang, Yue-Hu; Chen, Ya-Hui; Mei, Ren-Qiang; Yang, Jun; Luo, Ji-Feng; Li, Yan; Long, Chun-Lin; Kong, Yi

    2016-09-01

    Six amides, piperbonamides A-F, three neolignans piperbonins A-C, and 11 known compounds were isolated from the aerial parts of Piper bonii (Piperaceae). The structures of piperbonamides A-F and piperbonins A-C were elucidated based on the analysis of 1D and 2D NMR and MS data. Piperbonin A, (+)-trans-acuminatin, (+)-cis-acuminatin, (+)-kadsurenone, and pipernonaline showed weak activity against platelet aggregation with IC50 values of 118.2, 108.5, 90.02, 107.3, and 116.3 μM, respectively, as compared with the positive control, tirofiban, with an IC50 value of 5.24 μM. Piperbonamides A-F were inactive against five tumor cell lines at concentrations up to 40 μM. Copyright © 2016. Published by Elsevier Ltd.

  15. Effect of Antimicrobial Peptide-Amide: Indolicidin on Biological Membranes

    Directory of Open Access Journals (Sweden)

    Attila Gergely Végh

    2011-01-01

    Full Text Available Indolicidin, a cationic antimicrobial tridecapeptide amide, is rich in proline and tryptophan residues. Its biological activity is intensively studied, but the details how indolicidin interacts with membranes are not fully understood yet. We report here an in situ atomic force microscopic study describing the effect of indolicidin on an artificial supported planar bilayer membrane of dipalmitoyl phosphatidylcholine (DPPC and on purple membrane of Halobacterium salinarum. Concentration dependent interaction of the peptide and membranes was found in case of DPPC resulting the destruction of the membrane. Purple membrane was much more resistant against indolicidin, probably due to its high protein content. Indolicidin preferred the border of membrane disks, where the lipids are more accessible. These data suggest that the atomic force microscope is a powerful tool in the study of indolicidin-membrane interaction.

  16. Polymer amide in the Allende and Murchison meteorites

    Science.gov (United States)

    McGeoch, Julie E. M.; McGeoch, Malcolm W.

    2015-11-01

    It has been proposed that exothermic gas phase polymerization of amino acids can occur in the conditions of a warm dense molecular cloud to form hydrophobic polymer amide (HPA) (McGeoch and McGeoch 2014). In a search for evidence of this presolar chemistry Allende and Murchison meteorites and a volcano control were diamond burr-etched and Folch extracted for potential HPA yielding 85 unique peaks in the meteorite samples via matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI TOF/MS). The amino acids after acid hydrolysis in Allende were below the level of detection but many of the Allende peaks via the more sensitive MALDI/TOF analysis could be fitted to a polymer combination of glycine, alanine, and alpha-hydroxyglycine with high statistical significance. A similar significant fit using these three amino acids could not be applied to the Murchison data indicating more complex polymer chemistry.

  17. Comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin).

    Science.gov (United States)

    Carson, Louise; Cathcart, George R; Scott, Christopher J; Hollenberg, Morley D; Walker, Brian; Ceri, Howard; Gilmore, Brendan F

    2011-10-01

    In this study we report for the first time the comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin) using a 160 compound focused library of N-alpha mercaptoamide dipeptides, in order to map the S(1)(') and S(2)(') binding site preferences of this important enzyme. This study has revealed a preference for the aromatic residues tyrosine and tryptophan in P(1)(') and aliphatic residues in P(2)('). From this library, six compounds were identified which exhibited sub- to low-micromolar K(i) values. The most potent inactivator, SH-CO(2)-Y-V-NH(2) was capable of preventing ZapA-mediated hydrolysis of heat-denatured IgA, indicating that these inhibitors may be capable of protecting host proteins against ZapA during colonisation and infection. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  18. Application of DEPBT on the Synthesis of the Protected Dipeptides Containing Histidine with Unprotected Imidazole Group by Solution Method

    Institute of Scientific and Technical Information of China (English)

    沈鸿雁; 田桂玲; 朱文江; 哈莎; 叶蕴华

    2003-01-01

    3- (Diethoxyphosphoryloxy)- 1,2,3-benzotriazln-4 (3H)-one (DE-PBT) was an organophosphorus coupling reagent developed by our group. It was an effective coupling reagent for the synthesis of protected peptides containing Tyr, Ser and Thr with unprotected hydroxy group on their side chain. The further study of the synthesis of a series of protected dipeptides containing hisfidine with unprotected imidazole group using DEPBT is reported. During the synthetic procedure, the imidazole group of histidine did not need to be protected. When the carboxyl components were N-protected aromatic amino acids or basic amino acids, the yields were relatively high (63%--81%). However,when the carboxyl components were N-protected acidic amino acids, the yields were relatively low (47%--48%). The results expanded the application of DEPBT on the synthesis of bioactive peptides containing histidine.

  19. Model prodrugs designed for the intestinal peptide transporter. A synthetic approach for coupling of hydroxy-containing compounds to dipeptides

    DEFF Research Database (Denmark)

    Friedrichsen, G M; Nielsen, C U; Steffansen, B

    2001-01-01

    The human peptide transporter, hPepT1, situated in the small intestine, may be exploited to increase absorption of drugs or model drugs by attaching them to a dipeptide, which is recognised by hPepT1. A synthetic protocol for this kind of model prodrugs was developed, in which model drugs...... intestine and be converted to the parent drug during or after transport into the blood circulation. Therefore, we investigated the influence of the electronegativity of the substituent in the 4-position of the phenyl ring on stability in aqueous solution at pH 6.0 and 7.4, corresponding to pH in jejunum...... and blood, respectively. In addition, the influence of the electronegativity of the substituent on stability upon storage was examined. Model prodrugs containing electron donating substituents in the 4-position of the phenyl ring decomposed upon storage, while model prodrugs containing no substituents...

  20. Bioinspired fluorescent dipeptide nanoparticles for targeted cancer cell imaging and real-time monitoring of drug release

    Science.gov (United States)

    Fan, Zhen; Sun, Leming; Huang, Yujian; Wang, Yongzhong; Zhang, Mingjun

    2016-04-01

    Peptide nanostructures are biodegradable and are suitable for many biomedical applications. However, to be useful imaging probes, the limited intrinsic optical properties of peptides must be overcome. Here we show the formation of tryptophan-phenylalanine dipeptide nanoparticles (DNPs) that can shift the peptide's intrinsic fluorescent signal from the ultraviolet to the visible range. The visible emission signal allows the DNPs to act as imaging and sensing probes. The peptide design is inspired by the red shift seen in the yellow fluorescent protein that results from π-π stacking and by the enhanced fluorescence intensity seen in the green fluorescent protein mutant, BFPms1, which results from the structure rigidification by Zn(II). We show that DNPs are photostable, biocompatible and have a narrow emission bandwidth and visible fluorescence properties. DNPs functionalized with the MUC1 aptamer and doxorubicin can target cancer cells and can be used to image and monitor drug release in real time.

  1. PARP inhibitors.

    Science.gov (United States)

    Anwar, Maheen; Aslam, Hafiz Muhammad; Anwar, Shahzad

    2015-01-01

    Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b) .The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD). PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities of breast, uterine, colorectal and ovarian cancer. This review summarizes current insights into the mechanism of action of PARP inhibitors, its recent clinical trials, and potential next steps in the evaluation of this promising class of anti-cancer drugs.

  2. Interaction of Thioamides, Selenoamides, and Amides With Diiodine

    Directory of Open Access Journals (Sweden)

    Nick Hadjiliadis

    2006-12-01

    Full Text Available We review the results of our work on the iodine interaction with thioamides, selenoamides, and amides. Complexes with (i “spoke” or “extended spoke” structures, D⋅I2 and D⋅I2⋅I2, respectively, (D is the ligand donor (ii iodonium salts of {[D2−I]+[In]−} (n=3, 7 and {[D2−I]+[FeCl4]−} formulae and (iii disulfides of the categories (a [D-D], (b {[D-DH]+[I3]−} have been isolated and characterized. A compound of formula {[D2−I]+[I3]−[D⋅I2]} containing both types of complexes (i and (ii was also isolated. The interaction of diiodine with selenium analogs of the antithyroid drug 6-n-propyl-2-thiouracil (PTU, of formulae RSeU (6-alkyl-2-Selenouracil results in the formation of complexes with formulae [(RSeUI2]. All these results are correlated with the mechanism of action of antithyroid drugs. Finally, we review here our work on the diiodine interaction with the amides (LO.

  3. In vitro transport and satiety of a beta-lactoglobulin dipeptide and beta-casomorphin-7 and its metabolites.

    Science.gov (United States)

    Osborne, Simone; Chen, Wei; Addepalli, Rama; Colgrave, Michelle; Singh, Tanoj; Tran, Cuong; Day, Li

    2014-11-01

    Understanding the digestive behaviour and biological activities of dairy proteins may help to develop model dairy products with targeted health outcomes including increased satiety and healthy weight maintenance. Caseins and whey proteins constitute over 95% of milk proteins with consumption of these proteins associated with increased satiety and a decreased prevalence of metabolic disorders. To investigate the in vitro digestive behaviour and satiety of dairy proteins at the intestinal epithelium, the in vitro transport and hydrolysis of 500-2000 μM β-casomorphin-7 (YPFPGPI or β-CM7) and a β-lactoglobulin (β-Lg) dipeptide (YL) was measured using Caco-2 cell monolayers grown on transwells as a model of the intestinal epithelium. Transport of YL was concentration dependent and ranged from 0.37-5.26 × 10(-6) cm s(-1), whereas transport of β-CM7 was only detected at 2000 μM and was significantly lower at 0.13 × 10(-6) cm s(-1). Rapid hydrolysis of β-CM7 in the apical chamber by the Caco-2 cells produced three peptide metabolites: YP, GPI and FPGPI. All of these metabolites were detected in the basolateral chamber after 30 min with both the YP and GPI peptides transporting at a higher rate than intact β-CM7. In vitro satiety was indicated by the secretion of cholecystokinin [26-33] (CCK-8) and glucagon-like peptide 1 (GLP-17-36NH2) in the STC-1 enteroendocrine cell model. CCK-8 secretion was highest in response to β-CM7 followed by the β-CM7 metabolite FPGPI. CCK-8 secretion however was not significantly stimulated by the tri- or dipeptides. Secretion of GLP-1 was not significantly stimulated by β-CM7 or YL. These in vitro results suggest that dairy peptide size enhances CCK-8 secretion, whilst limiting transport across Caco-2 monolayers.

  4. Ground-State Distortion in N-Acyl-tert-butyl-carbamates (Boc) and N-Acyl-tosylamides (Ts): Twisted Amides of Relevance to Amide N-C Cross-Coupling.

    Science.gov (United States)

    Szostak, Roman; Shi, Shicheng; Meng, Guangrong; Lalancette, Roger; Szostak, Michal

    2016-09-02

    Amide N-C(O) bonds are generally unreactive in cross-coupling reactions employing low-valent transition metals due to nN → π*C═O resonance. Herein we demonstrate that N-acyl-tert-butyl-carbamates (Boc) and N-acyl-tosylamides (Ts), two classes of acyclic amides that have recently enabled the development of elusive amide bond N-C cross-coupling reactions with organometallic reagents, are intrinsically twisted around the N-C(O) axis. The data have important implications for the design of new amide cross-coupling reactions with the N-C(O) amide bond cleavage as a key step.

  5. Finding Potent Sirt Inhibitor in Coffee: Isolation, Confirmation and Synthesis of Javamide-II (N-Caffeoyltryptophan as Sirt1/2 Inhibitor.

    Directory of Open Access Journals (Sweden)

    Jae B Park

    Full Text Available Recent studies suggest that Sirt inhibition may have beneficial effects on several human diseases such as neurodegenerative diseases and cancer. Coffee is one of most popular beverages with several positive health effects. Therefore, in this paper, potential Sirt inhibitors were screened using coffee extract. First, HPLC was utilized to fractionate coffee extract, then screened using a Sirt1/2 inhibition assay. The screening led to the isolation of a potent Sirt1/2 inhibitor, whose structure was determined as javamide-II (N-caffeoyltryptophan by NMR. For confirmation, the amide was chemically synthesized and its capacity of inhibiting Sirt1/2 was also compared with the isolated amide. Javamide-II inhibited Sirt2 (IC50; 8.7 μM better than Sirt1(IC50; 34μM. Since javamide-II is a stronger inhibitor for Sirt2 than Sirt1. The kinetic study was performed against Sirt2. The amide exhibited noncompetitive Sirt2 inhibition against the NAD+ (Ki = 9.8 μM and showed competitive inhibition against the peptide substrate (Ki = 5.3 μM. Also, a docking simulation showed stronger binding pose of javamide-II to Sirt2 than AGK2. In cellular levels, javamide-II was able to increase the acetylation of total lysine, cortactin and histone H3 in neuronal NG108-15 cells. In the same cells, the amide also increased the acetylation of lysine (K382 in p53, but not (K305. This study suggests that Javamide-II found in coffee may be a potent Sirt1/2 inhibitor, probably with potential use in some conditions of human diseases.

  6. Finding Potent Sirt Inhibitor in Coffee: Isolation, Confirmation and Synthesis of Javamide-II (N-Caffeoyltryptophan) as Sirt1/2 Inhibitor.

    Science.gov (United States)

    Park, Jae B

    2016-01-01

    Recent studies suggest that Sirt inhibition may have beneficial effects on several human diseases such as neurodegenerative diseases and cancer. Coffee is one of most popular beverages with several positive health effects. Therefore, in this paper, potential Sirt inhibitors were screened using coffee extract. First, HPLC was utilized to fractionate coffee extract, then screened using a Sirt1/2 inhibition assay. The screening led to the isolation of a potent Sirt1/2 inhibitor, whose structure was determined as javamide-II (N-caffeoyltryptophan) by NMR. For confirmation, the amide was chemically synthesized and its capacity of inhibiting Sirt1/2 was also compared with the isolated amide. Javamide-II inhibited Sirt2 (IC50; 8.7 μM) better than Sirt1(IC50; 34μM). Since javamide-II is a stronger inhibitor for Sirt2 than Sirt1. The kinetic study was performed against Sirt2. The amide exhibited noncompetitive Sirt2 inhibition against the NAD+ (Ki = 9.8 μM) and showed competitive inhibition against the peptide substrate (Ki = 5.3 μM). Also, a docking simulation showed stronger binding pose of javamide-II to Sirt2 than AGK2. In cellular levels, javamide-II was able to increase the acetylation of total lysine, cortactin and histone H3 in neuronal NG108-15 cells. In the same cells, the amide also increased the acetylation of lysine (K382) in p53, but not (K305). This study suggests that Javamide-II found in coffee may be a potent Sirt1/2 inhibitor, probably with potential use in some conditions of human diseases.

  7. Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator

    DEFF Research Database (Denmark)

    Roodbeen, Renée; Paaske, Berit; Jiang, Longguang;

    2013-01-01

    The development of protease inhibitors for pharmacological intervention has taken a new turn with the use of peptidebased inhibitors. Here, we report the rational design of bicyclic peptide inhibitors of the serine protease urokinase-type plasminogen activator (uPA), based on the established...... monocyclic peptide, upain-2. It was successfully converted to a bicyclic peptide, without loss of inhibitory properties. The aim was to produce a peptide cyclised by an amide bond with an additional stabilising across-the-ring covalent bond. We expected this bicyclic peptide to exhibit a lower entropic...... burden upon binding. Two bicyclic peptides were synthesised with affinities similar to that of upain-2, and their binding energetics were evaluated by isothermal titration calorimetry. Indeed, compared to upain-2, the bicyclic peptides showed reduced loss of entropy upon binding to uPA. We also...

  8. Synergistic effects of amides from two piper species on generalist and specialist herbivores.

    Science.gov (United States)

    Richards, Lora A; Dyer, Lee A; Smilanich, Angela M; Dodson, Craig D

    2010-10-01

    Plants use a diverse mix of defenses against herbivores, including multiple secondary metabolites, which often affect herbivores synergistically. Chemical defenses also can affect natural enemies of herbivores via limiting herbivore populations or by affecting herbivore resistance to parasitoids. In this study, we performed feeding experiments to examine the synergistic effects of imides and amides (hereafter "amides") from Piper cenocladum and P. imperiale on specialist (Eois nympha, Geometridae) and generalist (Spodoptera frugiperda, Noctuidae) lepidopteran larvae. Each Piper species has three unique amides, and in each experiment, larvae were fed diets containing different concentrations of single amides or combinations of the three. The amides from P. imperiale had negative synergistic effects on generalist survival and specialist pupal mass, but had no effect on specialist survival. Piper cenocladum amides also acted synergistically to increase mortality caused by parasitoids, and the direct negative effects of mixtures on parasitoid resistance and pupal mass were stronger than indirect effects via changes in growth rate and approximate digestibility. Our results are consistent with plant defense theory that predicts different effects of plant chemistry on generalist versus adapted specialist herbivores. The toxicity of Piper amide mixtures to generalist herbivores are standard bottom-up effects, while specialists experienced the top-down mediated effect of mixtures causing reduced parasitoid resistance and associated decreases in pupal mass.

  9. Characteristic conformation of Mosher's amide elucidated using the cambridge structural database.

    Science.gov (United States)

    Ichikawa, Akio; Ono, Hiroshi; Mikata, Yuji

    2015-07-16

    Conformations of the crystalline 3,3,3-trifluoro-2-methoxy-2-phenylpropanamide derivatives (MTPA amides) deposited in the Cambridge Structural Database (CSD) were examined statistically as Racid-enantiomers. The majority of dihedral angles (48/58, ca. 83%) of the amide carbonyl groups and the trifluoromethyl groups ranged from -30° to 0° with an average angle θ1 of -13°. The other conformational properties were also clarified: (1) one of the fluorine atoms was antiperiplanar (ap) to the amide carbonyl group, forming a staggered conformation; (2) the MTPA amides prepared from primary amines showed a Z form in amide moieties; (3) in the case of the MTPA amide prepared from a primary amine possessing secondary alkyl groups (i.e., Mosher-type MTPA amide), the dihedral angles between the methine groups and the carbonyl groups were syn and indicative of a moderate conformational flexibility; (4) the phenyl plane was inclined from the O-Cchiral bond of the methoxy moiety with an average dihedral angle θ2 of +21°; (5) the methyl group of the methoxy moiety was ap to the ipso-carbon atom of the phenyl group.

  10. Amides are excellent mimics of phosphate internucleoside linkages and are well tolerated in short interfering RNAs.

    Science.gov (United States)

    Mutisya, Daniel; Selvam, Chelliah; Lunstad, Benjamin D; Pallan, Pradeep S; Haas, Amanda; Leake, Devin; Egli, Martin; Rozners, Eriks

    2014-06-01

    RNA interference (RNAi) has become an important tool in functional genomics and has an intriguing therapeutic potential. However, the current design of short interfering RNAs (siRNAs) is not optimal for in vivo applications. Non-ionic phosphate backbone modifications may have the potential to improve the properties of siRNAs, but are little explored in RNAi technologies. Using X-ray crystallography and RNAi activity assays, the present study demonstrates that 3'-CH2-CO-NH-5' amides are excellent replacements for phosphodiester internucleoside linkages in RNA. The crystal structure shows that amide-modified RNA forms a typical A-form duplex. The amide carbonyl group points into the major groove and assumes an orientation that is similar to the P-OP2 bond in the phosphate linkage. Amide linkages are well hydrated by tandem waters linking the carbonyl group and adjacent phosphate oxygens. Amides are tolerated at internal positions of both the guide and passenger strand of siRNAs and may increase the silencing activity when placed near the 5'-end of the passenger strand. As a result, an siRNA containing eight amide linkages is more active than the unmodified control. The results suggest that RNAi may tolerate even more extensive amide modification, which may be useful for optimization of siRNAs for in vivo applications.

  11. Characteristic Conformation of Mosher’s Amide Elucidated Using the Cambridge Structural Database

    Directory of Open Access Journals (Sweden)

    Akio Ichikawa

    2015-07-01

    Full Text Available Conformations of the crystalline 3,3,3-trifluoro-2-methoxy-2-phenylpropanamide derivatives (MTPA amides deposited in the Cambridge Structural Database (CSD were examined statistically as Racid-enantiomers. The majority of dihedral angles (48/58, ca. 83% of the amide carbonyl groups and the trifluoromethyl groups ranged from –30° to 0° with an average angle θ1 of −13°. The other conformational properties were also clarified: (1 one of the fluorine atoms was antiperiplanar (ap to the amide carbonyl group, forming a staggered conformation; (2 the MTPA amides prepared from primary amines showed a Z form in amide moieties; (3 in the case of the MTPA amide prepared from a primary amine possessing secondary alkyl groups (i.e., Mosher-type MTPA amide, the dihedral angles between the methine groups and the carbonyl groups were syn and indicative of a moderate conformational flexibility; (4 the phenyl plane was inclined from the O–Cchiral bond of the methoxy moiety with an average dihedral angle θ2 of +21°; (5 the methyl group of the methoxy moiety was ap to the ipso-carbon atom of the phenyl group.

  12. New synthesis route for ternary transition metal amides as well as ultrafast amide-hydride hydrogen storage materials.

    Science.gov (United States)

    Cao, Hujun; Santoru, Antonio; Pistidda, Claudio; Richter, Theresia M M; Chaudhary, Anna-Lisa; Gizer, Gökhan; Niewa, Rainer; Chen, Ping; Klassen, Thomas; Dornheim, Martin

    2016-04-14

    K2[Mn(NH2)4] and K2[Zn(NH2)4] were successfully synthesized via a mechanochemical method. The mixture of K2[Mn(NH2)4] and LiH showed excellent rehydrogenation properties. In fact, after dehydrogenation K2[Mn(NH2)4]-8LiH fully rehydrogenates within 60 seconds at ca. 230 °C and 5 MPa of H2. This is one of the fastest rehydrogenation rates in amide-hydride systems known to date. This work also shows a strategy for the synthesis of transition metal nitrides by decomposition of the mixtures of M[M'(NH2)n] (where M is an alkali or alkaline earth metal and M' is a transition metal) and metal hydrides.

  13. Probing the production of amidated peptides following genetic and dietary copper manipulations.

    Directory of Open Access Journals (Sweden)

    Ping Yin

    Full Text Available Amidated neuropeptides play essential roles throughout the nervous and endocrine systems. Mice lacking peptidylglycine α-amidating monooxygenase (PAM, the only enzyme capable of producing amidated peptides, are not viable. In the amidation reaction, the reactant (glycine-extended peptide is converted into a reaction intermediate (hydroxyglycine-extended peptide by the copper-dependent peptidylglycine-α-hydroxylating monooxygenase (PHM domain of PAM. The hydroxyglycine-extended peptide is then converted into amidated product by the peptidyl-α-hydroxyglycine α-amidating lyase (PAL domain of PAM. PHM and PAL are stitched together in vertebrates, but separated in some invertebrates such as Drosophila and Hydra. In addition to its luminal catalytic domains, PAM includes a cytosolic domain that can enter the nucleus following release from the membrane by γ-secretase. In this work, several glycine- and hydroxyglycine-extended peptides as well as amidated peptides were qualitatively and quantitatively assessed from pituitaries of wild-type mice and mice with a single copy of the Pam gene (PAM(+/- via liquid chromatography-mass spectrometry-based methods. We provide the first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates. Wild-type mice fed a copper deficient diet and PAM(+/- mice exhibit similar behavioral deficits. While glycine-extended reaction intermediates accumulated in the PAM(+/- mice and reflected dietary copper availability, amidated products were far more prevalent under the conditions examined, suggesting that the behavioral deficits observed do not simply reflect a lack of amidated peptides.

  14. Probing the production of amidated peptides following genetic and dietary copper manipulations.

    Science.gov (United States)

    Yin, Ping; Bousquet-Moore, Danielle; Annangudi, Suresh P; Southey, Bruce R; Mains, Richard E; Eipper, Betty A; Sweedler, Jonathan V

    2011-01-01

    Amidated neuropeptides play essential roles throughout the nervous and endocrine systems. Mice lacking peptidylglycine α-amidating monooxygenase (PAM), the only enzyme capable of producing amidated peptides, are not viable. In the amidation reaction, the reactant (glycine-extended peptide) is converted into a reaction intermediate (hydroxyglycine-extended peptide) by the copper-dependent peptidylglycine-α-hydroxylating monooxygenase (PHM) domain of PAM. The hydroxyglycine-extended peptide is then converted into amidated product by the peptidyl-α-hydroxyglycine α-amidating lyase (PAL) domain of PAM. PHM and PAL are stitched together in vertebrates, but separated in some invertebrates such as Drosophila and Hydra. In addition to its luminal catalytic domains, PAM includes a cytosolic domain that can enter the nucleus following release from the membrane by γ-secretase. In this work, several glycine- and hydroxyglycine-extended peptides as well as amidated peptides were qualitatively and quantitatively assessed from pituitaries of wild-type mice and mice with a single copy of the Pam gene (PAM(+/-)) via liquid chromatography-mass spectrometry-based methods. We provide the first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates. Wild-type mice fed a copper deficient diet and PAM(+/-) mice exhibit similar behavioral deficits. While glycine-extended reaction intermediates accumulated in the PAM(+/-) mice and reflected dietary copper availability, amidated products were far more prevalent under the conditions examined, suggesting that the behavioral deficits observed do not simply reflect a lack of amidated peptides.

  15. Acceleration of Amide Bond Rotation by Encapsulation in the Hydrophobic Interior of a Water-Soluble Supramolecular Assembly

    Energy Technology Data Exchange (ETDEWEB)

    Pluth, Michael D.; Bergman, Robert G.; Raymond, Kenneth N.

    2008-04-08

    The hydrophobic interior cavity of a self-assembled supramolecular assembly exploits the hydrophobic effect for the encapsulation of tertiary amides. Variable temperature 1H NMR experiments reveal that the free energy barrier for rotation around the C-N amide bond is lowered by up to 3.6 kcal/mol upon encapsulation. The hydrophobic cavity of the assembly is able to stabilize the less polar transition state of the amide rotation process. Carbon-13 labeling studies showed that the {sup 13}C NMR carbonyl resonance increases with temperature for the encapsulated amides which suggests that the assembly is able to favor a twisted for of the amide.

  16. The Catalysis of NAD+, NADP+ and Nicotinic Amide for Methanol Electrooxidation at Platinum Electrode

    Institute of Scientific and Technical Information of China (English)

    ZHANG Ping; SHI Yufang; ZHANG Qiaolian; TANG Zhiyong; ZHENG Hongtao; YUAN Runzhang

    2006-01-01

    A group of liquid catalysts composed of nicotinic amide functioning on the anode of DMFC were investigated at a Pt electrode, which were nicotinic amide, nicotinamide adenine dinucleotide (NAD+) and its phosphate (NAD(P)+). The kinetics of methanol anode oxidation in the three reaction systems was compared by measuring potentiodynamic current-potential curves and AC impedances. The experimental results show that the dynamic behavior of methanol oxidation at a Pt electrode has been changed with adding the three substances. The influence of temperature on the catalysis of these coenzymes and nicotinic amide was discussed by comparing the AC impedances spectra of methanol oxidation at different temperatures.

  17. Chelate effects in sulfate binding by amide/urea-based ligands.

    Science.gov (United States)

    Jia, Chuandong; Wang, Qi-Qiang; Begum, Rowshan Ara; Day, Victor W; Bowman-James, Kristin

    2015-07-01

    The influence of chelate and mini-chelate effects on sulfate binding was explored for six amide-, amide/amine-, urea-, and urea/amine-based ligands. Two of the urea-based hosts were selective for SO4(2-) in water-mixed DMSO-d6 systems. Results indicated that the mini-chelate effect provided by a single urea group with two NH binding sites appears to provide enhanced binding over two amide groups. Furthermore, additional urea binding sites incorporated into the host framework appeared to overcome to some extent competing hydration effects with increasing water content.

  18. Studies and Applications of Metals for the Synthesis of Carbinols, Amides and Carbohydrates

    DEFF Research Database (Denmark)

    Osztrovszky, Gyorgyi

    the carbonyl addition was found to be faster or comparable to the protonation by the reagent. Project 2: Ruthenium catalyzed synthesis of amides from primary alcohols and amines The direct synthesis of amides from alcohols and amines with the simultaneous liberation of dihydrogen was previously discovered...... for the amidation. These two systems do not show any significant differences in reactivity indicating that the same catalytically active species is operating. Project 3: Synthesis of a trisaccharide probe as a putative dengue virus receptor At the Institute for Glycomics major research has been devoted to identify...

  19. Poly(methylhydrosiloxane) as a green reducing agent in organophosphorus-catalysed amide bond formation.

    Science.gov (United States)

    Hamstra, Daan F J; Lenstra, Danny C; Koenders, Tjeu J; Rutjes, Floris P J T; Mecinović, Jasmin

    2017-08-02

    Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green reducing agent for in situ reduction of phosphine oxide to phosphine. The reported method enables the synthesis of a wide range of secondary and tertiary amides in very good to excellent yields.

  20. Ruthenium(II)-Catalyzed Regioselective Ortho Amidation of Imidazo Heterocycles with Isocyanates.

    Science.gov (United States)

    Shakoor, S M Abdul; Kumari, Santosh; Khullar, Sadhika; Mandal, Sanjay K; Kumar, Anil; Sakhuja, Rajeev

    2016-12-16

    Direct ortho amidation at the phenyl ring of 2-phenylimidazo heterocycles with aryl isocyanates has been achieved via a chelation-assisted cationic ruthenium(II) complex catalyzed mechanism. The methodology provides a straightforward, high-yielding regioselective approach toward the synthesis of an array of ortho-amidated phenylimidazo heterocycles without prior activation of C(sp(2))-H. This also reports the first method for coupling of aryl isocyanates with the imidazo[1,2-a]pyridine system via a pentacyclometalated intermediate. The methodology is found to be easily scalable and could be applied toward the selective ortho amidation of 2-heteroarylimidazo[1,2-a]pyridine frameworks.

  1. Amide Synthesis from Alcohols and Amines by the Extrusion of Dihydrogen

    DEFF Research Database (Denmark)

    Nordstrøm, Lars Ulrik Rubæk; Vogt, Henning; Madsen, R.

    2008-01-01

    An environmentally friendly method for synthesis of amides is presented where a simple ruthenium catalyst mediates the direct coupling between an alcohol and an amine with the liberation of two molecules of dihydrogen. The active catalyst is generated in situ from an easily available ruthenium...... complex, an N-heterocyclic carbene and a phosphine. The reaction allows primary alcohols to be coupled with primary alkyamines to afford the corresponding secondary amides in good yields. The amide formation presumably proceeds through a catalytic cycle where the intermediate aldehyde and hemiaminal...... are both coordinated to the metal catalyst....

  2. Mesoporous Niobium Oxide Spheres as an Effective Catalyst for the Transamidation of Primary Amides with Amines

    KAUST Repository

    Ghosh, Subhash Chandra

    2014-02-06

    Mesoporous niobium oxide spheres (MNOS), conveniently prepared by a novel antisolvent precipitation approach, have been shown to be an effective catalyst for the transamidation of primary amides with amines. This novel transamidation can be efficiently carried out under solvent-free conditions and is applicable to a wide range of primary amides and amines to provide N-alkyl amides in good to excellent yields. The catalyst is highly stable and reusable. The application of this transamidation reaction has been demonstrated in the synthesis of antidepressant drug moclobemide and other druglike compounds. © 2014 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim.

  3. Palladium-catalyzed Suzuki-Miyaura coupling of amides by carbon-nitrogen cleavage: general strategy for amide N-C bond activation.

    Science.gov (United States)

    Meng, Guangrong; Szostak, Michal

    2016-06-15

    The first palladium-catalyzed Suzuki-Miyaura cross-coupling of amides with boronic acids for the synthesis of ketones by sterically-controlled N-C bond activation is reported. The transformation is characterized by operational simplicity using bench-stable, commercial reagents and catalysts, and a broad substrate scope, including substrates with electron-donating and withdrawing groups on both coupling partners, steric-hindrance, heterocycles, halides, esters and ketones. The scope and limitations are presented in the synthesis of >60 functionalized ketones. Mechanistic studies provide insight into the catalytic cycle of the cross-coupling, including the first experimental evidence for Pd insertion into the amide N-C bond. The synthetic utility is showcased by a gram-scale cross-coupling and cross-coupling at room temperature. Most importantly, this process provides a blueprint for the development of a plethora of metal catalyzed reactions of typically inert amide bonds via acyl-metal intermediates. A unified strategy for amide bond activation to enable metal insertion into N-C amide bond is outlined ().

  4. The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent.

    Science.gov (United States)

    Xie, Gang; Cheng, Ka-Wing; Huang, Liqun; Rigas, Basil

    2014-09-15

    Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked-COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism.

  5. Evidence for a Phe-Gly-Leu-amide-like allatostatin in the beetle Tenebrio molitor.

    Science.gov (United States)

    Elliott, Karen L; Chan, Kuen Kuen; Stay, Barbara

    2010-03-01

    The allatostatins (ASTs) with Phe-Gly-Leu-amide C-terminal sequence are multifunctional neuropeptides discovered as inhibitors of juvenile hormone (JH) synthesis by corpora allata (CA) of cockroaches. Although these ASTs inhibit JH synthesis only in cockroaches, crickets, termites and locusts, isolation of peptides or of cDNA/genomic DNA or analysis of genomes indicates their occurrence in many orders of insects with the exception of coleopterans. The gene for these ASTs has not been found in the genome of the red flour beetle Tribolium castaneum (Family Tenebrionidae). Yet, in view of widespread occurrence of these peptides in insects, crustaceans and nematodes, they would be expected to occur in beetles. This study provides evidence for the presence of FGLa-like ASTs in the tenebrionid beetle, Tenebrio molitor, and scarabid beetle, Popillia japonica. Extract of brain from both beetles inhibited JH synthesis by cockroach CA dose dependently and reversibly. 20 brain equivalents of T. molitor and P. japonica extracts inhibited JH synthesis 64+/-5 and 65+/-0.6% respectively. Antibody against cockroach allatostatin (Diploptera punctata AST-7) used in an enzyme-linked immunosorbent assay reacted with brain extract of these beetles. Antibody against D. punctata AST-5 localized FGLa-like ASTs in the brain and subesophageal ganglion of T. molitor and P. japonica. In addition, pretreatment of T. molitor brain extract with anti-D. punctata AST-5 reduced the inhibition of JH synthesis and pretreatment of anti-D. punctata AST-5 with D. punctata AST-5 diminished the immunoreactivity of the antibody. Thus we predict that FGLa-like allatostatins will be found in beetles.

  6. Design, Synthesis and Biological Evaluation of Novel Primaquine-Cinnamic Acid Conjugates of the Amide and Acylsemicarbazide Type

    Directory of Open Access Journals (Sweden)

    Kristina Pavić

    2016-11-01

    Full Text Available In this paper design and synthesis of a scaffold comprising primaquine (PQ motif and cinnamic acid derivatives (CADs bound directly (compounds 3a–k or via a spacer (compounds 7a–k are reported. In the first series of compounds, PQ and various CADs were connected by amide bonds and in the second series by acylsemicarbazide functional groups built from the PQ amino group, CONHNH spacer and the carbonyl group originating from the CADs. PQ-CAD amides 3a–k were prepared by a simple one-step condensation reaction of PQ with a series of CAD chlorides (method A or benzotriazolides 2 (method B. The synthesis of acylsemicarbazides 7a–k included activation of PQ with benzotriazole, preparation of PQ-semicarbazide 6 and its condensation with CAD chlorides 4. All synthesized PQ-CAD conjugates were evaluated for their anticancer, antiviral and antioxidative activities. Almost all compounds from series 3 were selective towards the MCF-7 cell line and active at micromolar concentrations. The o-fluoro derivative 3h showed high activity against HeLa, MCF-7 and in particular against the SW 620 cell line, while acylsemicarbazide 7f with a benzodioxole ring and 7c, 7g and especially 7j with methoxy-, chloro- or trifluoromethyl-substituents in the para position showed high selectivity and high inhibitory activity against MCF-7 cell line at micromolar (7c, 7f, 7g and nanomolar (7j levels. Acylsemicarbazide derivatives with trifluoromethyl group(s 7i, 7j and 7k showed specific activity against human coronavirus (229E at concentrations which did not alter the normal cell morphology. The same compounds exerted the most potent reducing activity in the DPPH test, together with 7d and 7g, while methoxy (compounds 7c–e, benzodioxole (7f, p-Cl (7g and m-CF3 (7i acylsemicarbazides and amide 3f presented the highest LP inhibition (83%–89%. The dimethoxy derivative 7d was the most potent LOX inhibitor (IC50 = 10 μΜ. The performed biological tests gave evidence of

  7. Design, Synthesis and Biological Evaluation of Novel Primaquine-Cinnamic Acid Conjugates of the Amide and Acylsemicarbazide Type.

    Science.gov (United States)

    Pavić, Kristina; Perković, Ivana; Gilja, Petra; Kozlina, Filip; Ester, Katja; Kralj, Marijeta; Schols, Dominique; Hadjipavlou-Litina, Dimitra; Pontiki, Eleni; Zorc, Branka

    2016-11-28

    In this paper design and synthesis of a scaffold comprising primaquine (PQ) motif and cinnamic acid derivatives (CADs) bound directly (compounds 3a-k) or via a spacer (compounds 7a-k) are reported. In the first series of compounds, PQ and various CADs were connected by amide bonds and in the second series by acylsemicarbazide functional groups built from the PQ amino group, CONHNH spacer and the carbonyl group originating from the CADs. PQ-CAD amides 3a-k were prepared by a simple one-step condensation reaction of PQ with a series of CAD chlorides (method A) or benzotriazolides 2 (method B). The synthesis of acylsemicarbazides 7a-k included activation of PQ with benzotriazole, preparation of PQ-semicarbazide 6 and its condensation with CAD chlorides 4. All synthesized PQ-CAD conjugates were evaluated for their anticancer, antiviral and antioxidative activities. Almost all compounds from series 3 were selective towards the MCF-7 cell line and active at micromolar concentrations. The o-fluoro derivative 3h showed high activity against HeLa, MCF-7 and in particular against the SW 620 cell line, while acylsemicarbazide 7f with a benzodioxole ring and 7c, 7g and especially 7j with methoxy-, chloro- or trifluoromethyl-substituents in the para position showed high selectivity and high inhibitory activity against MCF-7 cell line at micromolar (7c, 7f, 7g) and nanomolar (7j) levels. Acylsemicarbazide derivatives with trifluoromethyl group(s) 7i, 7j and 7k showed specific activity against human coronavirus (229E) at concentrations which did not alter the normal cell morphology. The same compounds exerted the most potent reducing activity in the DPPH test, together with 7d and 7g, while methoxy (compounds 7c-e), benzodioxole (7f), p-Cl (7g) and m-CF₃ (7i) acylsemicarbazides and amide 3f presented the highest LP inhibition (83%-89%). The dimethoxy derivative 7d was the most potent LOX inhibitor (IC50 = 10 μΜ). The performed biological tests gave evidence of

  8. Novel peptide-based protease inhibitors

    DEFF Research Database (Denmark)

    Roodbeen, Renée

    This thesis describes the design and synthesis of peptide-based serine protease inhibitors. The targeted protease, urokinase-type plasminogen activator (uPA) activates plasminogen, which plays a major role in cancer metastasis. The peptide upain-2 (S 1 ,S 12-cyclo-AcCSWRGLENHAAC-NH2) is a highly......, the disulfide bridge was replaced with amide bonds of various lengths. The novel peptides did not retain their inhibitory activity, but formed the basis for another strategy. Second, bicyclic peptides were obtained by creating head-to-tail cyclized peptides that were made bicyclic by the addition of a covalent...... increased. Finally, the effect of multivalent display of upain-2 was investigated. Several dimers of upain-2 were made and the attachment of upain-2 via the Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC) onto an alkyne functionalized carbohydrate scaffold was investigated. Besides the synthesis...

  9. Design of potent substrate-analogue inhibitors of canine renin

    Science.gov (United States)

    Hui, K. Y.; Siragy, H. M.; Haber, E.

    1992-01-01

    Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect.

  10. Intestinal drug transport via the proton-coupled amino acid transporter PAT1 (SLC36A1) is inhibited by Gly-X(aa) dipeptides

    DEFF Research Database (Denmark)

    Frølund, Sidsel; Langthaler, Louise; Kall, Morten A

    2012-01-01

    The oral absorption of some drug substances is mediated by nutrient transporters. As a consequence, nutrients and drugs may compete for available transporters, and interactions at the level of intestinal absorption are possible. Recently, we have identified δ-aminolevulinic acid, Gly-Gly, and Gly......-Sar as substrates of the amino acid transporter PAT1. The aim of the present study is to investigate if other Gly-containing dipeptides interact with PAT1, and whether they can inhibit PAT1 mediated drug absorption, in vitro and in vivo. The in vitro methods included two-electrode voltage clamp measurements on h......PAT1 expressing Xenopus laevis oocytes, which were used to investigate the PAT1-mediated transport of 17 different Gly-containing dipeptides (Gly-X(aa) or X(aa)-Gly). Also, the transepithelial transport of the PAT1 substrate gaboxadol was investigated across Caco-2 cell monolayers in the presence...

  11. Lead identification of novel and selective TYK2 inhibitors.

    Science.gov (United States)

    Liang, Jun; Tsui, Vickie; Van Abbema, Anne; Bao, Liang; Barrett, Kathy; Beresini, Maureen; Berezhkovskiy, Leo; Blair, Wade S; Chang, Christine; Driscoll, James; Eigenbrot, Charles; Ghilardi, Nico; Gibbons, Paul; Halladay, Jason; Johnson, Adam; Kohli, Pawan Bir; Lai, Yingjie; Liimatta, Marya; Mantik, Priscilla; Menghrajani, Kapil; Murray, Jeremy; Sambrone, Amy; Xiao, Yisong; Shia, Steven; Shin, Young; Smith, Jan; Sohn, Sue; Stanley, Mark; Ultsch, Mark; Zhang, Birong; Wu, Lawren C; Magnuson, Steven

    2013-09-01

    A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.

  12. First Novozym 435 lipase-catalyzed Morita-Baylis-Hillman reaction in the presence of amides.

    Science.gov (United States)

    Tian, Xuemei; Zhang, Suoqin; Zheng, Liangyu

    2016-03-01

    The first Novozym 435 lipase-catalyzed Morita-Baylis-Hillman (MBH) reaction with amides as co-catalyst was realized. Results showed that neither Novozym 435 nor amide can independently catalyze the reaction. This co-catalytic system that used a catalytic amount of Novozym 435 with a corresponding amount of amide was established and optimized. The MBH reaction strongly depended on the structure of aldehyde substrate, amide co-catalyst, and reaction additives. The optimized reaction yield (43.4%) was achieved in the Novozym 435-catalyzed MBH reaction of 2, 4-dinitrobenzaldehyde and cyclohexenone with isonicotinamide as co-catalyst and β-cyclodextrin as additive only in 2 days. Although enantioselectivity of Novozym 435 was not found, the results were still significant because an MBH reaction using lipase as biocatalyst was realized for the first time.

  13. Comparison of pH-sensitive degradability of maleic acid amide derivatives.

    Science.gov (United States)

    Kang, Sunyoung; Kim, Youngeun; Song, Youngjun; Choi, Jin Uk; Park, Euddeum; Choi, Wonmin; Park, Jeongseon; Lee, Yan

    2014-05-15

    We synthesized five maleic acid amide derivatives (maleic, citraconic, cis-aconitic, 2-(2'-carboxyethyl) maleic, 1-methyl-2-(2'-carboxyethyl) maleic acid amide), and compared their degradability for the future development of pH-sensitive biomaterials with tailored kinetics of the release of drugs, the change of charge density, and the degradation of scaffolds. The degradation kinetics was highly dependent upon the substituents on the cis-double bond. Among the maleic acid amide derivatives, 2-(2'-carboxyethyl) maleic acid amide with one carboxyethyl and one hydrogen substituent showed appropriate degradability at weakly acidic pH, and the additional carboxyl group can be used as a pH-sensitive linker.

  14. Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides.

    Science.gov (United States)

    Reid, Robert C; Yau, Mei-Kwan; Singh, Ranee; Lim, Junxian; Fairlie, David P

    2014-08-27

    Heterocycles adjacent to amides can have important influences on molecular conformation due to stereoelectronic effects exerted by the heteroatom. This was shown for imidazole- and thiazole-amides by comparing low energy conformations (ab initio MP2 and DFT calculations), charge distribution, dipole moments, and known crystal structures which support a general principle. Switching a heteroatom from nitrogen to sulfur altered the amide conformation, producing different three-dimensional electrostatic surfaces. Differences were attributed to different dipole and orbital alignments and spectacularly translated into opposing agonist vs antagonist functions in modulating a G-protein coupled receptor for inflammatory protein complement C3a on human macrophages. Influences of the heteroatom were confirmed by locking the amide conformation using fused bicyclic rings. These findings show that stereoelectronic effects of heterocycles modulate molecular conformation and can impart strikingly different biological properties.

  15. Functional properties of Pfr(Tic)amide and BIBP3226 at human neuropeptide FF2 receptors.

    Science.gov (United States)

    Engström, Mia; Wurster, Siegfried; Savola, Juha-Matti; Panula, Pertti

    2003-12-01

    The functional characteristics of two putative neuropeptide FF (NPFF) antagonists, BIBP3226 and PFR(Tic)amide, on the human neuropeptide FF receptor subtype 2 (hNPFF2) were investigated. Surprisingly, PFR(Tic)amide was shown to exhibit agonist properties in the [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding assay. The efficacy of PFR(Tic)amide was significantly greater than that of (1DMe)Y8Fa, a stable analog of NPFF, and PFR(Tic)amide can therefore be classified as a 'super-agonist'. BIBP3226 did act as a reversible competitive antagonist on the hNPFF2 receptor. However, high concentrations of BIBP3226 also non-specifically increased [35S]GTP-gammaS binding. The usefulness of BIBP3226 as an antagonist tool on the NPFF receptor is thus limited.

  16. Relaxation Study of N-Submitted Amides with Alcohol Mixtures by Time Domain Reflectometry

    Directory of Open Access Journals (Sweden)

    A. Arunkumar

    2016-08-01

    Full Text Available Using Time Domain Reflectometry (TDR, dielectric relaxation studies have been carried out on binary mixtures of amides (N-methylacetamide, N,N-dimethylacetamide with alcohols (1-butanol, 1-pentanol for various concentrations over the frequency range from 10 MHz to 10 GHz at 303 K. The Kirkwood correlation factor and excess dielectric constant properties were determined and discussed to yield information on the molecular interactions of the systems. The relaxation time is vary with the chain length of alcohols and substituted amides are noticed. The Bruggeman plot shows a deviation from linearity. This deviation was attributed to some sort of molecular interaction which may take place between the alcohols and substituted amides. The excess static permittivity and excess inverse relaxation time values vary from negative to positive for all the systems indicating the solute-solvent interaction to exist between alcohols and substituted amides for all the dynamics of the mixture.

  17. Copper-mediated amidation of alkenylzirconocenes with acyl azides: formation of enamides.

    Science.gov (United States)

    Liu, Hailan; Zhou, Yiqing; Yan, Xiaoyu; Chen, Chao; Liu, Qingbin; Xi, Chanjuan

    2013-10-18

    Copper-mediated amidation of alkenylzirconocenes generated in situ from alkynes and zirconocenes with acyl azides is accomplished under mild conditions. The reaction can be used to prepare various enamides.

  18. Crystal structure of the high-energy-density material guanylurea dipicryl-amide.

    Science.gov (United States)

    Deblitz, Raik; Hrib, Cristian G; Hilfert, Liane; Edelmann, Frank T

    2014-08-01

    The title compound, 1-carbamoylguanidinium bis-(2,4,6-tri-nitro-phen-yl)amide [H2NC(=O)NHC(NH2)2](+)[N{C6H2(NO2)3-2,4,6}2](-) (= guanylurea dipicryl-amide), was prepared as dark-red block-like crystals in 70% yield by salt-metathesis reaction between guanylurea sulfate and sodium dipicryl-amide. In the solid state, the new compound builds up an array of mutually linked guanylurea cations and dipicryl-amide anions. The crystal packing is dominated by an extensive network of N-H⋯O hydrogen bonds, resulting in a high density of 1.795 Mg m(-3), which makes the title compound a potential secondary explosive.

  19. Manipulation of neuropeptide biosynthesis through the expression of antisense RNA for peptidylglycine alpha-amidating monooxygenase.

    Science.gov (United States)

    Mains, R E; Bloomquist, B T; Eipper, B A

    1991-02-01

    Stable cell lines with significantly elevated or diminished levels of a key neuropeptide processing enzyme, peptidylglycine alpha-amidating monooxygenase (PAM), were generated by transfection of a mouse pituitary cell line with expression vectors containing PAM cDNA in the sense or antisense orientation. By evaluating the ability of these cell lines to alpha-amidate endogenous neuropeptides, a rate-limiting role for PAM in neuropeptide alpha-amidation was demonstrated. Overexpression of either the full-length PAM precursor with its trans-membrane domain or a soluble protein containing only the monooxygenase domain of PAM led to increased alpha-amidation of endogenous neuropeptides. Overexpression of the full-length PAM led to an unexpected decrease in the endoproteolytic processing of endogenous prohormone; conversely, underexpression of PAM led to significantly enhanced endoproteolytic processing of endogenous prohormone. These data suggest that PAM may have additional functions in peptide processing.

  20. Studies on DNA Cleaved by Seryl-histidine Dipeptide%丝组二肽对DNA的切割作用的研究

    Institute of Scientific and Technical Information of China (English)

    万荣; 王宁; 赵玉芬

    2001-01-01

    Linear and supercoiled DNA were cleaved by HPLC purified seryl-histidine dipeptide(SH). It was found that the DNA fragments produced by the reaction of SH and DNA could be ligated together by T4 DNA ligase. This result implied that the SH was the first example of the ion-free artificial DNA cleavage agent that could split DNA by hydrolysis mechanism.

  1. Ligand binding analyses of the putative peptide transporter YjdL from E. coli display a significant selectivity towards dipeptides

    DEFF Research Database (Denmark)

    Ernst, Heidi Asschenfeldt; Pham, Antony; Hald, Helle;

    2009-01-01

    -expressed the previously uncharacterized YjdL and investigated the peptide specificity by means of uptake inhibition. The IC(50) value for the dipeptide Ala-Ala was measured to 22mM while Ala-Ala-Ala was not able to inhibit uptake. In addition, IC(50) values of 0.3mM and 1.5mM were observed for Ala-Lys and Tyr...

  2. Aromatic dipeptides and their salts—Solid-state linear-dichroic infrared (IR-LD) spectral analysis and ab initio calculations

    Science.gov (United States)

    Ivanova, Bojidarka B.

    2008-07-01

    Stereo-structural analysis and IR-bands assignment of the aromatic dipeptides L-tryrosyl- L-phenylalanine ( Tyr-Phe), L-phenylalanyl- L-tyrosine ( Phe-Tyr) and their hydrochloride salts have been carried out by means of IR-LD spectroscopy of oriented as nematic liquid crystal suspension solid samples. The experimental data are compared with known crystallographic ones and theoretical predicted geometries at RHF/ and UHF/6-31G**.

  3. GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion

    DEFF Research Database (Denmark)

    Deacon, Carolyn F; Plamboeck, Astrid; Møller, Søren;

    2002-01-01

    impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7-36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1......-(9-36) amide, was investigated for any ability to influence these responses. GLP-1-(7-36) amide enhanced insulin secretion (P amide was without effect, either alone or when coinfused with GLP-1-(7-36) amide. In contrast, GLP-1-(9-36) amide did affect glucose responses (P...... amide (73 +/- 19 mmol x l(-1) x min; P amide (62 +/- 13 mmol x l(-1) x min; P amide + GLP-1-(9-36) amide (50 +/-13 mmol x l(-1) x min; P

  4. Zirconyl chloride promoted highly efficient solid phase synthesis of amide derivatives

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    An efficient solid phase route for the synthesis of amide derivatives by the reaction of carboxylic acids with urea in the presence of catalytic amount of zirconyl chloride under microwave irradiation conditions was described. In this way, a range of interesting amide derivatives was obtained in good to excellent yields. The catalyst was recycled with fresh reactants and it gave almost similar results without significant loss of activity up to the third run.

  5. Electron capture dissociation proceeds with a low degree of intramolecular migration of peptide amide hydrogens

    DEFF Research Database (Denmark)

    Rand, Kasper D; Adams, Christopher M; Zubarev, Roman A;

    2008-01-01

    scrambling) that occurs during vibrational excitation of gas-phase ions. Unlike traditional collisional ion activation, electron capture dissociation (ECD) is not associated with substantial vibrational excitation. We investigated the extent of intramolecular backbone amide hydrogen (1H/2H) migration upon...... ECD using peptides with a unique selective deuterium incorporation. Our results show that only limited amide hydrogen migration occurs upon ECD, provided that vibrational excitation prior to the electron capture event is minimized. Peptide ions that are excessively vibrationally excited...

  6. Syntheses of Macrocyclic Amides from L-Amino Acid Esters by RCM

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A series of succinate-derived macrocyclic amides( 1 ) was synthesized via ring-closing metathesis (RCM) as the key step. The substrate included 12 to 15 members. The metathesis precursors were obtained from the amide coupling of tert-butyl 3-carboxyhex-5-enoate(2) with numerous side-chain alkenylated amino acid esters of general type(3)derived from L-lysine and L-ornithine.

  7. The Synthesis and Characterisation of Novel Amide Initiators for the ATRP of OEGMA

    OpenAIRE

    Kliene, Aaron

    2015-01-01

    Whilst atom transfer radical polymerisation (ATRP) has been shown to be a robust and versatile technique for the creation of a wide range of polymers from many different initiators, there is relatively little previous research into the usage of initiators containing amide functionality. Low initiator efficiencies, often resulting in higher than predicted molecular weight parameters, and slow polymerisations with variable rates of reaction are generally reported when amide initiators have prev...

  8. Preparation and phytotoxicity of novel kaurane diterpene amides with potential use as herbicides.

    Science.gov (United States)

    Boaventura, Maria Amélia Diamantino; Pereira, Rondinelle Gomes; de Oliveira Freitas, Luiza B; Dos Reis, Leandro Alves; da Silva Vieira, Henriete

    2008-05-14

    Novel kaurane ditepene monoamides were synthesized in good yields directly from kaurenoic ( 1) and grandiflorenic ( 2) acids and unprotected symmetrical diamines, using a modified protocol for monoacylation. Amides from 1 and 2 and monoamines were also obtained and tested against seed germination and growth of radicle and shoot of Lactuca sativa (lettuce), at 10 (-3), 10 (-5), and 10 (-7) M. Amides from symmetrical diamines showed significant inhibitory activity at higher concentrations.

  9. Fatty Amide Determination in Neutral Molecular Fractions of Green Crude Hydrothermal Liquefaction Oils From Algal Biomass

    Energy Technology Data Exchange (ETDEWEB)

    Palardy, Oliver [National Renewable Energy Laboratory, 15013 Denver West Parkway, Golden, Colorado 80401, United States; Behnke, Craig [Sapphire Energy, 10996 Torreyana; Laurens, Lieve M. L. [National Renewable Energy Laboratory, 15013 Denver West Parkway, Golden, Colorado 80401, United States

    2017-07-19

    Even though hydrothermal liquefaction (HTL) is a promising route to produce crude oils (referred to as 'green crude'), the molecular composition of the nitrogen fraction of such green crude oils is not fully understood. The goal of this work was to identify and quantify the fraction of fatty amides in green crude oils obtained from five different samples derived from Desmodesmus armatus, Tetraselmis sp., and Chlorella sp. biomass treated under different HTL conditions (260 or 340 degrees C as batch or continuous processes). The goal of this work was to elucidate the nature of the high nitrogen content of the green crude oils. We identified at least 19 distinct fatty amides present in green crude oils and quantified them based on relevant standards in purified fractions after functional group-based separation and enrichment. It was not known how much these compounds contributed to the oils or which molecular fraction they are associated with. We found that fatty amides exclusively partitioned with the neutral fraction of the oils and belonged mainly to one of five categories, based on their functional group substitution, i.e., fatty amides, monomethyl, dimethyl, monoethanolamide, and diethanolamide. The quantification of fatty amides in the neutral oil fraction was based on respective fatty amide standards, after verification of consistency in response factors between molecules with different substitutions of the amide group. We found that the amount of fatty amides found in each of the five samples varied considerably and ranged between 1.4 and 3.0% of the green crude oils, with the highest levels detected in the sample with the highest oil content, after HTL of biomass derived from a nutrient deprived Chlorella sp. culture.

  10. Copper-catalyzed C(sp2)-H amidation with azides as amino sources.

    Science.gov (United States)

    Peng, Jiangling; Xie, Zeqiang; Chen, Ming; Wang, Jian; Zhu, Qiang

    2014-09-19

    A copper-catalyzed C-H amidation process, with azides as amino sources under oxidant-free conditions, has been developed. When N-heterocycles were employed as directing groups, sulfonylazide and benzoylazide could be used as amidating reagents to provide corresponding N-arylamides. When amidines or imine were used, tandem C-N/N-N bond formation occurred to afford indazole derivatives in one pot.

  11. Polycarbonate modified with crystallisable bis-ester tetra-amide units in a reaction extrusion process

    NARCIS (Netherlands)

    Zuiderduin, W.C.J.; Gaymans, R.J.

    2008-01-01

    Dry blends of polycarbonate (PC) and a bis-ester tetra-amide were extruded at 305 °C with a mini twin screw extruder. The bis-ester tetra-amide diamide (T6T6T-dimethyl) was composed of two and a half repeat units of Nylon 6,T and had methyl ester endgroups. During the extrusion, a trans-esterificati

  12. Assessment of CCSD(T), MP2, DFT-D, CBS-QB3, and G4(MP2) methods for conformational study of alanine and proline dipeptides

    Science.gov (United States)

    Kang, Young Kee; Park, Hae Sook

    2014-04-01

    The CCSD(T), MP2, dispersion-corrected DFT, CBS-QB3, and G4(MP2) levels of theory with various basis sets are assessed for their ability to describe the conformational preferences of the Ala and Pro dipeptides. The ωB97X-D/6-311++G(d,p) level of theory provided the rotational constants of the most stable conformer of the Ala dipeptide consistent with the values from microwave experiments. The double-hybrid DSD-PBEP86-D3BJ DFT method provided the best performance for relative energies of both dipeptides consistent with CCSD(T)/CBS limit values. The DSD-PBEP86-D3BJ/cc-pVTZ//M06-2X/6-31+G(d), B2PLYPD-D3BJ/cc-pVTZ//M06-2X/6-31+G(d), and M06-2X/cc-pVTZ//M06-2X/6-31+G(d) levels of theory may be an alternative to the CCSD(T)/CBS limit//ωB97X-D/6-311++G(d,p) level of theory with marginal deviations for conformational study of peptides.

  13. The dipeptide Pro-Asp promotes IGF-1 secretion and expression in hepatocytes by enhancing JAK2/STAT5 signaling pathway.

    Science.gov (United States)

    Wang, Songbo; Wang, Guoqing; Zhang, Mengyuan; Zhuang, Lu; Wan, Xiaojuan; Xu, Jingren; Wang, Lina; Zhu, Xiaotong; Gao, Ping; Xi, Qianyun; Zhang, Yongliang; Shu, Gang; Jiang, Qingyan

    2016-11-15

    It has been implicated that IGF-1 secretion can be regulated by dietary protein. However, whether the dipeptides, one of digested products of dietary protein, have influence on IGF-1 secretion remain largely unknown. Our study aimed to investigate the effects of the dipeptide Pro-Asp on IGF-1 secretion and expression in hepatocytes and to explore the possible underlying mechanisms. Our findings demonstrated that Pro-Asp promoted the secretion and gene expression of IGF-1 in HepG2 cells and primary porcine hepatocytes. Meanwhile, Pro-Asp activated the ERK and Akt signaling pathways, downstream of IGF-1. In addition, Pro-Asp enhanced GH-mediated JAK2/STAT5 signaling pathway, while inhibition of JAK2/STAT5 blocked the promotive effect of Pro-Asp on IGF-1 secretion and expression. Moreover, acute injection of Pro-Asp stimulated IGF-1 expression and activated JAK2/STAT5 signaling pathway in mice liver. Together, these results suggested that the dipeptide Pro-Asp promoted IGF-1 secretion and expression in hepatocytes by enhancing GH-mediated JAK2/STAT5 signaling pathway.

  14. NMR study of hydroxy and amide protons in hyaluronan polymers.

    Science.gov (United States)

    Nestor, Gustav; Sandström, Corine

    2017-02-10

    Hyaluronan (HA) is an important and well characterized glycosaminoglycan with high viscosity and water-retaining capacity. Nonetheless, it is not fully understood whether conformational properties of the easily characterized HA oligomers can be transferred to HA polymers. To investigate possible differences in hydration, hydrogen bonding and flexibility between HA polymers and oligomers, hydroxy and amide protons of HA polymers were studied by solution-state and high-resolution magic angle spinning (HR-MAS) NMR spectroscopy. Measurements of chemical shifts, temperature coefficients and NOEs in HA polymers revealed that the NMR data are very similar compared to the interior of a HA octasaccharide, supporting transient hydrogen bond interactions across the β(1→3) and β(1→4) glycosidic linkages. However, differences in NOEs suggested a cis-like orientation between NH and H2 in the HA polymer. The lack of concentration dependence of the hydroxy proton chemical shifts suggests that there are no direct inter-chain interactions involving hydroxy protons at the concentrations investigated.

  15. Hyperbranched Poly(amide-ester) Mildly Synthesized and Its Characterization

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AB2-type-prepolymerized monomer was rapidly (2 h) prepared atIoom temperature (25℃) using commercially available maleic anhydride (MA) and diethanolamine (DEA) as raw materials.By employing toluene-p-sulfonic acid as a catalyzer, a series of hyperbranched poly(amide-ester) (HBPAE) were successfully synthesized from prepared AB2 monomer by solution condensation polymerization through "one-step process" or "pseudo one-step process" (using pen taerythritol as a center core).The processes were carried out at high temperature of 120 C for 6 h in air atmosphere (inert protection free) with reduced pressure distillation (0.08~0.096 MPa).The results of FT-IR, UV-Vis, TGA, and intrinsic viscosity testing by Ubbelodhe viscometer showed that the prepared HBPAEspossess three-dimensional configuration with unsaturated conjugate structure,large numbers of branches and numerous terminal hydroxyl groups.These result in their lowviscosity, high solubility and thermal stability.

  16. Synthesis, characterization and pharmacological evaluation of amide prodrugs of Flurbiprofen

    Energy Technology Data Exchange (ETDEWEB)

    Mishra, Ashutosh; Veerasamy, Ravichandran; Jain, Prateek Kumar; Dixit, Vinod Kumar; Agrawal, Ram Kishor [Dr. H. S. Gour Vishwavidyalaya, Sagar (India). Dept. of Pharmaceutical Sciences. Pharmaceutical Chemistry Research Lab.]. E-mail: dragrawal2001@yahoo.co.in

    2008-07-01

    Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and {beta} alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailability studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, antiinflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose. (author)

  17. Aza-peptidyl Michael acceptor and epoxide inhibitors--potent and selective inhibitors of Schistosoma mansoni and Ixodes ricinus legumains (asparaginyl endopeptidases).

    Science.gov (United States)

    Ovat, Asli; Muindi, Fanuel; Fagan, Crystal; Brouner, Michelle; Hansell, Elizabeth; Dvorák, Jan; Sojka, Daniel; Kopácek, Petr; McKerrow, James H; Caffrey, Conor R; Powers, James C

    2009-11-26

    Aza-peptide Michael acceptors and epoxides with the general structure of YCO-Ala-Ala-AAsn-trans-CH horizontal lineCHCOR and YCO-Ala-Ala-AAsn-EP-COR, respectively, are shown to be potent inhibitors of asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE), and the hard tick, Ixodes ricinus (IrAE). Structure-activity relationships (SARs) were determined for a set of 41 aza-peptide Michael acceptors and eight aza-peptide epoxides. Both enzymes prefer disubstituted amides to monosubstituted amides in the P1' position, and potency increased as we increased the hydrophobicity of the inhibitor in this position. Extending the inhibitor to P5 resulted in increased potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues at P2. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors, and for some of these compounds, second-order inhibiton rate constants are the fastest yet discovered. Given the central functions of these enzymes in both parasites, the data presented here may facilitate the eventual design of selective antiparasitic drugs.

  18. Computational Amide I Spectroscopy for Refinement of Disordered Peptide Ensembles: Maximum Entropy and Related Approaches

    Science.gov (United States)

    Reppert, Michael; Tokmakoff, Andrei

    The structural characterization of intrinsically disordered peptides (IDPs) presents a challenging biophysical problem. Extreme heterogeneity and rapid conformational interconversion make traditional methods difficult to interpret. Due to its ultrafast (ps) shutter speed, Amide I vibrational spectroscopy has received considerable interest as a novel technique to probe IDP structure and dynamics. Historically, Amide I spectroscopy has been limited to delivering global secondary structural information. More recently, however, the method has been adapted to study structure at the local level through incorporation of isotope labels into the protein backbone at specific amide bonds. Thanks to the acute sensitivity of Amide I frequencies to local electrostatic interactions-particularly hydrogen bonds-spectroscopic data on isotope labeled residues directly reports on local peptide conformation. Quantitative information can be extracted using electrostatic frequency maps which translate molecular dynamics trajectories into Amide I spectra for comparison with experiment. Here we present our recent efforts in the development of a rigorous approach to incorporating Amide I spectroscopic restraints into refined molecular dynamics structural ensembles using maximum entropy and related approaches. By combining force field predictions with experimental spectroscopic data, we construct refined structural ensembles for a family of short, strongly disordered, elastin-like peptides in aqueous solution.

  19. UV resonance Raman investigation of the aqueous solvation dependence of primary amide vibrations.

    Science.gov (United States)

    Punihaole, David; Jakubek, Ryan S; Dahlburg, Elizabeth M; Hong, Zhenmin; Myshakina, Nataliya S; Geib, Steven; Asher, Sanford A

    2015-03-12

    We investigated the normal mode composition and the aqueous solvation dependence of the primary amide vibrations of propanamide. Infrared, normal Raman, and UV resonance Raman (UVRR) spectroscopy were applied in conjunction with density functional theory (DFT) to assign the vibrations of crystalline propanamide. We examined the aqueous solvation dependence of the primary amide UVRR bands by measuring spectra in different acetonitrile/water mixtures. As previously observed in the UVRR spectra of N-methylacetamide, all of the resonance enhanced primary amide bands, except for the Amide I (AmI), show increased UVRR cross sections as the solvent becomes water-rich. These spectral trends are rationalized by a model wherein the hydrogen bonding and the high dielectric constant of water stabilizes the ground state dipolar (-)O-C═NH2(+) resonance structure over the neutral O═C-NH2 resonance structure. Thus, vibrations with large C-N stretching show increased UVRR cross sections because the C-N displacement between the electronic ground and excited state increases along the C-N bond. In contrast, vibrations dominated by C═O stretching, such as the AmI, show a decreased displacement between the electronic ground and excited state, which result in a decreased UVRR cross section upon aqueous solvation. The UVRR primary amide vibrations can be used as sensitive spectroscopic markers to study the local dielectric constant and hydrogen bonding environments of the primary amide side chains of glutamine (Gln) and asparagine (Asn).

  20. Retinoic acid amide inhibits JAK/STAT pathway in lung cancer which leads to apoptosis.

    Science.gov (United States)

    Li, Hong-Xing; Zhao, Wei; Shi, Yan; Li, Ya-Na; Zhang, Lian-Shuang; Zhang, Hong-Qin; Wang, Dong

    2015-11-01

    Small cell lung cancer (SCLC) accounts for 12 to 16% of lung neoplasms and has a high rate of metastasis. The present study demonstrates the antiproliferative effect of retinoic acid amide in vitro and in vivo against human lung cancer cells. The results from MTT assay showed a significant growth inhibition of six tested lung cancer cell lines and inhibition of clonogenic growth at 30 μM. Retinoic acid amide also leads to G2/M-phase cell cycle arrest and apoptosis of lung cancer cells. It caused inhibition of JAK2, STAT3, and STAT5, increased the level of p21WAF1, and decreased cyclin A, cyclin B1, and Bcl-XL expression. Retinoic acid amide exhibited a synergistic effect on antiproliferative effects of methotrexate in lung cancer cells. In lung tumor xenografts, the tumor volume was decreased by 82.4% compared to controls. The retinoic acid amide-treated tumors showed inhibition of JAK2/STAT3 activation and Bcl-XL expression. There was also increase in expression of caspase-3 and caspase-9 in tumors on treatment with retinoic acid amide. Thus, retinoic acid amide exhibits promising antiproliferative effects against human lung cancer cells in vitro and in vivo and enhances the antiproliferative effect of methotrexate.