Science.gov

Sample records for acid amide derivatives

  1. Pharmaceuticals and Surfactants from Alga-Derived Feedstock: Amidation of Fatty Acids and Their Derivatives with Amino Alcohols.

    PubMed

    Tkacheva, Anastasia; Dosmagambetova, Inkar; Chapellier, Yann; Mäki-Arvela, Päivi; Hachemi, Imane; Savela, Risto; Leino, Reko; Viegas, Carolina; Kumar, Narendra; Eränen, Kari; Hemming, Jarl; Smeds, Annika; Murzin, Dmitry Yu

    2015-08-24

    Amidation of renewable feedstocks, such as fatty acids, esters, and Chlorella alga based biodiesel, was demonstrated with zeolites and mesoporous materials as catalysts and ethanolamine, alaninol, and leucinol. The last two can be derived from amino acids present in alga. The main products were fatty alkanol amides and the corresponding ester amines, as confirmed by NMR and IR spectroscopy. Thermal amidation of technical-grade oleic acid and stearic acid at 180 °C with ethanolamine were non-negligible; both gave 61% conversion. In the amidation of stearic acid with ethanolamine, the conversion over H-Beta-150 was 80% after 3 h, whereas only 63% conversion was achieved for oleic acid; this shows that a microporous catalyst is not suitable for this acid and exhibits a wrinkled conformation. The highest selectivity to stearoyl ethanolamide of 92% was achieved with mildly acidic H-MCM-41 at 70% conversion in 3 h at 180 °C. Highly acidic catalysts favored the formation of the ester amine, whereas the amide was obtained with a catalyst that exhibited an optimum acidity. The conversion levels achieved with different fatty acids in the range C12-C18 were similar; this shows that the fatty acid length does not affect the amidation rate. The amidation of methyl palmitate and biodiesel gave low conversions over an acidic catalyst, which suggested that the reaction mechanism in the amidation of esters was different. PMID:26197759

  2. Synthesis and preliminary biological evaluations of (+)-isocampholenic acid-derived amides.

    PubMed

    Grošelj, Uroš; Golobič, Amalija; Knez, Damijan; Hrast, Martina; Gobec, Stanislav; Ričko, Sebastijan; Svete, Jurij

    2016-08-01

    The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1S)-(+)-10-camphorsulfonic acid. The novel amines as well as (+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer's disease. Compounds 20c and 20e showed promising selective sub-micromolar inhibition of human butyrylcholinesterase [Formula: see text] ([Formula: see text] values [Formula: see text] and [Formula: see text], respectively). PMID:27017352

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

    PubMed

    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. PMID:26230212

  4. Targeting leukemic side population cells by isatin derivatives of nicotinic acid amide.

    PubMed

    Naglah, A M; Shinwari, Z; Bhat, M A; Al-Tahhan, M; Al-Omar, M A; Al-Dhfyan, A

    2016-01-01

    Side population (SP) cells mediate chemoresistance in leukemia. However, chemical inhibition approach to target SP cells has been poorly studied. Herein, we report the discovery of isatin derivatives of nicotinic acid amide as potent side population cell inhibitors. The selected derivatives showed superior potency over the reference drug verapamil. Furthermore, the treatment increased chemosensitivity and inhibited the cell proliferation on three different leukemic cell lines, K562, THP-1 and U937, suggesting that both SP and the bulk of leukemic cells are affected. Moreover, treatment with the most potent compound Nic9 reduced the expression of ABCG2, demonstrating that side population inhibition effect of the target derivatives is at least via ABCG2 inhibition. Importantly, the target derivatives induced erythrocyte/dendritic differentiation to leukemic cells mainly through Musashi/Numb pathway modulation. PMID:27358121

  5. Synthesis, Properties and Applications of Biodegradable Polymers Derived from Diols and Dicarboxylic Acids: From Polyesters to Poly(ester amide)s

    PubMed Central

    Díaz, Angélica; Katsarava, Ramaz; Puiggalí, Jordi

    2014-01-01

    Poly(alkylene dicarboxylate)s constitute a family of biodegradable polymers with increasing interest for both commodity and speciality applications. Most of these polymers can be prepared from biobased diols and dicarboxylic acids such as 1,4-butanediol, succinic acid and carbohydrates. This review provides a current status report concerning synthesis, biodegradation and applications of a series of polymers that cover a wide range of properties, namely, materials from elastomeric to rigid characteristics that are suitable for applications such as hydrogels, soft tissue engineering, drug delivery systems and liquid crystals. Finally, the incorporation of aromatic units and α-amino acids is considered since stiffness of molecular chains and intermolecular interactions can be drastically changed. In fact, poly(ester amide)s derived from naturally occurring amino acids offer great possibilities as biodegradable materials for biomedical applications which are also extensively discussed. PMID:24776758

  6. Fuel and lubricant additives from acid treated mixtures of vegetable oil derived amides and esters

    SciTech Connect

    Bonazza, B.R.; Devault, A.N.

    1981-05-26

    Vegetable oils such as corn oil, peanut oil, and soy oil are reacted with polyamines to form a mixture containing amides, imides, half esters, and glycerol with subsequent treatment with a strong acid such as sulfonic acid to produce a product mix that has good detergent properties in fuels and lubricants.

  7. A comparative study of the complexation of uranium(VI) withoxydiacetic acid and its amide derivatives

    SciTech Connect

    Rao, Linfeng; Tian, Guoxin

    2005-05-01

    There has been significant interest in recent years in the studies of alkyl-substituted amides as extractants for actinide separation because the products of radiolytic and hydrolytic degradation of amides are less detrimental to separation processes than those of organophosphorus compounds traditionally used in actinide separations. Stripping of actinides from the amide-containing organic solvents is relatively easy. In addition, the amide ligands are completely incinerable so that the amount of secondary wastes generated in nuclear waste treatment could be significantly reduced. One group of alkyl-substituted oxa-diamides have been shown to be promising in the separation of actinides from nuclear wastes. For example, tetraoctyl-3-oxa-glutaramide and tetraisobutyl-oxa-glutaramide form actinide complexes that can be effectively extracted from nitric acid solutions. To understand the thermodynamic principles governing the complexation of actinides with oxa-diamides, we have studied the complexation of U(VI) with dimethyl-3-oxa-glutaramic acid (DMOGA) and tetramethyl-3-oxa-glutaramide (TMOGA) in aqueous solutions, in comparison with oxydiacetic acid (ODA) (Figure 1). Previous studies have indicated that the complexation of U(VI) with ODA is strong and entropy-driven. Comparing the results for DMOGA and TMOGA with those for ODA could provide insight into the energetics of amide complexation with U(VI) and the relationship between the thermodynamic properties and the ligand structure.

  8. Poly(carbonate–amide)s Derived from Bio-Based Resources: Poly(ferulic acid-co-tyrosine)

    PubMed Central

    2015-01-01

    Ferulic acid (FA), a bio-based resource found in fruits and vegetables, was coupled with a hydroxyl-amino acid to generate a new class of monomers to afford poly(carbonate–amide)s with potential to degrade into natural products. l-Serine was first selected as the hydroxyl-amino partner for FA, from which the activated p-nitrophenyl carbonate monomer was synthesized. Unfortunately, polymerizations were unsuccessful, and the elimination product was systematically obtained. To avoid elimination, we revised our strategy and used l-tyrosine ethyl ester, which lacks an acidic proton on the α position of the ethyl ester. Four new monomers were synthesized and converted into the corresponding poly(carbonate–amide)s with specific regioselectivities. The polymers were fully characterized through thermal and spectroscopic analyses. Preliminary fluorescent studies revealed interesting photophysical properties for the monomers and their corresponding poly(carbonate–amide)s, beyond the fluorescence characteristics of l-tyrosine and FA, making these materials potentially viable for sensing and/or imaging applications, in addition to their attractiveness as engineering materials derived from renewable resources. PMID:24839309

  9. 11-Keto-boswellic acid derived amides and monodesmosidic saponins induce apoptosis in breast and cervical cancers cells.

    PubMed

    Csuk, René; Barthel-Niesen, Anja; Barthel, Alexander; Schäfer, Renate; Al-Harrasi, Ahmed

    2015-07-15

    Beta-boswellic acids are considered the main bioactive components of frankincense. Their potential to act as cytotoxic agents, as well as that of their derivatives remained unexploited so far. In this study we were able to prepare derivatives of 11-keto-β-boswellic acid (KBA) that showed lower IC50 values as determined by a sulphorhodamine B (SRB) assay using several different human tumour cell lines. Monodesmosidic saponins of KBA are as cytotoxic as 3-acetyl-KBA. The presence of a free hydroxyl group at position C-3 seems to lower cytotoxicity while the presence of an amide function at C-24 improves cytotoxicity. The most active compound of this series gave IC50 values as low as 4.5 μM. Cell death proceeded mainly via apoptosis. PMID:26073487

  10. Lipase-catalyzed production of a bioactive fatty amide derivative of 7,10-dihydroxy-8(E)-octadecenoic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fatty amides are of considerable interest due to their wide ranging industrial applications in detergents, shampoo, cosmetics and surfactant formulations. They are produced commercially from fatty acids by reacting with anhydrous ammonia at approximately 200 deg C and 345-690 KPa pressure. We inve...

  11. Relationship between chromatographic resolution and amide structure of chiral 2-hydroxy acids as O-(-)-menthoxycarbonylated diastereomeric derivatives for enantiomeric separation on achiral gas chromatography.

    PubMed

    Cha, Eunju; Kim, Sohee; Lee, Kang Mi; Kim, Ho Jun; Kim, Ki Hun; Kwon, Oh-Seung; Park, Ki Duk; Lee, Jaeick

    2016-02-15

    The relationship between chromatographic resolution and amide structure of chiral 2-hydroxy acids as O-(-)-menthoxycarbonylated diastereomeric derivatives on achiral gas chromatography was investigated to elucidate the best diastereomeric conformation for enantiomeric separation of chiral 2-hydroxy acids. Thirteen chiral 2-hydroxy acids were converted into nine different diastereomeric O-(-)-menthoxycarbonylated amide derivatives using the primary, secondary and cyclic amines to achieve complete enantiomeric separation through an achiral column. Each enantiomeric pair of 2-hydroxy acids as O-(-)-menthoxycarbonylated tert-butylamide derivatives was resolved on both the DB-5 and DB-17 columns with resolution factors ranging from 1.7 to 4.8 and 1.7 to 3.4, respectively. The results revealed that the structure of the amide moiety is shown to significantly affect chromatographic resolution. In addition, O-(-)-menthoxycarbonylated tert-butylamide derivatives were shown to be the best diastereomeric conformations for enantiomeric separation of 2-hydroxy acids. When comparing with our previous O-trifluoroacetylated(-)-menthyl ester derivatization method, the present results suggested that size differences between groups attached to the chiral center and conformational rigidity can have stronger effects on resolution than the distance between chiral centers. The elution of R- and S-stereoisomers was affected by the class of amine; i.e., primary, secondary, or cyclic, regardless of the substituents on the amine group, the structure of the 2-hydroxy acid, and the polarity of the column. PMID:26800225

  12. Cooling rate effects on the microstructure, solid content, and rheological properties of organogels of amides derived from stearic and (R)-12-hydroxystearic acid in vegetable oil.

    PubMed

    Toro-Vazquez, Jorge F; Morales-Rueda, Juan; Torres-Martínez, Adriana; Charó-Alonso, Miriam A; Mallia, V Ajay; Weiss, Richard G

    2013-06-25

    Using safflower oil as the liquid phase, we investigated the organogelation properties of stearic acid (SA), (R)-12-hydroxystearic acid (HSA), and different primary and secondary amides synthesized from SA and HSA. The objective was to establish the relationship between the gelator's molecular structure, solid content, and gels' microstructure that determines the rheological properties of organogels developed at two cooling rates, 1 and 20 °C/min. The results showed that the presence of a 12-OH group in the gelator molecule makes its crystallization kinetics cooling rate dependent and modifies its crystallization behavior. Thus, SA crystallizes as large platelets, while HSA crystallizes as fibers forming gels with higher solid content, particularly at 20 °C/min. The addition to HSA of a primary or a secondary amide bonded with an alkyl group resulted in gelator molecules that crystallized as fibrillar spherulites at both cooling rates. Independent of the cooling rate, gels of HSA and its amide derivatives showed thixotropic behavior. The rheological properties of the amide's organogels depend on a balance between hydrogen-bonding sites and the alkyl chain length bonded to the amide group. However, it might also be associated with the effect that the gelators' molecular weight has on crystal growth and its consequence on fiber interpenetration among vicinal spherulites. These results were compared with those obtained with candelilla wax (CW), a well-known edible gelling additive used by the food industry. CW organogels had higher elasticity than HSA gels but lower than the gels formed by amides. Additionally, CW gels showed similar or even higher thixotropic behavior than HSA and the amide's gels. These remarkable rheological properties resulted from the microstructural organization of CW organogels. We concluded that microstructure has a more important role determining the organogels' rheology than the solid content. The fitting models developed to describe the

  13. Diaminopimelic Acid Amidation in Corynebacteriales

    PubMed Central

    Levefaudes, Marjorie; Patin, Delphine; de Sousa-d'Auria, Célia; Chami, Mohamed; Blanot, Didier; Hervé, Mireille; Arthur, Michel; Houssin, Christine; Mengin-Lecreulx, Dominique

    2015-01-01

    A gene named ltsA was earlier identified in Rhodococcus and Corynebacterium species while screening for mutations leading to increased cell susceptibility to lysozyme. The encoded protein belonged to a huge family of glutamine amidotransferases whose members catalyze amide nitrogen transfer from glutamine to various specific acceptor substrates. We here describe detailed physiological and biochemical investigations demonstrating the specific role of LtsA protein from Corynebacterium glutamicum (LtsACg) in the modification by amidation of cell wall peptidoglycan diaminopimelic acid (DAP) residues. A morphologically altered but viable ΔltsA mutant was generated, which displays a high susceptibility to lysozyme and β-lactam antibiotics. Analysis of its peptidoglycan structure revealed a total loss of DAP amidation, a modification that was found in 80% of DAP residues in the wild-type polymer. The cell peptidoglycan content and cross-linking were otherwise not modified in the mutant. Heterologous expression of LtsACg in Escherichia coli yielded a massive and toxic incorporation of amidated DAP into the peptidoglycan that ultimately led to cell lysis. In vitro assays confirmed the amidotransferase activity of LtsACg and showed that this enzyme used the peptidoglycan lipid intermediates I and II but not, or only marginally, the UDP-MurNAc pentapeptide nucleotide precursor as acceptor substrates. As is generally the case for glutamine amidotransferases, either glutamine or NH4+ could serve as the donor substrate for LtsACg. The enzyme did not amidate tripeptide- and tetrapeptide-truncated versions of lipid I, indicating a strict specificity for a pentapeptide chain length. PMID:25847251

  14. Synthesis and structural studies of amino amide salts derived from 2-(aminomethyl)benzimidazole and α-amino acids

    NASA Astrophysics Data System (ADS)

    Avila-Montiel, Concepción; Tapia-Benavides, Antonio R.; Falcón-León, Martha; Ariza-Castolo, Armando; Tlahuext, Hugo; Tlahuextl, Margarita

    2015-11-01

    2-{[(Ammoniumacetyl)amino]methyl}-1H-benzimidazol-3-ium dichloride 4, 2-{[(2-ammoniumpropanoyl)amino]methyl}-1H-benzimidazol-3-ium dichloride 5, and 2-{[(2-ammonium-3-phenylpropanoyl)amino]methyl}-1H-benzimidazol-3-ium dichloride 6 amino amides were synthesized via condensation of 2AMBZ dihydrochloride with the corresponding amino acid. Compounds 7-12 were obtained by replacing chloride ions (in salts 4-6) with nitrate or tetrachlorozincate ions. The results of X-ray diffraction crystallographic studies indicated that the geometries, charges and sizes of the anions are essential for the formation of the strong hydrogen bond interactions of compounds 4, 5, 9-12. Moreover, in most cases, the presence of water and solvent molecules stabilizes the supramolecular structures of these compounds. Nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy indicated that the presence of chloride or tetrachlorozincate anions increases the acidity of the benzimidazolic and amide groups more significantly than the presence of nitrate anions. However, Quantum Theory of Atoms in Molecules (QTAIM) computations of the crystal structures demonstrate that amino amides interact more strongly with NO3- than with Cl- and ZnCl42- anions; this difference explains the spectroscopic results.

  15. Synthesis of quinaldinic acid amide derivative of styrene-divinylbenzene copolymer and its application in preconcentration of mercury(II)

    SciTech Connect

    Das, J.; Das, N.

    1988-09-01

    A new chelating resin has been synthesized by introducing a quinaldinic acid amide group into styrene-divinyl benzene (8%) copolymer beads. The resin is stable in fairly strong acids or alkali and has been characterized by elemental analysis for nitrogen and from i.r. spectra. The water regain value is 0.37g/g. The sorption patterns of Na(I), K(I), Ca(II), Mg(II), Pb(II), Cu(II), Ni(II), Zn(II), Cd(II), Hg(II) and Fe(III) on the chelating resin have been studied as a function of pH. The resin selectively sorbs Hg(II) over a wide pH-range of 2.5 - 7.6 with high efficiency. The maximum exchange capacity for Hg(II) is 1.98 mmols g/sup -1/ at pH 5.5. Over 99% of Hg(II) sorbed has been recovered by using 10% thiourea in 1M HClO/sub 4/ both by batch and column operations. The method has been utilized in the preconcentration and recovery of Hg(II) from industrial and laboratory waste water.

  16. Fine-Tuning of Lewis Acidity: The Case of Borenium Hydride Complexes Derived from Bis(phosphinimino)amide Boron Precursors.

    PubMed

    Jaiswal, Kuldeep; Prashanth, Billa; Singh, Sanjay

    2016-07-25

    Reactions of bis(phosphinimino)amines LH and L'H with Me2 S⋅BH2 Cl afforded chloroborane complexes LBHCl (1) and L'BHCl (2), and the reaction of L'H with BH3 ⋅Me2 S gave a dihydridoborane complex L'BH2 (3) (LH=[{(2,4,6-Me3 C6 H2 N)P(Ph2 )}2 N]H and L'H=[{(2,6-iPr2 C6 H3 N)P(Ph2 )}2 N]H). Furthermore, abstraction of a hydride ion from L'BH2 (3) and LBH2 (4) mediated by Lewis acid B(C6 F5 )3 or the weakly coordinating ion pair [Ph3 C][B(C6 F5 )4 ] smoothly yielded a series of borenium hydride cations: [L'BH](+) [HB(C6 F5 )3 ](-) (5), [L'BH](+) [B(C6 F5 )4 ](-) (6), [LBH](+) [HB(C6 F5 )3 ](-) (7), and [LBH](+) [B(C6 F5 )4 ](-) (8). Synthesis of a chloroborenium species [LBCl](+) [BCl4 ](-) (9) without involvement of a weakly coordinating anion was also demonstrated from a reaction of LBH2 (4) with three equivalents of BCl3 . It is clear from this study that the sterically bulky strong donor bis(phosphinimino)amide ligand plays a crucial role in facilitating the synthesis and stabilization of these three-coordinated cationic species of boron. Therefore, the present synthetic approach is not dependent on the requirement of weakly coordinating anions; even simple BCl4 (-) can act as a counteranion with borenium cations. The high Lewis acidity of the boron atom in complex 8 enables the formation of an adduct with 4-dimethylaminopyridine (DMAP), [LBH⋅(DMAP)](+) [B(C6 F5 )4 ](-) (10). The solid-state structures of complexes 1, 5, and 9 were investigated by means of single-crystal X-ray structural analysis. PMID:27351275

  17. Characterization of fatty amides produced by lipase-catalyzed amidation of multihydroxylated fatty acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Novel multi-hydroxylated primary fatty amides produced by direct amidation of 7,10-dihydroxy-8(E)-octadecenoic acid (DOD) and 7,10,12-trihydroxy-8(E)-octadecenoic acid (TOD) were characterized by GC-MS and NMR. The amidation reactions were catalyzed by immobilized Pseudozyma (Candida) antarctica li...

  18. PLANT FATTY ACID (ETHANOL) AMIDE HYDROLASES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fatty acid amide hydrolase (FAAH) plays a central role in modulating endogenous N-acylethanolamine (NAE) levels in vertebrates, and, in part, constitutes an “endocannabinoid” signaling pathway that regulates diverse physiological and behavioral processes in animals. Recently, an Arabidopsis FAAH hom...

  19. 40 CFR 721.10320 - Fatty acid amide (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Fatty acid amide (generic). 721.10320... Substances § 721.10320 Fatty acid amide (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as fatty acid amide (PMN P-03-186) is...

  20. 40 CFR 721.10463 - Fatty acid amides (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Fatty acid amides (generic). 721.10463... Substances § 721.10463 Fatty acid amides (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as fatty acid amides (PMN...

  1. Anticonvulsant and antinociceptive activity of new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in mice.

    PubMed

    Rapacz, Anna; Obniska, Jolanta; Wiklik-Poudel, Beata; Rybka, Sabina; Sałat, Kinga; Filipek, Barbara

    2016-06-15

    The aim of the present experiments was to examine the anticonvulsant and antinociceptive activity of five new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in animal models of seizures and pain. The antiseizure activity was investigated in three acute models of seizures, namely, the maximal electroshock (MES), the subcutaneous pentylenetetrazole (scPTZ), and 6Hz psychomotor seizure tests in mice. The antinociceptive properties were estimated in the formalin model of tonic pain, and in the oxaliplatin-induced neuropathic pain model in mice. Considering drug safety evaluation, acute neurological toxicity was determined in the rotarod test. Three tested compounds (3, 4, and 7) displayed a broad spectrum of anticonvulsant activity and showed better protective indices than those obtained for MES/scPTZ/6Hz active reference drug - valproic acid. Furthermore, three compounds (3, 4, and 6) demonstrated a significant antinociceptive effect in the formalin test, as well as antiallodynic activity in the oxaliplatin-induced neuropathic pain model. Among the tested agents, compounds 3 and 4 displayed not only antiseizure properties, but also collateral prominent analgesic properties. The in vitro binding study indicated that the plausible mechanism of action of chosen compound (4) was the influence on neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. PMID:27089821

  2. Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids.

    PubMed

    Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Góra, Małgorzata; Kamiński, Krzysztof; Sałat, Kinga; Żmudzki, Paweł

    2016-04-15

    This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08mg/kg, MES test) and 9 (ED50=40.34mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. PMID:26970661

  3. Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists.

    PubMed

    Kajita, Daisuke; Nakamura, Masaharu; Matsumoto, Yotaro; Ishikawa, Minoru; Hashimoto, Yuichi; Fujii, Shinya

    2015-08-15

    We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds. PMID:26071639

  4. New substituted amides and hydrazides of pectic acid

    SciTech Connect

    Lapenko, V.L.; Potapova, L.B.; Slivkin, A.I.; Razumnaya, Z.A.

    1988-05-10

    Structural variants of pectin amides and hydrazides are of practical value as flocculants in water treatment. The purpose of this work was to further investigate the synthesis of substituted amides and hydrazides of pectic acid and to study their activity as flocculants. They used pectin, methylation products of pectin, pectic acid, and methyl pectates. The synthesized analogs of pectinic materials containing nitrogen are essentially copolymers of hydrazido (amido) and carboxyl (methoxyl) derivatives of D-galacturonic acid. The flocculant activity of the new polymers was monitored with simulated drainage water containing kaolin or abrasive powder (for glass manufacture) in the presence of polyvalent metal ions. The use of the new ampholytic flocculants in the purification of water from suspended impurities permits a high degree of clarification with a sharp decrease in reagent consumption.

  5. Synthesis and pharmacological properties of 1-(4-substituted)butyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimi dine-5 -carboxylic acid.

    PubMed

    Sladowska, H; Sieklucka-Dziuba, M; Rejdak, R; Kleinrok, Z

    2000-01-01

    The synthesis of 1-(4-substituted)butyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimid ine-5- carboxylic acid and the results of the preliminary pharmacological screening are described in this paper. Some of them showed a weak analgesic action and caused suppression of the spontaneous locomotor activity of mice. PMID:10755225

  6. Antiproliferative activity of synthetic fatty acid amides from renewable resources.

    PubMed

    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. PMID:25510639

  7. Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, István; Kolok, Sándor; Galgóczy, Kornél; Gere, Anikó; Horváth, Csilla; Farkas, Sándor; Greiner, István; Domány, György

    2007-01-15

    A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed. PMID:17074483

  8. Iodine-Catalyzed Decarboxylative Amidation of β,γ-Unsaturated Carboxylic Acids with Chloramine Salts Leading to Allylic Amides.

    PubMed

    Kiyokawa, Kensuke; Kojima, Takumi; Hishikawa, Yusuke; Minakata, Satoshi

    2015-10-26

    The iodine-catalyzed decarboxylative amidation of β,γ-unsaturated carboxylic acids with chloramine salts is described. This method enables the regioselective synthesis of allylic amides from various types of β,γ-unsaturated carboxylic acids containing substituents at the α- and β-positions. In the reaction, N-iodo-N-chloroamides, generated by the reaction of a chloramine salt with I2 , function as a key active species. The reaction provides an attractive alternative to existing methods for the synthesis of useful secondary allylic amine derivatives. PMID:26493878

  9. 40 CFR 721.10512 - Fatty acid maleic acid amides (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Fatty acid maleic acid amides (generic... Specific Chemical Substances § 721.10512 Fatty acid maleic acid amides (generic). (a) Chemical substance... fatty acid maleic acid amides (PMNs P-07-563 and P-07-564) are subject to reporting under this...

  10. 40 CFR 721.10512 - Fatty acid maleic acid amides (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Fatty acid maleic acid amides (generic... Specific Chemical Substances § 721.10512 Fatty acid maleic acid amides (generic). (a) Chemical substance... fatty acid maleic acid amides (PMNs P-07-563 and P-07-564) are subject to reporting under this...

  11. Fatty acid amides from freshwater green alga Rhizoclonium hieroglyphicum.

    PubMed

    Dembitsky, V M; Shkrob, I; Rozentsvet, O A

    2000-08-01

    Freshwater green algae Rhizoclonium hieroglyphicum growing in the Ural Mountains were examined for their fatty acid amides using capillary gas chromatography-mass spectrometry (GC-MS). Eight fatty acid amides were identified by GC-MS. (Z)-9-octadecenamide was found to be the major component (2.26%). PMID:11014298

  12. Synthesis and characterization of ester and amide derivatives of titanium(IV) carboxymethylphosphonate

    SciTech Connect

    Melánová, Klára; Beneš, Ludvík; Trchová, Miroslava; Svoboda, Jan; Zima, Vítězslav

    2013-06-15

    A set of layered ester and amide derivatives of titanium(IV) carboxymethylphosphonate was prepared by solvothermal treatment of amorphous titanium(IV) carboxymethylphosphonate with corresponding 1-alkanols, 1,ω-alkanediols, 1-aminoalkanes, 1,ω-diaminoalkanes and 1,ω-amino alcohols and characterized by powder X-ray diffraction, IR spectroscopy and thermogravimetric analysis. Whereas alkyl chains with one functional group form bilayers tilted to the layers, 1,ω-diaminoalkanes and most of 1,ω-alkanediols form bridges connecting the adjacent layers. In the case of amino alcohols, the alkyl chains form bilayer and either hydroxyl or amino group is used for bonding. This simple method for the synthesis of ester and amide derivatives does not require preparation of acid chloride derivative as a precursor or pre-intercalation with alkylamines and can be used also for the preparation of ester and amide derivatives of titanium carboxyethylphosphonate and zirconium carboxymethylphosphonate. - Graphical abstract: Ester and amide derivatives of layered titanium carboxymethylphosphonate were prepared by solvothermal treatment of amorphous solid with alkanol or alkylamine. - Highlights: • Ester and amide derivatives of titanium carboxymethylphosphonate. • Solvothermal treatment of amorphous solid with alkanol or alkylamine. • Ester and amide formation confirmed by IR spectroscopy.

  13. A New Derivative of Valproic Acid Amide Possesses a Broad-spectrum Antiseizure Profile and Unique Activity Against Status Epilepticus and Organophosphate Neuronal Damage

    PubMed Central

    White, H. Steve; Alex, Anitha B.; Pollock, Amanda; Hen, Naama; Shekh-Ahmad, Tawfeeq; Wilcox, Karen S.; McDonough, John H.; Stables, James P.; Kaufmann, Dan; Yagen, Boris; Bialer, Meir

    2011-01-01

    Summary Purpose sec-Butyl-propylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a CNS-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The current study evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death. Methods SPD’s anticonvulsant activity was evaluated in several rodent seizure and epilepsy models including: maximal electroshock (MES), 6Hz psychomotor, subcutaneous (s.c.) metrazol-, s.c., picrotoxin, s.c. bicuculline, audiogenic and corneal and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-Aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model. Key Findings SPD was highly effective and displayed a wide protective index (PI=TD50/ED50) in the standardized seizure and epilepsy models employed. SPD’s wide PI values demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also

  14. Fuel additives from SO/sub 2/ treated mixtures of amides and esters derived from vegetable oil, tall oil acid, or aralkyl acid

    SciTech Connect

    Efner, H. F.; Schiff, S.

    1985-03-12

    Vegetable oils, particularly soybean oil, tall oil acid, or aralkyl acids, particularly phenylstearic acid, are reacted with multiamines, particularly tetraethylenepentamine, to form a product mixture for subsequent reaction with SO/sub 2/ to produce a product mix that has good detergent properties in fuels.

  15. Biocatalytic amidation of carboxylic acids and their antinemic activity.

    PubMed

    Bose, Abinesh; Shakil, Najam Akhtar; Pankaj; Kumar, Jitendra; Singh, Manish K

    2010-04-01

    A series of novel N-alkyl substituted amides, synthesized by enzyme catalysis, were evaluated against root-knot nematode, Meloidogyne incognita and found to have potential antinemic activity. The corresponding amides were prepared by the condensation of equimolar amounts of carboxylic acids with different alkyl amines in the presence of Candida antarctica lipase at 60-90 degrees C in 16-20 h. The reactions were carried out in a non - solvent system without the use of any activating agents. All the products were obtained in appreciable amounts and the yields for different compounds varied between 77.4-82.3%. The synthesized compounds were characterized using spectroscopy techniques namely Infra Red (IR) and Nuclear Magnetic Resonance (NMR) ((1)H and (13)C). Nematicidal activity of synthesized amides was evaluated against J(2)s of Meloidogyne incognita at 500, 250, 125 and 62.5 ppm concentrations after 24 h, 48 h and 72 h of exposure. Among all the tested compounds, N-propyl-butyramide, N-propyl-pentanamide and N-propyl-hexanamide were found to possess significant activity with LC(50) values of 67.46, 83.49 and 96.53 respectively. N-propyl-butyramide with LC(50) value of 67.46 ppm was found to be most active amide against J(2)s of Meloidogyne incognita. The bioactivity study showed that an increase in alkyl chain significantly decreased the activity of amides against root-knot nematode. PMID:20390959

  16. Gas-Phase Amidation of Carboxylic Acids with Woodward's Reagent K Ions

    NASA Astrophysics Data System (ADS)

    Peng, Zhou; Pilo, Alice L.; Luongo, Carl A.; McLuckey, Scott A.

    2015-06-01

    Gas-phase amidation of carboxylic acids in multiply-charged peptides is demonstrated via ion/ion reactions with Woodward's reagent K (wrk) in both positive and negative mode. Woodward's reagent K, N-ethyl-3-phenylisoxazolium-3'-sulfonate, is a commonly used reagent that activates carboxylates to form amide bonds with amines in solution. Here, we demonstrate that the analogous gas-phase chemistry occurs upon reaction of the wrk ions and doubly protonated (or doubly deprotonated) peptide ions containing the carboxylic acid functionality. The reaction involves the formation of the enol ester intermediate in the electrostatic complex. Upon collisional activation, the ethyl amine on the reagent is transferred to the activated carbonyl carbon on the peptide, resulting in the formation of an ethyl amide (addition of 27 Da to the peptide) with loss of a neutral ketene derivative. Further collision-induced dissociation (CID) of the products and comparison with solution-phase amidation product confirms the structure of the ethyl amide.

  17. Fatty acid sulphoalkyl amides and esters as cosmetic surfactants.

    PubMed

    Petter, P J

    1984-10-01

    Synopsis A review is given of the manufacture, properties and applications of the anionic surfactants commonly known as taurates and isethionates (fatty acid sulphoalkyl amides and esters, respectively). Originally developed in the 1930s for textile processing, these surfactants are used increasingly in the cosmetic field, particularly those derived from coconut fatty acid. Both types are produced from sodium isethionate, HO degrees C(2)H(4)SO(3)Na. The acyl isethionate, R degrees COO degrees C(2)H(4)SO(3)Na, is obtained by reaction with a fatty acid ('direct process'). or fatty acid chloride ('indirect process'). The direct process is cheaper but requires extreme conditions which can lead to discoloration of the product and a loss of shorter chain fatty acid components. The N-methyl-N-acyltaurate, R degrees CON(R(1))C(2)H(4)SO(3)Na, is obtained by Schotten-Baumann reaction of a fatty acid chloride with N-methyltaurine, which is derived from sodium isethionate via methylamine. Taurates and isethionates retain the benefits of the soaps to which they are structurally similar, but chemical modifications have eliminated many undesirable features. Thus they combine good detergency and wetting with high foaming, and maintain their performance in hard or salt water. Taurates are stable to hydrolysis over the whole pH range. Isethionates are prone to hydrolysis at high (>8) or low (<5) pH, but this does not normally present a problem in cosmetic formulations. Above all, these surfactants are characterized by their extreme mildness to skin. Syndet and syndet/soap bars based on isethionate can be formulated at neutral pH ('Dove type'bars) instead of the alkaline pH of soap, and have been shown in various studies to be milder than soap and better tolerated by the young, the old and those with sensitive skins. Similarly, isethionates have been shown to be less irritating than other anionic or amphoteric surfactants used in cosmetics. The difference has been related to the

  18. Synthesis of imides via palladium-catalyzed decarboxylative amidation of α-oxocarboxylic acids with secondary amides.

    PubMed

    Xu, Ning; Liu, Jie; Li, Dengke; Wang, Lei

    2016-05-18

    An efficient synthesis of imides has been developed through a Pd-catalyzed decarboxylative amidation of α-oxocarboxylic acids with secondary amides. The reactions of N-substituted N-heteroarene-2-carboxamides with 2-oxo-2-arylacetic acids proceeded smoothly to generate the corresponding products in good yields in the presence of Pd(OAc)2 and K2S2O8. PMID:27143171

  19. Simple Amides of Oleanolic Acid as Effective Penetration Enhancers

    PubMed Central

    Bednarczyk-Cwynar, Barbara; Partyka, Danuta; Zaprutko, Lucjusz

    2015-01-01

    Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their in vitro penetration promoter activity. The above activity was evaluated by means of using the Fürst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented. PMID:26010090

  20. Toxocara canis: Larvicidal activity of fatty acid amides.

    PubMed

    Mata-Santos, Taís; D'Oca, Caroline da Ros Montes; Mata-Santos, Hílton Antônio; Fenalti, Juliana; Pinto, Nitza; Coelho, Tatiane; Berne, Maria Elisabeth; da Silva, Pedro Eduardo Almeida; D'Oca, Marcelo Gonçalves Montes; Scaini, Carlos James

    2016-02-01

    Considering the therapeutic potential of fatty acid amides, the present study aimed to evaluate their in vitro activity against Toxocara canis larvae and their cytotoxicity for the first time. Linoleylpyrrolidilamide was the most potent, with a minimal larvicidal concentration (MLC) of 0.05 mg/mL and 27% cytotoxicity against murine peritoneal macrophages C57BL/6 mice, as assessed by the MTT assay. PMID:26783180

  1. MATE Transporter-Dependent Export of Hydroxycinnamic Acid Amides.

    PubMed

    Dobritzsch, Melanie; Lübken, Tilo; Eschen-Lippold, Lennart; Gorzolka, Karin; Blum, Elke; Matern, Andreas; Marillonnet, Sylvestre; Böttcher, Christoph; Dräger, Birgit; Rosahl, Sabine

    2016-02-01

    The ability of Arabidopsis thaliana to successfully prevent colonization by Phytophthora infestans, the causal agent of late blight disease of potato (Solanum tuberosum), depends on multilayered defense responses. To address the role of surface-localized secondary metabolites for entry control, droplets of a P. infestans zoospore suspension, incubated on Arabidopsis leaves, were subjected to untargeted metabolite profiling. The hydroxycinnamic acid amide coumaroylagmatine was among the metabolites secreted into the inoculum. In vitro assays revealed an inhibitory activity of coumaroylagmatine on P. infestans spore germination. Mutant analyses suggested a requirement of the p-coumaroyl-CoA:agmatine N4-p-coumaroyl transferase ACT for the biosynthesis and of the MATE transporter DTX18 for the extracellular accumulation of coumaroylagmatine. The host plant potato is not able to efficiently secrete coumaroylagmatine. This inability is overcome in transgenic potato plants expressing the two Arabidopsis genes ACT and DTX18. These plants secrete agmatine and putrescine conjugates to high levels, indicating that DTX18 is a hydroxycinnamic acid amide transporter with a distinct specificity. The export of hydroxycinnamic acid amides correlates with a decreased ability of P. infestans spores to germinate, suggesting a contribution of secreted antimicrobial compounds to pathogen defense at the leaf surface. PMID:26744218

  2. Synthesis of new polysialic acid derivatives.

    PubMed

    Su, Yi; Kasper, Cornelia; Kirschning, Andreas; Dräger, Gerald; Berski, Silke

    2010-09-01

    In this paper we report the first synthesis of novel polysialic acid derivatives which is initiated by treatment of polysialic acid with EDC-HCl to yield the inter-residual delta-lactone. Subsequent reaction with amines or hydrazine gives the corresponding polysialic acid amides and hydrazide. Alkylation of the tetrabutylammonium salt of polysialic acid yields polysialic acid esters. In contrast a variety of N-derivatives of polysialic acid can be prepared starting from deacetylated polysialic acid. The N-derivatives prepared in this communication can be used for the Cu-catalyzed as well as Cu-free "click" chemistry. PMID:20602419

  3. Copper-Catalyzed Reductive N-Alkylation of Amides with N-Tosylhydrazones Derived from Ketones.

    PubMed

    Xu, Peng; Qi, Fu-Ling; Han, Fu-She; Wang, Yan-Hua

    2016-07-20

    A CuI-catalyzed reductive coupling of ketone-derived N-tosylhydrazones with amides is presented. Under the optimized conditions, an array of N-tosylhydrazones derived from aryl-alkyl and diaryl ketones could couple effectively with a wide variety of (hetero)aryl as well as aliphatic amides to afford the N-alkylated amides in high yields. The method represents the very few examples for reliably accessing secondary and tertiary amides through a reductive N-alkylation protocol. PMID:27346856

  4. Design, synthesis and biological activity of new amides derived from 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid.

    PubMed

    Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Powroźnik, Beata; Pękala, Elżbieta; Filipek, Barbara; Żmudzki, Paweł; Kamiński, Krzysztof

    2015-09-18

    A series of new 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides (6-23) has been synthesized and evaluated for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotarod test. The in vivo preliminary pharmacological results showed that in the whole series only two compounds (15, 21) were devoid of activity, whereas other molecules revealed protection in at least one animal model of epilepsy (MES or/and scPTZ). The in vivo quantitative studies in mice showed that in the MES test the most active were 1-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (17), 1-{2-[4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8), and its 2-fluorophenyl analog (7) with ED50 values of 97.51 mg/kg (17), 104.11 mg/kg (8), and 114.68 mg/kg (7), respectively. In the scPTZ screen the most potent were compound 6 with an ED50 = 40.87 mg/kg, and 4-benzylpiperidine derivative 22 - ED50 = 60.00 mg/kg. Furthermore, selected compounds 8, 14, 17, and 23 were tested in the psychomotor seizure 6-Hz test. Compounds 7, 8, and 17 revealed significant analgesic activity in the formalin model of tonic pain in mice, without impairment of the motor coordination in the chimney test. The in vitro binding studies showed that the mechanism of anticonvulsant activity may be partially related with the influence on the voltage-gated sodium and calcium channels. The mutagenic and antimutagenic effects of 13, 17, and 22 were evaluated using the novel Vibrio harveyi assay. PMID:26241874

  5. Synthesis and pharmacological properties of 1-[2-hydroxy-3-(4-o,m,p-halogenophenyl)- and 3-(4-m-chlorophenyl)-1-piperazinyl]propyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d]pyrimidine-5-carboxylic acid with analgesic and sedative activities.

    PubMed

    Sabiniarz, Aleksandra; Sladowska, Helena; Filipek, Barbara; Sapa, Jacek; Dudek, Magdalena; Slepokura, Katarzyna

    2007-01-01

    Synthesis of 1-[2-hydroxy-3-(4-o,m,p-halogenophenyl)- and 3-(4-m-chlorophenyl)-1-piperazinyl]propyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (18, 20-23, 25, 27-30 and 19, 24, 26) is described. All substances were active as analgesic agents in "writhing syndrome" test and except of 18 and 23 they acted stronger than acetylsalicylic acid. All final derivatives tested significantly suppressed the spontaneous locomotor activity of mice. PMID:18536164

  6. Isolation and identification of fatty acid amides from Shengli coal

    SciTech Connect

    Ming-Jie Ding; Zhi-Min Zong; Ying Zong; Xiao-Dong Ou-Yang; Yao-Guo Huang; Lei Zhou; Feng Wang; Jiang-Pei Cao; Xian-Yong Wei

    2008-07-15

    Shengli coal, a Chinese brown coal, was extracted with carbon disulfide and the extract was gradiently eluted with n-hexane and ethyl acetate (EA)/n-hexane mixed solvents with different concentrations of EA in a silica gel-filled column. A series of fatty acid amides, including fourteen alkanamides (C{sub 15}-C{sub 28}) and three alkenamides (C{sub 18} and C{sub 22}), were isolated from the coal by this method and analyzed with a gas chromatography/mass spectrometry. 26 refs., 2 figs., 2 tabs.

  7. Lipase-catalyzed synthesis of fatty acid amide (erucamide) using fatty acid and urea.

    PubMed

    Awasthi, Neeraj Praphulla; Singh, R P

    2007-01-01

    Ammonolysis of fatty acids to the corresponding fatty acid amides is efficiently catalysed by Candida antartica lipase (Novozym 435). In the present paper lipase-catalysed synthesis of erucamide by ammonolysis of erucic acid and urea in organic solvent medium was studied and optimal conditions for fatty amides synthesis were established. In this process erucic acid gave 88.74 % pure erucamide after 48 hour and 250 rpm at 60 degrees C with 1:4 molar ratio of erucic acid and urea, the organic solvent media is 50 ml tert-butyl alcohol (2-methyl-2-propanol). This process for synthesis is economical as we used urea in place of ammonia or other amidation reactant at atmospheric pressure. The amount of catalyst used is 3 %. PMID:17898456

  8. Pd-Catalyzed Coupling of γ-C(sp(3))-H Bonds of Oxalyl Amide-Protected Amino Acids with Heteroaryl and Aryl Iodides.

    PubMed

    Han, Jian; Zheng, Yongxiang; Wang, Chao; Zhu, Yan; Huang, Zhi-Bin; Shi, Da-Qing; Zeng, Runsheng; Zhao, Yingsheng

    2016-07-01

    Pd-catalyzed regioselective coupling of γ-C(sp(3))-H bonds of oxalyl amide-protected amino acids with heteroaryl and aryl iodides is reported. A wide variety of iodides are tolerated, giving the corresponding products in moderate to good yields. Various oxalyl amide-protected amino acids were compatible in this C-H transformation, thus representing a practical method for constructing non-natural amino acid derivatives. PMID:27286881

  9. [Activated Sludge Bacteria Transforming Cyanopyridines and Amides of Pyridinecarboxylic Acids].

    PubMed

    Demakov, V A; Vasil'ev, D M; Maksimova, Yu G; Pavlova, Yu A; Ovechkina, G V; Maksimov, A Yu

    2015-01-01

    Species diversity of bacteria from the activated sludge of Perm biological waste treatment facilities capable of transformation of cyanopyridines and amides of pyridinecarboxylic acids was investigated. Enrichment cultures in mineral media with 3-cyanopyridine as the sole carbon and nitrogen source were used to obtain 32 clones of gram-negative heterotrophic bacteria exhibiting moderate growth on solid and liquid media with 3- and 4-cyanopyridine. Sequencing of the 16S rRNA gene fragments revealed that the clones with homology of at least 99% belonged to the genera Acinetobacte, Alcaligenes, Delftia, Ochrobactrum, Pseudomonas, Stenotrophomonas, and Xanthobacter. PCR analysis showed that 13 out of 32 isolates contained the sequences (-1070 bp) homologous to the nitrilase genes reported previously in Alcaligenes faecalis JM3 (GenBank, D13419.1). Nine clones were capable of nitrile and amide transformation in minimal salt medium. Acinetobacter sp. 11 h and Alcaligenes sp. osv transformed 3-cyanopyridine to nicotinamide, while most of the clones possessed amidase activity (0.5 to 46.3 mmol/(g h) for acetamide and 0.1 to 5.6 mmol/(g h) for nicotinamide). Nicotinamide utilization by strain A. faecalis 2 was shown to result in excretion of a secondary metabolite, which was identified as dodecyl acrylate at 91% probability. PMID:26263697

  10. 40 CFR 721.720 - Alkoxylated fatty acid amide, alkylsulfate salt.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., alkylsulfate salt. 721.720 Section 721.720 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... 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...

  11. 40 CFR 721.720 - Alkoxylated fatty acid amide, alkylsulfate salt.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., alkylsulfate salt. 721.720 Section 721.720 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... 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...

  12. 40 CFR 721.720 - Alkoxylated fatty acid amide, alkylsulfate salt.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., alkylsulfate salt. 721.720 Section 721.720 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... 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...

  13. 40 CFR 721.720 - Alkoxylated fatty acid amide, alkylsulfate salt.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., alkylsulfate salt. 721.720 Section 721.720 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... 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...

  14. 40 CFR 721.720 - Alkoxylated fatty acid amide, alkylsulfate salt.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., alkylsulfate salt. 721.720 Section 721.720 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... 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...

  15. Stereoselective synthesis of (E)-trisubstituted alpha,beta-unsaturated amides and acids.

    PubMed

    Feuillet, Fred J P; Cheeseman, Matt; Mahon, Mary F; Bull, Steven D

    2005-08-21

    Potassium alkoxides of N-acyl-oxazolidin-2-one-syn-aldols undergo stereoselective elimination reactions to afford a range of trisubstituted (E)-alpha,beta-unsaturated amides in >95% de, that may be subsequently converted into their corresponding (E)-alpha,beta-unsaturated acids or (E)-alpha,beta-unsaturated oxazolines in good yield. syn-Aldols derived from alpha,beta-unsaturated aldehydes gave their corresponding trisubstituted (E)-alpha,beta-unsaturated-amides with poorer levels of diastereocontrol, whilst there was a similar loss in (E)-selectivity during elimination of syn-aldols derived from chiral aldehydes. These elimination reactions proceed via rearrangement of the potassium alkoxide of the syn-aldol to a 1,3-oxazinane-2,4-dione enolate intermediate that subsequently eliminates carbon dioxide to afford a trisubstituted (E)-alpha,beta-unsaturated amide. The (E)-selectivity observed during the E1cB-type elimination step has been rationalised using a simple conformational model that employs a chair-like transition state to explain the observed stereocontrol. PMID:16186928

  16. Sulfonyl fluoride inhibitors of fatty acid amide hydrolase.

    PubMed

    Alapafuja, Shakiru O; Nikas, Spyros P; Bharathan, Indu T; Shukla, Vidyanand G; Nasr, Mahmoud L; Bowman, Anna L; Zvonok, Nikolai; Li, Jing; Shi, Xiaomeng; Engen, John R; Makriyannis, Alexandros

    2012-11-26

    Sulfonyl fluorides are known to inhibit esterases. Early work from our laboratory has identified hexadecyl sulfonylfluoride (AM374) as a potent in vitro and in vivo inhibitor of fatty acid amide hydrolase (FAAH). We now report on later generation sulfonyl fluoride analogs that exhibit potent and selective inhibition of FAAH. Using recombinant rat and human FAAH, we show that 5-(4-hydroxyphenyl)pentanesulfonyl fluoride (AM3506) has similar inhibitory activity for both the rat and the human enzyme, while rapid dilution assays and mass spectrometry analysis suggest that the compound is a covalent modifier for FAAH and inhibits its action in an irreversible manner. Our SAR results are highlighted by molecular docking of key analogs. PMID:23083016

  17. Synthesis and structural characterisation of amides from picolinic acid and pyridine-2,6-dicarboxylic acid

    PubMed Central

    Devi, Prarthana; Barry, Sarah M.; Houlihan, Kate M.; Murphy, Michael J.; Turner, Peter; Jensen, Paul; Rutledge, Peter J.

    2015-01-01

    Coupling picolinic acid (pyridine-2-carboxylic acid) and pyridine-2,6-dicarboxylic acid with N-alkylanilines affords a range of mono- and bis-amides in good to moderate yields. These amides are of interest for potential applications in catalysis, coordination chemistry and molecular devices. The reaction of picolinic acid with thionyl chloride to generate the acid chloride in situ leads not only to the N-alkyl-N-phenylpicolinamides as expected but also the corresponding 4-chloro-N-alkyl-N-phenylpicolinamides in the one pot. The two products are readily separated by column chromatography. Chlorinated products are not observed from the corresponding reactions of pyridine-2,6-dicarboxylic acid. X-Ray crystal structures for six of these compounds are described. These structures reveal a general preference for cis amide geometry in which the aromatic groups (N-phenyl and pyridyl) are cis to each other and the pyridine nitrogen anti to the carbonyl oxygen. Variable temperature 1H NMR experiments provide a window on amide bond isomerisation in solution. PMID:25954918

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

    PubMed

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

    2015-06-01

    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. PMID:26002335

  19. Antimicrobial effects of esters and amides of 3-(5-nitro-2-furyl)acrylic acid.

    PubMed

    Kellová, G; Sturdík, E; Stibrányi, L; Drobnica, L; Augustín, J

    1984-01-01

    The effect of 18 newly synthesized esters and amides of 3-(5-nitro-2-furyl)acrylic acid on bacteria (Escherichia coli, Staphylococcus aureus), yeasts (Saccharomyces cerevisiae, Candida albicans), molds (Aspergillus niger, Penicillium cyclopium, Rhizopus oryzae) and algae (Chlorella pyrenoidosa, Euglena gracilis, Scenedesmus obliquus) was investigated. The MIC values revealed antimycotic, antialgal and antibacterial activity of the studied derivatives. The antimycotic activity was found to decrease with increasing the length of the alkyl chain of esters and after introduction of amino nitrogen into the furylethylene backbone. The inhibitory effect on growth is caused by blocking bioenergetic processes, glycolysis in particular. PMID:6714854

  20. Fatty acid amide supplementation decreases impulsivity in young adult heavy drinkers.

    PubMed

    van Kooten, Maria J; Veldhuizen, Maria G; de Araujo, Ivan E; O'Malley, Stephanie S; Small, Dana M

    2016-03-01

    Compromised dopamine signaling in the striatum has been associated with the expression of impulsive behaviors in addiction, obesity and alcoholism. In rodents, intragastric infusion of the fatty acid amide oleoylethanolamide increases striatal extracellular dopamine levels via vagal afferent signaling. Here we tested whether supplementation with PhosphoLean™, a dietary supplement that contains the precursor of the fatty acid amide oleoylethanolamide (N-oleyl-phosphatidylethanolamine), would reduce impulsive responding and alcohol use in heavy drinking young adults. Twenty-two individuals were assigned to a three-week supplementation regimen with PhosphoLean™ or placebo. Impulsivity was assessed with self-report questionnaires and behavioral tasks pre- and post-supplementation. Although self-report measures of impulsivity did not change, supplementation with PhosphoLean™, but not placebo, significantly reduced false alarm rate on a Go/No-Go task. In addition, an association was found between improved sensitivity on the Go/No-Go task and reduced alcohol intake. These findings provide preliminary evidence that promoting fatty acid derived gut-brain dopamine communication may have therapeutic potential for reducing impulsivity in heavy drinkers. PMID:26656766

  1. Microbial Transformation of Nitriles to High-Value Acids or Amides

    NASA Astrophysics Data System (ADS)

    Chen, Jing; Zheng, Ren-Chao; Zheng, Yu-Guo; Shen, Yin-Chu

    Biotransformation of nitriles mediated by nitrile-amide converting enzymes has attracted considerable attention and developed tremendously in the recent years in China since it offers a valuable alternative to traditional chemical reaction which requires harsh conditions. As a result, an upsurge of these promising enzymes (including nitrile hydratase, nitrilase and amidase) has been taking place. This review aims at describing these enzymes in detail. A variety of microorganisms harboring nitrile-amide converting activities have been isolated and identified in China, some of which have already applied with moderate success. Currently, a wide range of high-value compounds such as aliphatic, alicyclic, aromatic and heterocyclic amides and their corresponding acids were provided by these nitrile-amide degra-ding organisms. Simultaneously, with the increasing demand of chiral substances, the enantioselectivity of the nitrilase superfamily is widely investigated and exploited in China, especially the bioconversion of optically active α-substituted phenylacetamides, acids and 2,2-dimethylcyclopropanecarboxamide and 2,2-dimethylcyclopropanecarboxylic acid by means of the catalysts exhibiting excellent stereoselectivity. Besides their synthetic value, the nitrile-amide converting enzymes also play an important role in environmental protection. In this context, cloning of the genes and expression of these enzymes are presented. In the near future in China, an increasing number of novel nitrile-amide converting organisms will be screened and their potential in the synthesis of useful acids and amides will be further exploited.

  2. Effects of valproate derivatives I. Antiepileptic efficacy of amides, structural analogs and esters.

    PubMed

    Redecker, C; Altrup, U; Hoppe, D; Düsing, R; Speckmann, E J

    2000-01-01

    Derivatives of the antiepileptic drug valproate (VPA, 2-propylpentanoic acid) have been synthesized and tested in order to improve the intracellular availability of VPA. The buccal ganglia of Helix pomatia were used as a test nervous system and antiepileptic efficacies were reconfirmed using rat cortex in vivo. Epileptiform activities consisted of typical paroxysmal depolarization shifts (PDS) which appeared in the identified neuron B3 with application of pentylenetetrazol. Epileptiform activities were found to be accelerated, unaffected or blocked. (i) The Amide-derivatives 2-propylpentanamide and N,N-dipropyl-2-propylpentanamide, and short chain ester derivatives 1-O-(2-propylpentanoyl)-2,3-propandiol, 2,2-di(hydroxymethyl)-1-O-(2-propylpentanoyl)-1,3-propanediol and 2,2-di(hydroxymethyl)-1,3-di-O-(2-propylpentanoyl)-1,3-propanediol accelerated epileptiform activities. Membrane potential often shifted to a permanent depolarization which corresponded to the PDS-inactivation level. (ii) The structural analogs 1-cycloheptene-1-carboxylic acid and cyclooctanecarboxylic acid accelerated epileptiform activities only slightly or were without effects. (iii) The small VPA-ester, 2-propylpentanoic acid ethyl ester, decreased the epileptiform activities in a way that is comparable to the effects of VPA well known from previous studies. It thus could be thought as a VPA-pro-drug. (iv) The mannitol-esters 1-O-(2-propylpentanoyl)-D-mannitol and 3,4;5,6-Di-O-isopropylidene-1-O-(2-propylpentanoyl)-D-mannitol blocked the PDS in a way which is different from the known effects of VPA. These substances are interpreted not to exert their effects after being metabolized to VPA and thus they are thought to be new antiepileptic substances. PMID:10670421

  3. Retinoic acid amide inhibits JAK/STAT pathway in lung cancer which leads to apoptosis.

    PubMed

    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. PMID:26044560

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

    PubMed

    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. PMID:26974386

  5. An Experimental and Computational Study of the Gas-Phase Acidities of the Common Amino Acid Amides.

    PubMed

    Plummer, Chelsea E; Stover, Michele L; Bokatzian, Samantha S; Davis, John T M; Dixon, David A; Cassady, Carolyn J

    2015-07-30

    Using proton-transfer reactions in a Fourier transform ion cyclotron resonance mass spectrometer and correlated molecular orbital theory at the G3(MP2) level, gas-phase acidities (GAs) and the associated structures for amides corresponding to the common amino acids have been determined for the first time. These values are important because amino acid amides are models for residues in peptides and proteins. For compounds whose most acidic site is the C-terminal amide nitrogen, two ions populations were observed experimentally with GAs that differ by 4-7 kcal/mol. The lower energy, more acidic structure accounts for the majority of the ions formed by electrospray ionization. G3(MP2) calculations predict that the lowest energy anionic conformer has a cis-like orientation of the [-C(═O)NH](-) group whereas the higher energy, less acidic conformer has a trans-like orientation of this group. These two distinct conformers were predicted for compounds with aliphatic, amide, basic, hydroxyl, and thioether side chains. For the most acidic amino acid amides (tyrosine, cysteine, tryptophan, histidine, aspartic acid, and glutamic acid amides) only one conformer was observed experimentally, and its experimental GA correlates with the theoretical GA related to side chain deprotonation. PMID:26196065

  6. Binding of Fatty Acid Amide Amphiphiles to Bovine Serum Albumin: Role of Amide Hydrogen Bonding.

    PubMed

    Ghosh, Subhajit; Dey, Joykrishna

    2015-06-25

    The study of protein-surfactant interactions is important because of the widespread use of surfactants in industry, medicine, and pharmaceutical fields. Sodium N-lauroylsarcosinate (SL-Sar) is a widely used surfactant in cosmetics, shampoos. In this paper, we studied the interactions of bovine serum albumin (BSA) with SL-Sar and sodium N-lauroylglycinate (SL-Gly) by use of a number of techniques, including fluorescence and circular dichroism spectroscopy and isothermal titration calorimetry. The binding strength of SL-Sar is stronger than that of structurally similar SL-Gly, which differs only by the absence of a methyl group in the amide nitrogen atom. Also, these two surfactants exhibit different binding patterns with the BSA protein. The role of the amide bond and hence the surfactant headgroup in the binding mechanism is discussed in this paper. It was observed that while SL-Sar destabilized, SL-Gly stabilized the protein structure, even at concentrations less than the critical micelle concentration (cmc) value. The thermodynamics of surfactant binding to BSA was studied by use of ITC. From the ITC results, it is concluded that three molecules of SL-Sar in contrast to only one molecule of SL-Gly bind to BSA in one set of binding sites at room temperature. However, on increasing temperature four molecules of SL-Gly bind to the BSA through H-bonding and van der Waals interactions, due to loosening of the BSA structure. In contrast, with SL-Sar the binding process is enthalpy driven, and very little structural change of BSA was observed at higher temperature. PMID:26023820

  7. Process for chemical reaction of amino acids and amides yielding selective conversion products

    DOEpatents

    Holladay, Jonathan E.

    2006-05-23

    The invention relates to processes for converting amino acids and amides to desirable conversion products including pyrrolidines, pyrrolidinones, and other N-substituted products. L-glutamic acid and L-pyroglutamic acid provide general reaction pathways to numerous and valuable selective conversion products with varied potential industrial uses.

  8. Synthesis and effect of fatty acid amides as friction modifiers in petroleum base stock.

    PubMed

    Khalkar, Sharmishtha; Bhowmick, DiptiNarayan; Pratap, Amit

    2013-01-01

    Fatty acid amides were prepared by using Lewis acid as a catalyst. The products from reaction was subjected to solvent extraction with chloroform and then followed by purification with n-hexane, ethanol and acetonitrile. Fatty acid amide, characterized by various physicochemical and tribological properties like wear scar, weld load and coefficient of friction. These compounds found good antiwear (AW) and extreme pressure (EP) additive. The addition of various EP and AW additives in lubricating oil is an important and effective way to reduce friction and wear. Fatty acid amides were used as antiwear and friction modifier additive and a comparative study was carried out for 1%, 3%, 5% additive blend with commercial petroleum base stocks 150N and 500N. PMID:24200937

  9. Infrared and nuclear magnetic resonance spectroscopic study of secondary amide hydrogen bonding in benzoyl PABA derivatives (retinoids).

    PubMed

    Dalterio, Richard; Huang, Xiaohua Stella; Yu, Kuo-Long

    2007-06-01

    Attenuated total reflection (ATR) Fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR) data are used to characterize the hydrogen bonding of the secondary amide N-H group of several structurally similar benzoyl derivatives of p-aminobenzoic acid esters (retinoids) in chloroform solution. The amide N-H can form intermolecular hydrogen bonds to several proton acceptors in these molecules or it can form an intramolecular hydrogen bond to a fluorine or oxygen atom in some of the molecules. The concentration dependence of the solution N-H infrared absorption bands is used to determine the formation of intramolecular and/or intermolecular H-bonds. Proton NMR spectra were obtained from deuterated chloroform solutions and the sec-amide N-H resonance was assigned for each compound. The downfield shift in the N-H resonance is correlated to intramolecular H-bond formation. Also, the NMR spectra of fluorine-containing compounds provide J(F-H) through-space coupling values. Using infrared and NMR data, the relative intramolecular hydrogen bond strengths (N-H...F or N-H...O) of the compounds are approximately ranked. PMID:17650370

  10. Choline Chloride Catalyzed Amidation of Fatty Acid Ester to Monoethanolamide: A Green Approach.

    PubMed

    Patil, Pramod; Pratap, Amit

    2016-01-01

    Choline chloride catalyzed efficient method for amidation of fatty acid methyl ester to monoethanolamide respectively. This is a solvent free, ecofriendly, 100% chemo selective and economically viable path for alkanolamide synthesis. The Kinetics of amidation of methyl ester were studied and found to be first order with respect to the concentration of ethanolamine. The activation energy (Ea) for the amidation of lauric acid methyl ester catalyzed by choline chloride was found to be 50.20 KJ mol(-1). The 98% conversion of lauric acid monoethanolamide was obtained at 110°C in 1 h with 6% weight of catalyst and 1:1.5 molar ratio of methyl ester to ethanolamine under nitrogen atmosphere. PMID:26666271

  11. Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

    PubMed Central

    Surasani, Rajendra; Rao, A V Dhanunjaya; Chandrasekhar, K B

    2012-01-01

    Summary Simple and efficient procedures for palladium-catalyzed cross-coupling reactions of N-substituted 4-bromo-7-azaindole (1H-pyrrole[2,3-b]pyridine), with amides, amines, amino acid esters and phenols through C–N and C–O bond formation have been developed. The C–N cross-coupling reaction of amides, amines and amino acid esters takes place rapidly by using the combination of Xantphos, Cs2CO3, dioxane and palladium catalyst precursors Pd(OAc)2/Pd2(dba)3. The combination of Pd(OAc)2, Xantphos, K2CO3 and dioxane was found to be crucial for the C–O cross-coupling reaction. This is the first report on coupling of amides, amino acid esters and phenols with N-protected 4-bromo-7-azaindole derivatives. PMID:23209536

  12. Complexation of di-amides of dipicolinic acid with neodymium

    SciTech Connect

    Lapka, J.L.; Paulenova, A.

    2013-07-01

    Di-amides have undergone significant studies as possible ligands for use in the partitioning of trivalent minor actinides and lanthanides. The binding affinities of three isomeric ligands with neodymium in acetonitrile solution have been investigated. The stability constants of the metal-ligand complexes formed between different isomers of N,N'-diethyl-N,N'- ditolyl-di-picolinamide (EtTDPA) and trivalent neodymium in acetonitrile have been determined by spectrophotometric and calorimetric methods. Each isomer of EtTDPA has been found to be capable of forming three complexes with trivalent neodymium, Nd(EtTDPA), Nd(EtTDPA){sub 2}, and Nd(EtTDPA){sub 3}. Values from spectrophotometric and calorimetric titrations are within reasonable agreement with each other. The order of stability constants for each metal:ligand complex decreases in the order Et(m)TDPA > Et(p)TDPA > Et(o)TDPA. The obtained values are comparable to other di-amidic ligands obtained under similar system conditions and mirror previously obtained solvent extraction data for EtTDPA at low ionic strengths. (authors.

  13. A new feruloyl amide derivative from the fruits of Tribulus terrestris.

    PubMed

    Zhang, Xiaopo; Wei, Na; Huang, Jian; Tan, Yinfeng; Jin, Dejun

    2012-01-01

    A new feruloyl amide derivative, named tribulusamide C, was isolated from the fruits of Tribulus terrestris. Its structure was determined on the basis of spectroscopic analysis including IR, 1-D-, 2-D-NMR and HR-ESI-MS. The structure of tribulusamide C was characterised by a unit of pyrrolidine-2,5-dione, which distinguished it from other lignanamides previously isolated from the fruits of T. terrestris. PMID:22149942

  14. Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless Auxiliaries

    PubMed Central

    Stivala, Craig E.; Zakarian, Armen

    2012-01-01

    A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable. PMID:21744818

  15. On the relationship between NMR-derived amide order parameters and protein backbone entropy changes

    PubMed Central

    Sharp, Kim A.; O’Brien, Evan; Kasinath, Vignesh; Wand, A. Joshua

    2015-01-01

    Molecular dynamics simulations are used to analyze the relationship between NMR-derived squared generalized order parameters of amide NH groups and backbone entropy. Amide order parameters (O2NH) are largely determined by the secondary structure and average values appear unrelated to the overall flexibility of the protein. However, analysis of the more flexible subset (O2NH < 0.8) shows that these report both on the local flexibility of the protein and on a different component of the conformational entropy than that reported by the side chain methyl axis order parameters, O2axis. A calibration curve for backbone entropy vs. O2NH is developed which accounts for both correlations between amide group motions of different residues, and correlations between backbone and side chain motions. This calibration curve can be used with experimental values of O2NH changes obtained by NMR relaxation measurements to extract backbone entropy changes, e.g. upon ligand binding. In conjunction with our previous calibration for side chain entropy derived from measured O2axis values this provides a prescription for determination of the total protein conformational entropy changes from NMR relaxation measurements. PMID:25739366

  16. Benzothiazole derivatives bearing amide moiety: potential cytotoxic and apoptosis-inducing agents against cervical cancer.

    PubMed

    Singh, Meenakshi; Modi, Arusha; Narayan, Gopeshwar; Singh, Sushil K

    2016-07-01

    Cervical cancer is a major cause of morbidity and mortality in women worldwide. In recent years, benzothiazole analogues have attracted considerable attention in anticancer research. Therefore, in this study, the earlier reported amide series of benzothiazole derivatives were investigated for their antiproliferative activity. The activity of amide derivatives was evaluated using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometric analysis, apoptosis assay, and DNA fragmentation on two human cervical cancer cell lines: SiHa and C33-A. The data reported from this investigation indicated that benzothiazole derivatives show pronounced cytotoxicity in the HPV16-positive SiHa cells compared with HPV-negative C-33A cells. The in-vitro cytotoxicity of the compounds on the HEK-293 noncancer cell line was evaluated to establish selectivity. Cells treated with benzothiazole derivatives showed prominent morphological features as evidenced by cell shrinkage, membrane blebbing, apoptotic nuclei, and DNA fragmentation. The benzothiazole derivatives show accumulation of cells in the sub-G1 and S-phase of the cell cycle in SiHa and C33-A, respectively. In addition, these derivatives exert their beneficial effect by inducing apoptosis, in the chemoprevention of cervical cancer cells, and were further ascertained using a DNA fragmentation assay. The compounds studied showed potent cytotoxic and apoptotic properties against SiHa and C33-A cancer cell lines and thus represent an excellent starting point for further optimization of therapeutically effective anticancer drugs. PMID:26945135

  17. Cytotoxic Glycosylated Fatty Acid Amides from a Stelletta sp. Marine Sponge.

    PubMed

    Peddie, Victoria; Takada, Kentaro; Okuda, Shujiro; Ise, Yuji; Morii, Yasuhiro; Yamawaki, Nobuhiro; Takatani, Tomohiro; Arakawa, Osamu; Okada, Shigeru; Matsunaga, Shigeki

    2015-11-25

    We have discovered new glycosylated fatty acid amides, stellettosides, from a Stelletta sp. marine sponge. They were detected through LC-MS analysis of the extract combined with the cytotoxicity assay of the prefractionated sample. Their planar structures were determined by analyses of the NMR and tandem FABMS data. Stellettosides A1 and A2 (1 and 2) as well as stellettosides B1-B4 (3-6) were obtained as inseparable mixtures. Careful analysis of the NMR and tandem FABMS data of each mixture, along with comparison of the tandem FABMS data with that of a synthetic model compound, permitted us to assign the structure of the constituents in the mixture. The absolute configuration of the monosaccharide unit was determined by LC-MS after chiral derivatization. The relative configurations of the vicinal oxygenated methines in the fatty acid chains were assigned by the (1)H NMR data of the isopropylidene derivative. The mixture of stellettosides B1-B4 (3-6) exhibit moderate cytotoxic activity against HeLa cells with an IC50 value of 9 μM, whereas the mixture of stellettosides A1 and A2 (1 and 2) was not active at a concentration of 10 μM. PMID:26558480

  18. Syntheses of hydroxamic acid-containing bicyclic β-lactams via palladium-catalyzed oxidative amidation of alkenes.

    PubMed

    Jobbins, Maria O; Miller, Marvin J

    2014-02-21

    Palladium-catalyzed oxidative amidation has been used to synthesize hydroxamic acid-containing bicyclic β-lactam cores. Oxidative cleavage of the pendant alkene provides access to the carboxylic acid in one step. PMID:24483144

  19. Ameliorative effects of amide derivatives of 1,3,4-thiadiazoles on scopolamine induced cognitive dysfunction.

    PubMed

    Kulshreshtha, Akanksha; Piplani, Poonam

    2016-10-21

    The present study reports the effect of amide derivatives of 1,3,4-thiadizoles on scopolamine induced deficit cholinergic neurotransmission and oxidative stress serving as promising leads for the therapeutics of cognitive dysfunction. Fourteen compounds (2c-8d) have been synthesised and evaluated against behavioural alterations using step down passive avoidance protocol and morris water maze and at a dose of 0.5 mg/kg with reference to the standard, Rivastigmine. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, plasma nitrite, catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 5c, 6c and 8c displayed appreciable activity with an IC50 value of 3 μM, 3.033 μM and 2.743 μM, respectively towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably with the amino acids present in the active site of recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction. PMID:27448914

  20. Direct enantioselective conjugate addition of carboxylic acids with chiral lithium amides as traceless auxiliaries.

    PubMed

    Lu, Ping; Jackson, Jeffrey J; Eickhoff, John A; Zakarian, Armen

    2015-01-21

    Michael addition is a premier synthetic method for carbon-carbon and carbon-heteroatom bond formation. Using chiral dilithium amides as traceless auxiliaries, we report the direct enantioselective Michael addition of carboxylic acids. A free carboxyl group in the product provides versatility for further functionalization, and the chiral reagent can be readily recovered by extraction with aqueous acid. The method has been applied in the enantioselective total synthesis of the purported structure of pulveraven B. PMID:25562717

  1. Synthesis and Characterization of DOTA-(amide)4 Derivatives: Equilibrium and Kinetic Behavior of Their Lanthanide(III) Complexes

    PubMed Central

    Pasha, Azhar; Benyó, Enikő Tircsóné; Brücher, Ernő

    2009-01-01

    Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg2+, Ca2+, Cu2+, Zn2+, and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)]2− complexes, largely due to the lower basicity of the tetraamide ligands. The Mg2+ and Ca2+ complexes are well described by formation of only ML species at equilibrium while the Zn2+ and Cu2+ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide)4}]2+ complexes has been assigned to an amide deprotonation by 1H NMR spectroscopy. The first deprotonation step for the Cu2+ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H−1-type complexes. The trends in the stability constants of the [Ln{DOTA-(amide)4}]3+ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)]− complexes, but again, the stability constants are about 10–11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln3+ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm)4}]3+ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)]− complexes, while the variation in complex formation rates with Ln3+ ion size is opposite to that observed for the corresponding [Ln(DOTA)]− complexes. The Ce3+ and

  2. Infrared spectroscopic study of the amidation reaction of aminophenyl modified Au surfaces and p-nitrobenzoic acid as model system.

    PubMed

    Zhang, Xin; Sun, Guoguang; Hinrichs, Karsten; Janietz, Silvia; Rappich, Joerg

    2010-10-21

    We have investigated the fundamental amidation reaction by a model system consisting of an electrochemically functionalised Au surface by aminophenyl and 4-nitrobenzoic acid activated by EEDQ. The development of the NO(2) related stretching vibrations with time reveals that the amidation process is very slow at Au surfaces and is completed after about 2 days. PMID:20737098

  3. Antioxidant and antimicrobial activities of cinnamic acid derivatives.

    PubMed

    Sova, M

    2012-07-01

    Cinnamic acid is an organic acid occurring naturally in plants that has low toxicity and a broad spectrum of biological activities. In the search for novel pharmacologically active compounds, cinnamic acid derivatives are important and promising compounds with high potential for development into drugs. Many cinnamic acid derivatives, especially those with the phenolic hydroxyl group, are well-known antioxidants and are supposed to have several health benefits due to their strong free radical scavenging properties. It is also well known that cinnamic acid has antimicrobial activity. Cinnamic acid derivatives, both isolated from plant material and synthesized, have been reported to have antibacterial, antiviral and antifungal properties. Acids, esters, amides, hydrazides and related derivatives of cinnamic acid with such activities are here reviewed. PMID:22512578

  4. CUTICULAR LIPIDS OF THE STORED FOOD PEST, LIPOSCELIS BOSTRYCHOPHILA BADONNEL (PSOCOPTERA: LIPOSCELIDIDAE): HYDROCARBONS, ALDEHYDES, FATTY ACIDS AND FATTY ACID AMIDES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The booklouse, Liposcelis bostrychophila, has increasingly become a common pest of stored food products worldwide. We report here the cuticular hydrocarbon composition of this pest (the first report of the hydrocarbons of any member of the Order Psocoptera) and the first report of fatty acid amides...

  5. The formation of lipid hydroperoxide-derived amide-type lysine adducts on proteins: a review of current knowledge.

    PubMed

    Kato, Yoji

    2014-01-01

    Lipid peroxidation is an important biological reaction. In particular, polyunsaturated fatty acid (PUFA) can be oxidized easily. Peroxidized lipids often react with other amines accompanied by the formation of various covalent adducts. Novel amide-type lipid-lysine adducts have been identified from an in vitro reaction mixture of lipid hydroperoxide with a protein, biological tissues exposed to conditions of oxidative stress and human urine from a healthy person. In this chapter, the current knowledge of amide type adducts is reviewed with a focus on the evaluation of functional foods and diseases with a history of discovery of hexanoyl-lysine (HEL). Although there is extensive research on HEL and other amide-type adducts, the mechanism of generation of the amide bond remains unclear. We have found that the decomposed aldehyde plus peroxide combined with a lysine moiety does not fully explain the formation of the amide-type lipid-lysine adduct that is generated by lipid hydroperoxide. Singlet oxygen or an excited state of the ketone generated from the lipid hydroperoxide may also contribute to the formation of the amide linkage. The amide-adducts may prove useful not only for the detection of oxidative stress induced by disease but also for the estimation of damage caused by an excess intake of PUFA. PMID:24374915

  6. Investigation of the complex reaction coordinate of acid catalyzed amide hydrolysis from molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Zahn, Dirk

    2004-05-01

    The rate-determining step of acid catalyzed peptide hydrolysis is the nucleophilic attack of a water molecule to the carbon atom of the amide group. Therein the addition of the hydroxyl group to the amide carbon atom involves the association of a water molecule transferring one of its protons to an adjacent water molecule. The protonation of the amide nitrogen atom follows as a separate reaction step. Since the nucleophilic attack involves the breaking and formation of several bonds, the underlying reaction coordinate is rather complex. We investigate this reaction step from path sampling Car-Parrinello molecular dynamics simulations. This approach does not require the predefinition of reaction coordinates and is thus particularly suited for investigating reaction mechanisms. From our simulations the most relevant components of the reaction coordinate are elaborated. Though the C⋯O distance of the oxygen atom of the water molecule performing the nucleophilic attack and the corresponding amide carbon atom is a descriptor of the reaction progress, a complete picture of the reaction coordinate must include all three molecules taking part in the reaction. Moreover, the proton transfer is found to depend on favorable solvent configurations. Thus, also the arrangement of non-reacting, i.e. solvent water molecules needs to be considered in the reaction coordinate.

  7. Novel L-DOPA-derived poly(ester amide)s: monomers, polymers, and the first L-DOPA-functionalized biobased adhesive tape.

    PubMed

    Manolakis, Ioannis; Noordover, Bart A J; Vendamme, Richard; Eevers, Walter

    2014-01-01

    The synthesis, characterization, and testing of a range of novel bio-inspired L-DOPA-derived poly(ester amide)s is presented, using a widely applicable, straightforward chemistry. A model system is used to study and establish the monomer and polymer synthetic protocols, and to provide a set of optimum reaction conditions. It is further shown that fully biobased L-DOPA-containing adhesive tapes can be fabricated, which are positively evaluated in terms of their adhesive properties. The newly developed synthetic protocol constitutes a versatile platform for accessing and tailoring a plethora of relevant structures, including a variety of potentially biocompatible poly(ethylene glycol)-based materials. PMID:24265232

  8. N-Acetylcysteine amide: a derivative to fulfill the promises of N-Acetylcysteine.

    PubMed

    Sunitha, K; Hemshekhar, M; Thushara, R M; Santhosh, M Sebastin; Yariswamy, M; Kemparaju, K; Girish, K S

    2013-05-01

    In the present human health scenario, implication of oxidative stress in numerous pathologies including neurodegenerative, cardiovascular, liver, renal, pulmonary disorders, and cancer has gained attention. N-Acetylcysteine (NAC), a popular thiol antioxidant, has been clinically used to treat various pathophysiological disorders. However, NAC therapy is routine only in paracetamol intoxication and as a mucolytic agent. Over six decades, numerous studies involving NAC therapy have yielded inconsistent results, and this could be due to low bioavailability. In order to overcome the limitations of NAC, an amide derivative N-Acetylcysteine amide (NACA) has been synthesized to improve the lipophilicity, membrane permeability, and antioxidant property. Recent studies have demonstrated the blood-brain barrier permeability and therapeutic potentials of NACA in neurological disorders including Parkinson's disease, Alzheimer's disease, Multiple sclerosis, Tardive dyskinesia, and HIV-associated neurological disorders. In addition, NACA displays protective effect against pulmonary inflammation and antibiotic-induced apoptosis. Forthcoming research on the possible therapeutic properties of NACA and its generics in the management of pathologies associated with extracellular matrix degradation and oxidative stress-related inflammation is highly exiting. Superior bioavailability of NACA is likely to fulfill the promises of NAC as well as a molecule to improve the endurance and resident time of bioscaffolds and biomaterials. Till date, more than 800 reviews on NAC have been published. However, no comprehensive review is available on the therapeutic applications of NACA. Therefore, the current review would be the first to emphasize the therapeutic potentials of NACA and its derivatives. PMID:23472882

  9. MATE Transporter-Dependent Export of Hydroxycinnamic Acid Amides[OPEN

    PubMed Central

    Eschen-Lippold, Lennart; Gorzolka, Karin; Matern, Andreas; Marillonnet, Sylvestre; Böttcher, Christoph; Rosahl, Sabine

    2016-01-01

    The ability of Arabidopsis thaliana to successfully prevent colonization by Phytophthora infestans, the causal agent of late blight disease of potato (Solanum tuberosum), depends on multilayered defense responses. To address the role of surface-localized secondary metabolites for entry control, droplets of a P. infestans zoospore suspension, incubated on Arabidopsis leaves, were subjected to untargeted metabolite profiling. The hydroxycinnamic acid amide coumaroylagmatine was among the metabolites secreted into the inoculum. In vitro assays revealed an inhibitory activity of coumaroylagmatine on P. infestans spore germination. Mutant analyses suggested a requirement of the p-coumaroyl-CoA:agmatine N4-p-coumaroyl transferase ACT for the biosynthesis and of the MATE transporter DTX18 for the extracellular accumulation of coumaroylagmatine. The host plant potato is not able to efficiently secrete coumaroylagmatine. This inability is overcome in transgenic potato plants expressing the two Arabidopsis genes ACT and DTX18. These plants secrete agmatine and putrescine conjugates to high levels, indicating that DTX18 is a hydroxycinnamic acid amide transporter with a distinct specificity. The export of hydroxycinnamic acid amides correlates with a decreased ability of P. infestans spores to germinate, suggesting a contribution of secreted antimicrobial compounds to pathogen defense at the leaf surface. PMID:26744218

  10. Synthesis, biological activity, and bioavailability of moschamine, a safflomide-type phenylpropenoic acid amide found in Centaurea cyanus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Moschamine is a safflomide-type phenylpropenoic acid amide originally isolated from Centaurea cyanus. This paper describes the synthesis, detection of serotoninergic and COX inhibitory activities, and bioavailability of moschamine. Moschamine was chemically synthesized and identified using NMR spect...

  11. Piperazic acid derivatives inhibit Gli1 in Hedgehog signaling pathway.

    PubMed

    Khatra, Harleen; Kundu, Jayanta; Khan, Pragya Paramita; Duttagupta, Indranil; Pattanayak, Sankha; Sinha, Surajit

    2016-09-15

    Piperazic acid, a non-proteinogenic amino acid, found in complex secondary metabolites and peptide natural substances, has shown down regulation of Gli1 expression in Hedgehog signaling pathway in cell based assays. Further structure activity relationship study indicated that amide derivatives of piperazic acid are more potent than piperazic acid itself, with little to no toxicity. However, other cellular components involved in the pathway were not affected. To the best of our knowledge, this is the first report on the inhibitory property of piperazic acid in this pathway. Hence, this molecule could serve as a useful tool for studying Hedgehog signaling. PMID:27528433

  12. Synthesis and Biological Investigation of some Novel Sulfonamide and Amide Derivatives Containing Coumarin Moieties

    PubMed Central

    Saeedi, Mina; Goli, Fereshteh; Mahdavi, Mohammad; Dehghan, Gholamreza; Faramarzi, Mohammad Ali; Foroumadi, Alireza; Shafiee, Abbas

    2014-01-01

    New sulfonamide and amide derivatives containing coumarin moieties; oxo-2H-chromen-sulfamoylphenylacetamides and oxo-2H-chromen-arylacetamides were synthesized starting from diverse 2-chloroacetamide derivatives and a wide range of coumarins. The structures of compounds were elucidated by IR and NMR spectra and also analytical elemental analysis. In the next step, the above mentioned compounds were screened for their antimicrobial and antioxidant activities. Their antimicrobial activity was assigned using the conventional agar dilution method and the antioxidant activity was assessed using two methods, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and ferric reducing antioxidant power (FRAP) assay. Although the compounds showed no remarkable antimicrobial activities, most of them exhibited good antioxidant activities. Compounds 5b showed the most potent DPPH activity, whereas 8c was the most efficient compound in FRAP assay. PMID:25276188

  13. Synthesis and Biological Investigation of some Novel Sulfonamide and Amide Derivatives Containing Coumarin Moieties.

    PubMed

    Saeedi, Mina; Goli, Fereshteh; Mahdavi, Mohammad; Dehghan, Gholamreza; Faramarzi, Mohammad Ali; Foroumadi, Alireza; Shafiee, Abbas

    2014-01-01

    New sulfonamide and amide derivatives containing coumarin moieties; oxo-2H-chromen-sulfamoylphenylacetamides and oxo-2H-chromen-arylacetamides were synthesized starting from diverse 2-chloroacetamide derivatives and a wide range of coumarins. The structures of compounds were elucidated by IR and NMR spectra and also analytical elemental analysis. In the next step, the above mentioned compounds were screened for their antimicrobial and antioxidant activities. Their antimicrobial activity was assigned using the conventional agar dilution method and the antioxidant activity was assessed using two methods, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and ferric reducing antioxidant power (FRAP) assay. Although the compounds showed no remarkable antimicrobial activities, most of them exhibited good antioxidant activities. Compounds 5b showed the most potent DPPH activity, whereas 8c was the most efficient compound in FRAP assay. PMID:25276188

  14. Cysteine amide adduct formation from carboxylic acid drugs via UGT-mediated bioactivation in human liver microsomes.

    PubMed

    Harada, H; Toyoda, Y; Endo, T; Kobayashi, M

    2015-10-01

    Although chemical trapping has been widely used to evaluate cytochrome P450-mediated drug bioactivation, thus far, only a few in vitro-trapping studies have been performed on UDP-glucuronosyltransferase (UGT)-mediated drug bioactivation. In this study, we used cysteine (Cys) as trapping agent to gain new insights into the UGT-mediated bioactivation involving acyl glucuronides of carboxylic acid drugs. Diclofenac, ketoprofen and ibuprofen were incubated in human liver microsomes with UDPGA and Cys, followed by analysis using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The N-acyl-Cys amide adduct of diclofenac was characterized by mass analysis and was detectable even in photodiode array analysis. Our data indicated that the formation of such adducts reflects the reactivity of the corresponding acyl glucuronides. In addition, it was suggested that the adduct formation requires an N-terminal Cys moiety with both a free amine and a free thiol group, from the results using various cysteine derivatives. We propose that the S-acyl-Cys thioester adduct can form via transacylation of an acyl glucuronide and can then form to an N-acyl-Cys amide adduct through intramolecular S- to N-acyl rearrangement. This series of the reactions has important implications as a possible bioactivation mechanism for covalent binding of carboxylic acid drugs to macromolecules. PMID:26601426

  15. Synthesis and copper-dependent antimycoplasmal activity of amides and amidines derived from 2-amino-1,10-phenanthroline.

    PubMed

    de Zwart, M A; Bastiaans, H M; van der Goot, H; Timmerman, H

    1991-03-01

    A series of both aliphatic and aromatic amides and aromatic amidines derived from 2-amino-1,10-phenanthroline (3) according to the Topliss scheme were synthesized and subsequently tested for antimycoplasmal potency. Although the compounds themselves showed no activity, in the presence of a nontoxic copper concentration of 40 microM all compounds appeared to be very active against Mycoplasma gallisepticum K154. The most active compounds were found in the amide series and show growth inhibition in the nanomolar range. These compounds are 4 times more active than tylosin, a macrolide antibiotic, which is used therapeutically in veterinary practice. In the presence of copper, amides derived from 3 are more active than corresponding amidines. Increased activity following derivatization of 3 may be due to the presence of a third coordination site for copper in the title compounds. Evaluation of biological data revealed that antimycoplasmal activity of amides derived from 3 is dependent on lipophilicity. For these amides a good linear correlation was found between antimycoplasmal activity and hydrophobic fragmental values for substituents considered. This quantitative structure-activity relationship study indicated that antimycoplasmal activity was increased upon a decrease of these hydrophobic fragmental values. PMID:2002460

  16. Isoniazid is not a lead compound for its pyridyl ring derivatives, isonicotinoyl amides, hydrazides, and hydrazones: a critical review.

    PubMed

    Scior, T; Garcés-Eisele, S J

    2006-01-01

    The relationships between structure, disintegration and antituberculotic in vitro activity were studied for over 200 derivatives of isonicotinic acid hydrazide (isoniazid, INH). Conclusive evidence reflects that many compounds do not withstand the in vitro conditions. A pH dependant partial hydrolysis to INH occurs in the case of hydrazones, in analogy to well-known benzoic acid esters. Hydrazides and amides are cleaved into isonicotinic acid. In general, antimycobacterial potencies drop against INH except for two outliers probably with additional unspecific toxicity of their residues. Analyzing the complexity and heterogeneity of molecular events, trends linked to hydrolysis are found when structural features are clustered. Hammett sigma constants correlate to pK(a) values possessing a twofold descriptive meaning: (i) the cardinal increase of partial positive charge of the reaction center towards nucleophilic water attack and (ii) the ionization crucial for mycobacterial cell permeation through porins or lipid barriers. We review the literature concluding that many so-called "novel leads" are nothing else than precursors of an INH-based scaffold. In addition, INH ring-substitution or analogous backbones never achieve the efficiency of INH, itself a prodrug, which accumulates in Mycobacterium tuberculosis in form of its intrabacterial active principle(s) to which it is an optimal transport vehicle, evidencing that INH is not a promising lead compound at all. PMID:16918349

  17. Probing acid-amide intermolecular hydrogen bonding by NMR spectroscopy and DFT calculations

    NASA Astrophysics Data System (ADS)

    Chaudhari, Sachin Rama; Suryaprakash, N.

    2012-05-01

    Benzene carboxylic acids and benzamide act as their self-complement in molecular recognition to form inter-molecular hydrogen bonded dimers between amide and carboxylic acid groups, which have been investigated by 1H, 13C and 15N NMR spectroscopy. Extensive NMR studies using diffusion ordered spectroscopy (DOSY), variable temperature 1D, 2D NMR, established the formation of heterodimers of benzamide with benzoic acid, salicylic acid and phenyl acetic acid in deuterated chloroform solution. Association constants for the complex formation in the solution state have been determined. The results are ascertained by X-ray diffraction in the solid state. Intermolecular interactions in solution and in solid state were found to be similar. The structural parameters obtained by X-ray diffraction studies are compared with those obtained by DFT calculations.

  18. A Protein-derived Oxygen Is the Source of the Amide Oxygen of Nitrile Hydratases.

    PubMed

    Nelp, Micah T; Song, Yang; Wysocki, Vicki H; Bandarian, Vahe

    2016-04-01

    Nitrile hydratase metalloenzymes are unique and important biocatalysts that are used industrially to produce high value amides from their corresponding nitriles. After more than three decades since their discovery, the mechanism of this class of enzymes is becoming clear with evidence from multiple recent studies that the cysteine-derived sulfenato ligand of the active site metal serves as the nucleophile that initially attacks the nitrile. Herein we describe the first direct evidence from solution phase catalysis that the source of the product carboxamido oxygen is the protein. Using(18)O-labeled water under single turnover conditions and native high resolution protein mass spectrometry, we show that the incorporation of labeled oxygen into both product and protein is turnover-dependent and that only a single oxygen is exchanged into the protein even under multiple turnover conditions, lending significant support to proposals that the post-translationally modified sulfenato group serves as the nucleophile to initiate hydration of nitriles. PMID:26865634

  19. Synthesis and antifungal activity evaluation of new heterocycle containing amide derivatives.

    PubMed

    Wang, Xuesong; Gao, Sumei; Yang, Jian; Gao, Yang; Wang, Ling; Tang, Xiaorong

    2016-01-01

    A series of heterocycle containing amide derivatives (1-28) were synthesised by the combination of acyl chlorides (1a, 2a) and heterocyclic/homocyclic ring containing amines, and their in vitro antifungal activity was evaluated against five plant pathogenic fungi, namely Gibberella zeae, Helminthosporium maydis, Rhizoctonia solani, Botrytis cinerea and Sclerotinia sclerotiorum. Results of antifungal activity analysis indicated that some of the products showed good to excellent antifungal activity, as compound 2 showed excellent activity against G. zeae and R. solani and potent activity against H. maydi, B. cinerea and S. sclerotiorum, and compounds 1, 8 and 10 also displayed excellent antifungal potential against H. maydi, B. cinerea and S. sclerotiorum and good activity against R. solani when compared with the standard carbendazim. PMID:26140452

  20. Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity.

    PubMed

    Guzman, Juan David

    2014-01-01

    Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC) of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships. PMID:25429559

  1. Visible-Light-Mediated Synthesis of Amides from Aldehydes and Amines via in Situ Acid Chloride Formation.

    PubMed

    Iqbal, Naeem; Cho, Eun Jin

    2016-03-01

    An efficient visible-light photocatalysis-based one-pot amide synthesis method was developed; visible-light irradiation of a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-chlorosuccinimide using a Ru(bpy)3Cl2 photocatalyst afforded an acid chloride, which subsequently reacted with amine to yield the corresponding amide. The reaction was used to synthesize moclobemide and a D3 receptor intermediate. PMID:26836367

  2. Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase.

    PubMed

    Liu, Ping; Hamill, Terence G; Chioda, Marc; Chobanian, Harry; Fung, Selena; Guo, Yan; Chang, Linda; Bakshi, Raman; Hong, Qingmei; Dellureficio, James; Lin, Linus S; Abbadie, Catherine; Alexander, Jessica; Jin, Hong; Mandala, Suzanne; Shiao, Lin-Lin; Li, Wenping; Sanabria, Sandra; Williams, David; Zeng, Zhizhen; Hajdu, Richard; Jochnowitz, Nina; Rosenbach, Mark; Karanam, Bindhu; Madeira, Maria; Salituro, Gino; Powell, Joyce; Xu, Ling; Terebetski, Jenna L; Leone, Joseph F; Miller, Patricia; Cook, Jacquelynn; Holahan, Marie; Joshi, Aniket; O'Malley, Stacey; Purcell, Mona; Posavec, Diane; Chen, Tsing-Bau; Riffel, Kerry; Williams, Mangay; Hargreaves, Richard; Sullivan, Kathleen A; Nargund, Ravi P; DeVita, Robert J

    2013-06-13

    We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain. PMID:24900701

  3. Isolation, identification and quantification of unsaturated fatty acids, amides, phenolic compounds and glycoalkaloids from potato peel.

    PubMed

    Wu, Zhi-Gang; Xu, Hai-Yan; Ma, Qiong; Cao, Ye; Ma, Jian-Nan; Ma, Chao-Mei

    2012-12-15

    Eleven compounds were isolated from potato peels and identified. Their structures were determined by interpretation of UV, MS, 1D, and 2D NMR spectral data and by comparison with reported data. The main components of the potato peels were found to be chlorogenic acid and other phenolic compounds, accompanied by 2 glycoalkaloids, 3 low-molecular-weight amide compounds, and 2 unsaturated fatty acids, including an omega-3 fatty acid. The potato peels showed more potent radical scavenging activity than the flesh. The quantification of the 11 components indicated that the potato peels contained a higher amount of phenolic compounds than the flesh. These results suggest that peel waste from the industry of potato chips and fries may be a source of useful compounds for human health. PMID:22980823

  4. Synthesis and biological evaluation of piperic acid amides as free radical scavengers and α-glucosidase inhibitors.

    PubMed

    Takao, Koichi; Miyashiro, Takaki; Sugita, Yoshiaki

    2015-01-01

    A series of piperic acid amides (4-24, 29, 30) were synthesized and their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory activities were evaluated. Among the synthesized compounds, the amides 11, 13 and 15, which contain o-methoxyphenol, catechol or 5-hydroxyindole moieties, showed potent DPPH free radical scavenging activity (11: EC50 140 µM; 13: EC50 28 µM; 15: EC50 20 µM). The amides 10, 18 and 23 showed higher inhibitory activity of α-glucosidase (10: IC50 21 µM; 18: IC50 21 µM; 23: IC50 12 µM). These data suggest that the hydrophobicity of the conjugated amines is an important determinant of α-glucosidase inhibitory activity. In addition, the amides 13 and 15 showed both potent DPPH free radical scavenging activity and α-glucosidase inhibitory activity (13: IC50 46 µM; 15: IC50 46 µM). This is the first report identifying the DPPH free radical scavenging and α-glucosidase inhibitory activities of piperic acid amides and suggests that these amides may serve as lead compounds for the development of novel α-glucosidase inhibitors with antioxidant activity. PMID:25948326

  5. Computational insights into function and inhibition of fatty acid amide hydrolase.

    PubMed

    Palermo, Giulia; Rothlisberger, Ursula; Cavalli, Andrea; De Vivo, Marco

    2015-02-16

    The Fatty Acid Amide Hydrolase (FAAH) enzyme is a membrane-bound serine hydrolase responsible for the deactivating hydrolysis of a family of naturally occurring fatty acid amides. FAAH is a critical enzyme of the endocannabinoid system, being mainly responsible for regulating the level of its main cannabinoid substrate anandamide. For this reason, pharmacological inhibition of FAAH, which increases the level of endogenous anandamide, is a promising strategy to cure a variety of diseases including pain, inflammation, and cancer. Much structural, mutagenesis, and kinetic data on FAAH has been generated over the last couple of decades. This has prompted several informative computational investigations to elucidate, at the atomic-level, mechanistic details on catalysis and inhibition of this pharmaceutically relevant enzyme. Here, we review how these computational studies - based on classical molecular dynamics, full quantum mechanics, and hybrid QM/MM methods - have clarified the binding and reactivity of some relevant substrates and inhibitors of FAAH. We also discuss the experimental implications of these computational insights, which have provided a thoughtful elucidation of the complex physical and chemical steps of the enzymatic mechanism of FAAH. Finally, we discuss how computations have been helpful for building structure-activity relationships of potent FAAH inhibitors. PMID:25240419

  6. An Investigation of Solid-State Amidization and Imidization Reactions in Vapor Deposited Poly (amic acid)

    SciTech Connect

    Anthamatten, M; Letts, S A; Day, K; Cook, R C; Gies, A P; Hamilton, T P; Nonidez, W K

    2004-06-28

    The condensation polymerization reaction of 4,4'-oxydianiline (ODA) with pyromellitic dianhydride (PMDA) to form poly(amic acid) and the subsequent imidization reaction to form polyimide were investigated for films prepared using vapor deposition polymerization techniques. Fourier-transform infrared spectroscopy (FT-IR), thermal analysis, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of films at different temperatures indicate that additional solid-state polymerization occurs prior to imidization reactions. Experiments reveal that, upon vapor deposition, poly(amic acid) oligomers form that have a number-average molecular weight of about 1500 Daltons. Between 100 - 130 C these chains undergo additional condensation reaction to form slightly higher molecular weight oligomers. Calorimetry measurements show that this reaction is exothermic ({Delta}H {approx} -30 J/g) with an activation energy of about 120 kJ/mol. Experimental reaction enthalpies are compared to results from ab initio molecular modeling calculations to estimate the number of amide groups formed. At higher temperatures (150 - 300 C) imidization of amide linkages occurs as an endothermic reaction ({Delta}H {approx} +120 J/g) with an activation energy of about 130 kJ/mol. Solid-state kinetics were found to depend on reaction conversion as well as the processing conditions used to deposit films.

  7. The effect of pH on the toxicity of fatty acids and fatty acid amides to rainbow trout gill cells.

    PubMed

    Bertin, Matthew J; Voronca, Delia C; Chapman, Robert W; Moeller, Peter D R

    2014-01-01

    Harmful algal blooms (HABs) expose aquatic organisms to multiple physical and chemical stressors during an acute time period. Algal toxins themselves may be altered by water chemistry parameters affecting their bioavailability and resultant toxicity. The purpose of this study was to determine the effects of two abiotic parameters (pH, inorganic metal salts) on the toxicity of fatty acid amides and fatty acids, two classes of lipids produced by harmful algae, including the golden alga, Prymnesium parvum, that are toxic to aquatic organisms. Rainbow trout gill cells were used as a model of the fish gill and exposed to single compounds and mixtures of compounds along with variations in pH level and concentration of inorganic metal salts. We employed artificial neural networks (ANNs) and standard ANOVA statistical analysis to examine and predict the effects of these abiotic parameters on the toxicity of fatty acid amides and fatty acids. Our results demonstrate that increasing pH levels increases the toxicity of fatty acid amides and inhibits the toxicity of fatty acids. This phenomenon is reversed at lower pH levels. Exposing gill cells to complex mixtures of chemical factors resulted in dramatic increases in toxicity compared to tests of single compounds for both the fatty acid amides and fatty acids. These findings highlight the potential of physicochemical factors to affect the toxicity of chemicals released during algal blooms and demonstrate drastic differences in the effect of pH on fatty acid amides and fatty acids. PMID:24240104

  8. Synthesis and QSAR of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates

    PubMed Central

    Mor, Marco; Lodola, Alessio; Rivara, Silvia; Vacondio, Federica; Duranti, Andrea; Tontini, Andrea; Sanchini, Silvano; Piersanti, Giovanni; Clapper, Jason R.; King, Alvin R.; Tarzia, Giorgio; Piomelli, Daniele

    2013-01-01

    Alkylcarbamic acid biphenyl-3-yl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors that comprises cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester (URB597), a compound with analgesic, anxiolytic-like and antidepressant-like properties in rat and mouse models. Here, we extended the structure-activity relationships (SARs) for this class of compounds by replacing the cyclohexyl ring of the parent compound cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) (IC50, for FAAH = 63 nM) with a selected set of substituents of different size, shape, flexibility and lipophilicity. Docking experiments and Linear Interaction Energy (LIE) calculations indicated that the N-terminal group of O-arylcarbamates fits within the lipophilic region of the substrate-binding site, mimicking the arachidonoyl chain of anandamide. Significant potency improvements were observed for the β-naphthylmethyl derivative 4q (IC50 = 5.3 nM) and its 3′-carbamoylbiphenyl-3-yl ester 4z (URB880, IC50 = 0.63 nM), indicating that shape complementarity and hydrogen bonds are crucial to obtain highly potent inhibitors. PMID:18507372

  9. [Synthesis and anti-proliferative activity of fluoroquinolone (rhodanine unsaturated ketone) amide derivatives].

    PubMed

    Gao, Liu-zhou; Xie, Yu-suo; Yan, Qiang; Wu, Shu-min; Ni, Li-li; Zhao, Hui; Huang, Wen-long; Hu, Guo-qiang

    2015-08-01

    To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone (rhodanine α, β-unsaturated ketone) amine derivatives (5a-5r) were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone (rhodanine α, β-unsaturated ketone) amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues. PMID:26669001

  10. Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)

    PubMed Central

    Min, Xiaoshan; Thibault, Stephen T.; Porter, Amy C.; Gustin, Darin J.; Carlson, Timothy J.; Xu, Haoda; Lindstrom, Michelle; Xu, Guifen; Uyeda, Craig; Ma, Zhihua; Li, Yihong; Kayser, Frank; Walker, Nigel P. C.; Wang, Zhulun

    2011-01-01

    Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition. PMID:21502526

  11. Structure–Activity Relationships of α-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase

    PubMed Central

    Hardouin, Christophe; Kelso, Michael J.; Romero, F. Anthony; Rayl, Thomas J.; Leung, Donmienne; Hwang, Inkyu; Cravatt, Benjamin F.; Boger, Dale L.

    2008-01-01

    A systematic study of the structure–activity relationships (SAR) of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM) with 5hh (aryl = 3-Cl-Ph, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteomic-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases. PMID:17559203

  12. HPLC/ELSD analysis of amidated bile acids: an effective and rapid way to assist continuous flow chemistry processes.

    PubMed

    Sardella, Roccaldo; Gioiello, Antimo; Ianni, Federica; Venturoni, Francesco; Natalini, Benedetto

    2012-10-15

    The employment of the flow N-acyl amidation of natural bile acids (BAs) required the in-line connection with suitable analytical tools enabling the determination of reaction yields as well as of the purity grade of the synthesized glyco- and tauro-conjugated derivatives. In this framework, a unique HPLC method was successfully established and validated for ursodeoxycholic (UDCA), chenodeoxycholic (CDCA), deoxycholic (DCA) and cholic (CA) acids, as well as the corresponding glyco- and tauro-conjugated forms. Because of the shared absence of relevant chromophoric moieties in the sample structure, an evaporative light scattering detector (ELSD) was profitably utilized for the analysis of such steroidal species. For each of the investigated compounds, all the runs were contemporarily carried out on the acidic free and the two relative conjugated variants. The different ELSD response of the free and the corresponding conjugated BAs, imposed to build-up separate calibration curves. In all the cases, very good precision (RSD% values ranging from 1.04 to 6.40% in the long-period) and accuracy (Recovery% values ranging from 96.03 to 111.14% in the long-period) values along with appreciably low LOD and LOQ values (the former being within the range 1-27 ng mL(-1) and the latter within the range 2-44 ng mL(-1)) turned out. PMID:23141350

  13. Halogenated Fatty Acid Amides and Cyclic Depsipeptides from an Eastern Caribbean Collection of the Cyanobacterium Lyngbya majuscula†

    PubMed Central

    Jiménez, Jorge I.; Vansach, Tifanie; Yoshida, Wesley Y.; Sakamoto, Bryan; Pörzgen, Peter; Horgen, F. David

    2009-01-01

    A lipophilic extract of an eastern Caribbean collection of Lyngbya majuscula yielded two new halogenated fatty acid amides, grenadamides B (1) and C (2), and two new depsipeptides, itralamides A (3) and B (4), along with the known compounds hectochlorin and deacetylhectochlorin. The recently reported depsipeptide carriebowmide (5) was also present in the extract and isolated as its sulfone artifact (6). Compounds 1–4 were identified by spectroscopic methods. The configurations of the amino acid residues of 3, 4, and 6 were determined by LC-MS analyses of diastereomeric derivatives of the acid hydrolysates (advanced Marfey’s method). Based on the configurational analysis of 6, in direct comparison with authentic carriebowmide (5), a minor structural revision of 5 is proposed. Compounds 1 and 2 displayed marginal activity against the beet armyworm (Spodoptera exigua). Compounds 1–4, and 6 were assessed for general cell toxicity in human embryonic kidney (HEK293) cells. Only itralamide B (4) displayed significant cytotoxicity, showing an IC50 value of 6 ± 1 μM. PMID:19739598

  14. Physical Nature of Fatty Acid Amide Hydrolase Interactions with Its Inhibitors: Testing a Simple Nonempirical Scoring Model.

    PubMed

    Giedroyć-Piasecka, Wiktoria; Dyguda-Kazimierowicz, Edyta; Beker, Wiktor; Mor, Marco; Lodola, Alessio; Sokalski, W Andrzej

    2014-12-26

    Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the deactivating hydrolysis of fatty acid ethanolamide neuromodulators. FAAH inhibitors have gained considerable interest due to their possible application in the treatment of anxiety, inflammation, and pain. In the context of inhibitor design, the availability of reliable computational tools for predicting binding affinity is still a challenging task, and it is now well understood that empirical scoring functions have several limitations that in principle could be overcome by quantum mechanics. Herein, systematic ab initio analyses of FAAH interactions with a series of inhibitors belonging to the class of the N-alkylcarbamic acid aryl esters have been performed. In contrast to our earlier studies of other classes of enzyme-inhibitor complexes, reasonable correlation with experimental results required us to consider correlation effects along with electrostatic term. Therefore, the simplest comprehensive nonempirical model allowing for qualitative predictions of binding affinities for FAAH ligands consists of electrostatic multipole and second-order dispersion terms. Such a model has been validated against the relative stabilities of the benchmark S66 set of biomolecular complexes. As it does not involve parameters fitted to experimentally derived data, this model offers a unique opportunity for generally applicable inhibitor design and virtual screening. PMID:25420234

  15. Hydroalumination of Ketenimines and Subsequent Reactions with Heterocumulenes: Synthesis of Unsaturated Amide Derivatives and 1,3-Diimines.

    PubMed

    Jin, Xing; Willeke, Matthias; Lucchesi, Ralph; Daniliuc, Constantin-Gabriel; Fröhlich, Roland; Wibbeling, Birgit; Uhl, Werner; Würthwein, Ernst-Ulrich

    2015-06-19

    The series of differently substituted ketenimines 1 was hydroluminated using di-iso-butyl aluminum hydride. For the sterically congested ketenimine 1a, preferred hydroalumination of the C═N-bond was proven by X-ray crystallography (compound 5a). In situ treatment of the hydroaluminated ketenimines 5 with various heterocumulenes like carbodiimides, isocycanates, isothiocyanates and ketenimines as electrophiles and subsequent hydrolytic workup resulted in novel enamine derived amide species in case of N-attack (sterically less hindered ketenimines) under formation of a new C-N-bond or in 1,3-diimines by C-C-bond-formation in case of bulky substituents at the ketenimine-nitrogen atom. Furthermore, domino reactions with more than 1 equiv of the electrophile or by subsequent addition of two different electrophiles are possible and lead to polyfunctional amide derivatives of the biuret type which are otherwise not easily accessible. PMID:26031425

  16. Hydroxycinnamic acid amides from Scopolia tangutica inhibit the activity of M1 muscarinic acetylcholine receptor in vitro.

    PubMed

    Zhang, Yan; Long, Zhen; Guo, Zhimou; Wang, Zhiwei; Zhang, Xiuli; Ye, Richard D; Liang, Xinmiao; Civelli, Olivier

    2016-01-01

    Scopolia tangutica Maxim (S. tangutica) extracts have been traditionally used as antispasmodic, sedative, and analgesic agents in Tibet and in the Qinghai province of China. Their active compositions are however poorly understood. We have recently isolated five new hydroxycinnamic acid (HCA) amides along with two known HCA amides, one cinnamic acid amide from these extracts. In this study, we evaluate their abilities to inhibit carbacol-induced activity of M1 muscarinic acetylcholine receptor along with the crude extracts. Chinese hamster ovary cells stably expressing the recombinant human M1 receptor (CHO-M1 cells) were employed to evaluate the anticholinergic potentials. Intracellular Ca(2+) changes were monitored using the FLIPR system. Five HCA amides as well as the crude S. tangutica extract displayed dose-dependent inhibitory effects against M1 receptor. These findings demonstrate that HCA amides are part of the M1 receptor-inhibiting principles of S. tangutica. Since blockade of parasympathetic nerve impulse transmission through the inhibition of the M1 receptor lessens smooth muscle spasms, our findings provided a molecular explanation for the traditional use of S. tangutica against spasm. PMID:26586621

  17. Cellular viability effects of fatty acid amide hydrolase inhibition on cerebellar neurons

    PubMed Central

    2011-01-01

    The endocannabinoid anandamide (ANA) participates in the control of cell death inducing the formation of apoptotic bodies and DNA fragmentation. The aim of this study was to evaluate whether the ANA degrading enzyme, the fatty acid amide hydrolase (FAAH), would induce cellular death. Experiments were performed in cerebellar granule neurons cultured with the FAAH inhibitor, URB597 (25, 50 or 100 nM) as well as endogenous lipids such as oleoylethanolamide (OEA) or palmitoylethanolamide (PEA) and cellular viability was determined by MTT test. Neurons cultured with URB597 (25, 50 or 100 nM) displayed a decrease in cellular viability. In addition, if cultured with OEA (25 nM) or PEA (100 nM), cellular death was found. These results further suggest that URB597, OEA or PEA promote cellular death. PMID:21854612

  18. Free fatty acid determination in plasma by GC-MS after conversion to Weinreb amides.

    PubMed

    Ubhayasekera, Sarojini J K A; Staaf, Johan; Forslund, Anders; Bergsten, Peter; Bergquist, Jonas

    2013-02-01

    Circulating free fatty acids (FFAs) play important physiological roles as contributing components in cellular structure as well as energy utilization. Elevated levels of circulating FFAs are associated with metabolic aberrations in humans. FFAs differ in chain length and saturation and may be altered in metabolically dysregulated conditions, such as type 2 diabetes mellitus. Potentially, alterations in circulating levels of specific FFAs could also be important in terms of prognostic value. Various methods have been used to analyze FFAs. In this study, a straightforward and accurate method for the determination of FFAs in plasma has been established and evaluated, through conversion of plasma FFAs into acid fluorides followed by conversion to Weinreb amides (dimethylamide). The method is mild, efficient, selective, and quantitative for FFAs, when analyzed with capillary gas chromatography tandem mass spectrometry. Standard curves were linear over the range of 1,000-20,000 ng/mL with a correlation coefficient (r(2)) of 0.998, and coefficient of variation of triplicate analysis was <10 %. The gas chromatography-mass spectrometry (GC-MS) technique was reproducible and repeatable, and recoveries were above 90 %. From the generated MS spectra, five specific FFAs were identified. An explicit interest was the quantification of palmitate (C16:0) and palmitoleate (C16:1), which have been connected with detrimental and positive effects on the insulin-producing beta cells, respectively. The results demonstrate the suitability of Weinreb amides for efficient and rapid isolation of FFAs in plasma, prior to quantitative GC-MS analysis. We suggest that the method can be used as a routine standardized way of quantifying FFAs. PMID:23307129

  19. Inhibition of endocannabinoid-degrading enzyme fatty acid amide hydrolase increases atherosclerotic plaque vulnerability in mice.

    PubMed

    Hoyer, Friedrich Felix; Khoury, Mona; Slomka, Heike; Kebschull, Moritz; Lerner, Raissa; Lutz, Beat; Schott, Hans; Lütjohann, Dieter; Wojtalla, Alexandra; Becker, Astrid; Zimmer, Andreas; Nickenig, Georg

    2014-01-01

    The role of endocannabinoids such as anandamide during atherogenesis remains largely unknown. Fatty acid amide hydrolase (FAAH) represents the key enzyme in anandamide degradation, and its inhibition is associated with subsequent higher levels of anandamide. Here, we tested whether selective inhibition of FAAH influences the progression of atherosclerosis in mice. Selective inhibition of FAAH using URB597 resulted in significantly increased plasma levels of anandamide compared to control, as assessed by mass spectrometry experiments in mice. Apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-fat, cholesterol-rich diet to induce atherosclerotic conditions. Simultaneously, mice received either the pharmacological FAAH inhibitor URB597 1mg/kg body weight (n=28) or vehicle (n=25) via intraperitoneal injection three times a week. After eight weeks, mice were sacrificed, and experiments were performed. Vascular superoxide generation did not differ between both groups, as measured by L012 assay. To determine whether selective inhibition of FAAH affects atherosclerotic plaque inflammation, immunohistochemical staining of the aortic root was performed. Atherosclerotic plaque formation, vascular macrophage accumulation, as well as vascular T cell infiltration did not differ between both groups. Interestingly, neutrophil cell accumulation was significantly increased in mice receiving URB597 compared to control. Vascular collagen structures in atherosclerotic plaques were significantly diminished in mice treated with URB597 compared to control, as assessed by picro-sirius-red staining. This was accompanied by an increased aortic expression of matrix metalloproteinase-9, as determined by quantitative RT-PCR and western blot analysis. Inhibition of fatty acid amide hydrolase does not influence plaque size but increases plaque vulnerability in mice. PMID:24286707

  20. Role of the delta 8 double bond of agroclavine in lysergic acid amide biosynthesis by Claviceps purpurea.

    PubMed

    Willingale, J; Manzarpour, A; Mantle, P G

    1985-08-15

    Agroclavine, given to actively-growing sclerotial tissue of a strain of Claviceps purpurea which can not normally elaborate ergot alkaloids, was transformed by this tissue into lysergic acid amide with overall efficiency of approximately 40%. By contrast, festuclavine (8,9-dihydro-agroclavine) was not transformed, indicating specificity in the mechanism of lysergyl biosynthesis. PMID:4018228

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

    ERIC Educational Resources Information Center

    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.…

  2. GC AND LC CHROMATOGRAPHIC AND EI, CE, +/- CI, AND ES MASS SPECTRAL CHARACTERISTICS OF SALTS AND AMIDES OF PERFLUOROOCTANESULFONIC ACID

    EPA Science Inventory

    In 1976, fluorine in human blood serum was thought to be present as perfluorooctanic acid; however, in the 1990s it was correctly identified by LC/MS as perfluorooctanesulfonate (PFOS). PFOS was both a commercial product and an end-stage metabolite of numerous substituted amides ...

  3. Amino acid amides of piperic acid (PA) and 4-ethylpiperic acid (EPA) as NorA efflux pump inhibitors of Staphylococcus aureus.

    PubMed

    Wani, Naiem Ahmad; Singh, Samsher; Farooq, Saleem; Shankar, Sudha; Koul, Surrinder; Khan, Inshad Ali; Rai, Rajkishor

    2016-09-01

    A total of eighteen piperic acid (PA) and 4-ethylpiperic acid (EPA) amides (C1-C18) with α-, β- and γ-amino acids were synthesized, characterized and evaluated for their efflux pump inhibitory activity against ciprofloxacin resistant Staphylococcus aureus. The amides were screened against NorA overexpressing S. aureus SA-1199B and wild type S. aureus SA-1199 using ethidium bromide as NorA efflux pump substrate. EPI C6 was found to be most potent and reduced the MIC of ciprofloxacin by 16 fold followed by C18 which showed 4 fold reduction of MIC. Ethidium bromide efflux inhibition and accumulation assay proved these compounds as NorA inhibitors. PMID:27503686

  4. Efficient Amide Bond Formation through a Rapid and Strong Activation of Carboxylic Acids in a Microflow Reactor**

    PubMed Central

    Fuse, Shinichiro; Mifune, Yuto; Takahashi, Takashi

    2014-01-01

    The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74 %–quant.) without significant epimerization (≤3 %). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents. PMID:24402801

  5. Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors

    PubMed Central

    Dražić, Tonko; Sachdev, Vinay; Leopold, Christina; Patankar, Jay V.; Malnar, Martina; Hećimović, Silva; Levak-Frank, Sanja; Habuš, Ivan; Kratky, Dagmar

    2015-01-01

    The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo. PMID:25882530

  6. Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51.

    PubMed

    Gaali, Steffen; Feng, Xixi; Hähle, Andreas; Sippel, Claudia; Bracher, Andreas; Hausch, Felix

    2016-03-24

    The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51-favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides. This resulted in the first series of pipecolic acid amides, which had much lower molecular weights without affecting FKBP51 selectivity. We discovered a geminally substituted cyclopentyl amide as a preferred FKBP51-binding motif and elucidated its binding mode to provide a new lead structure for future drug optimization. PMID:26954324

  7. Atom-economic catalytic amide synthesis from amines and carboxylic acids activated in situ with acetylenes.

    PubMed

    Krause, Thilo; Baader, Sabrina; Erb, Benjamin; Gooßen, Lukas J

    2016-01-01

    Amide bond-forming reactions are of tremendous significance in synthetic chemistry. Methodological research has, in the past, focused on efficiency and selectivity, and these have reached impressive levels. However, the unacceptable amounts of waste produced have led the ACS GCI Roundtable to label 'amide bond formation avoiding poor atom economy' as the most pressing target for sustainable synthetic method development. In response to this acute demand, we herein disclose an efficient one-pot amide coupling protocol that is based on simple alkynes as coupling reagents: in the presence of a dichloro[(2,6,10-dodecatriene)-1,12-diyl]ruthenium catalyst, carboxylate salts of primary or secondary amines react with acetylene or ethoxyacetylene to vinyl ester intermediates, which undergo aminolysis to give the corresponding amides along only with volatile acetaldehyde or ethyl acetate, respectively. The new amide synthesis is broadly applicable to the synthesis of structurally diverse amides, including dipeptides. PMID:27282773

  8. Atom-economic catalytic amide synthesis from amines and carboxylic acids activated in situ with acetylenes

    PubMed Central

    Krause, Thilo; Baader, Sabrina; Erb, Benjamin; Gooßen, Lukas J.

    2016-01-01

    Amide bond-forming reactions are of tremendous significance in synthetic chemistry. Methodological research has, in the past, focused on efficiency and selectivity, and these have reached impressive levels. However, the unacceptable amounts of waste produced have led the ACS GCI Roundtable to label ‘amide bond formation avoiding poor atom economy' as the most pressing target for sustainable synthetic method development. In response to this acute demand, we herein disclose an efficient one-pot amide coupling protocol that is based on simple alkynes as coupling reagents: in the presence of a dichloro[(2,6,10-dodecatriene)-1,12-diyl]ruthenium catalyst, carboxylate salts of primary or secondary amines react with acetylene or ethoxyacetylene to vinyl ester intermediates, which undergo aminolysis to give the corresponding amides along only with volatile acetaldehyde or ethyl acetate, respectively. The new amide synthesis is broadly applicable to the synthesis of structurally diverse amides, including dipeptides. PMID:27282773

  9. Synthesis and biological evaluation of quinic acid derivatives as anti-inflammatory agents.

    PubMed

    Zeng, Kui; Thompson, Karin Emmons; Yates, Charles R; Miller, Duane D

    2009-09-15

    Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. cat's claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB). Herein, we describe the synthesis and biological testing of novel QA derivatives. Inhibition of NF-kappaB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-kappaB response element. A549-NF-kappaB cells were stimulated with TNF-alpha (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-kappaB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative being the most potent. Further examination of the SAR demonstrated that acetylation of the hydroxyl groups reduced NF-kappaB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 microM. In conclusion, we have discovered a novel series of non-toxic QA amides that potently inhibit NF-kappaB, despite their lack of anti-oxidant activity. Mechanistic studies and pre-clinical efficacy studies in various inflammatory animal models are on-going. PMID:19674895

  10. The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition.

    PubMed

    Palermo, Giulia; Favia, Angelo D; Convertino, Marino; De Vivo, Marco

    2016-06-20

    The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid). This potent dual inhibitor combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH and COX, that is, a carbamate moiety and the 2-arylpropionic acid functionality, respectively. Molecular modeling and molecular dynamics simulations suggest that ARN2508 uses a noncovalent mechanism of inhibition to block COXs, while inhibiting FAAH via the acetylation of the catalytic Ser241, in line with previous experimental evidence for covalent FAAH inhibition. This study proposes the molecular basis for the dual FAAH/COX inhibition by this novel hybrid scaffold, stimulating further experimental studies and offering new insights for the rational design of novel anti-inflammatory agents that simultaneously act on FAAH and COX. PMID:26593700

  11. Genetic Engineering Activates Biosynthesis of Aromatic Fumaric Acid Amides in the Human Pathogen Aspergillus fumigatus

    PubMed Central

    Kalb, Daniel; Heinekamp, Thorsten; Lackner, Gerald; Scharf, Daniel H.; Dahse, Hans-Martin; Brakhage, Axel A.

    2014-01-01

    The Aspergillus fumigatus nonribosomal peptide synthetase FtpA is among the few of this species whose natural product has remained unknown. Both FtpA adenylation domains were characterized in vitro. Fumaric acid was identified as preferred substrate of the first and both l-tyrosine and l-phenylalanine as preferred substrates of the second adenylation domain. Genetically engineered A. fumigatus strains expressed either ftpA or the regulator gene ftpR, encoded in the same cluster of genes, under the control of the doxycycline-inducible tetracycline-induced transcriptional activation (tet-on) cassette. These strains produced fumaryl-l-tyrosine and fumaryl-l-phenylalanine which were identified by liquid chromatography and high-resolution mass spectrometry. Modeling of the first adenylation domain in silico provided insight into the structural requirements to bind fumaric acid as peptide synthetase substrate. This work adds aromatic fumaric acid amides to the secondary metabolome of the important human pathogen A. fumigatus which was previously not known as a producer of these compounds. PMID:25527545

  12. Monoamine Oxidase Inhibitory Activity of Ferulic Acid Amides: Curcumin-Based Design and Synthesis.

    PubMed

    Badavath, Vishnu N; Baysal, İpek; Uçar, Gülberk; Mondal, Susanta K; Sinha, Barij N; Jayaprakash, Venkatesan

    2016-01-01

    Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a better pharmacokinetic profile than curcumin, ferulic acid, and selegiline. In order to understand the structural features responsible for the potency and selectivity of 6k, we carried out a molecular docking simulation study. PMID:26592858

  13. New bitter-masking compounds: hydroxylated benzoic acid amides of aromatic amines as structural analogues of homoeriodictyol.

    PubMed

    Ley, Jakob P; Blings, Maria; Paetz, Susanne; Krammer, Gerhard E; Bertram, Heinz-Jürgen

    2006-11-01

    Starting from the known bitter-masking flavanones eriodictyol and homoeriodictyol from herba santa some structurally related hydroxybenzoic acid amides of benzylamines were synthesized and evaluated as masking agents toward bitterness of caffeine by sensory methods. The closest structural relatives of homoeriodictyol, the hydroxybenzoic acid vanillylamides 5-9, were the most active and were able to reduce the bitterness of a 500 mg L(-1) caffeine solution by about 30% at a concentration of 100 mg L(-1). 2,4-Dihydroxybenzoic acid vanillylamide 7 showed a clear dose-dependent activity as inhibitor of the bitter taste of caffein between 5 and 500 mg L(-1). Additionally, it was possible to reduce the bitterness of quinine and salicine but not of the bitter peptide N-l-leucyl-l-tryptophan. Combinations of homoeriodictyol and amide 7 showed no synergistic or antagonistic changes in activity. The results for model compound 7 suggested that the hitherto unknown masking mechanism is probably the same for flavanones and the new amides. In the future, the new amides may be alternatives for the expensive flavanones to create flavor solutions to mask bitterness of pharmaceuticals or foodstuffs. PMID:17061836

  14. Complex investigation of the effects of lambertianic acid amide in female mice under conditions of social discomfort.

    PubMed

    Avgustinovich, D F; Fomina, M K; Sorokina, I V; Tolstikova, T G

    2014-09-01

    The effects of chronic administration of a new substance lambertianic acid amide and previously synthesized methyl ester of this acid were compared in female mice living under conditions of social discomfort. For modeling social discomfort, female mouse was housed for 30 days in a cage with aggressive male mouse kept behind a transparent perforated partition and observed its confrontations with another male mouse daily placed to the cage. The new agent more effectively than lambertianic acid methyl ester improved communicativeness and motor activity of animals, reduced hypertrophy of the adrenal glands, and enhanced catalase activity in the blood. These changes suggest that lambertianic acid amide produces a pronounced stress-protective effect under conditions of social discomfort. PMID:25257419

  15. Effects of synthetic alkamides on Arabidopsis fatty acid amide hydrolase activity and plant development.

    PubMed

    Faure, Lionel; Cavazos, Ronaldo; Khan, Bibi Rafeiza; Petros, Robby A; Koulen, Peter; Blancaflor, Elison B; Chapman, Kent D

    2015-02-01

    Alkamides and N-acylethanolamines (NAEs) are bioactive, amide-linked lipids that influence plant development. Alkamides are restricted to several families of higher plants and some fungi, whereas NAEs are widespread signaling molecules in both plants and animals. Fatty acid amide hydrolase (FAAH) has been described as a key contributor to NAE hydrolysis; however, no enzyme has been associated with alkamide degradation in plants. Herein reported is synthesis of 12 compounds structurally similar to a naturally occurring alkamide (N-isobutyl-(2E,6Z,8E)decatrienamide or affinin) with different acyl compositions more similar to plant NAEs and various amino alkyl head groups. These "hybrid" synthetic alkamides were tested for activity toward recombinant Arabidopsis FAAH and for their effects on plant development (i.e., cotyledon expansion and primary root length). A substantial increase in FAAH activity was discovered toward NAEs in vitro in the presence of some of these synthetic alkamides, such as N-ethyllauroylamide (4). This "enhancement" effect was found to be due, at least in part, to relief from product inhibition of FAAH by ethanolamine, and not due to an alteration in the oligomerization state of the FAAH enzyme. For several of these alkamides, an inhibition of seedling growth was observed with greater results in FAAH knockouts and less in FAAH over-expressing plants, suggesting that these alkamides could be hydrolyzed by FAAH in planta. The tight regulation of NAE levels in vivo appears to be important for proper seedling establishment, and as such, some of these synthetic alkamides may be useful pharmacological tools to manipulate the effects of NAEs in situ. PMID:25491532

  16. One-pot synthesis and antifungal activity against plant pathogens of quinazolinone derivatives containing an amide moiety.

    PubMed

    Zhang, Jin; Liu, Jia; Ma, Yangmin; Ren, Decheng; Cheng, Pei; Zhao, Jiawen; Zhang, Fan; Yao, Yuan

    2016-05-01

    An efficient one-pot, three-component synthesis of quinazolinone derivatives containing 3-acrylamino motif was carried out using CeO2 nanoparticles as catalyst. Thirty-nine synthesized compounds were obtained with satisfied yield and elucidated by spectroscopic analysis. Four phytopathogenic fungi were chosen to test the antifungal activities by minimum inhibitory concentration (MIC) method. Compounds 4ag, 4bb, 4bc showed broad antifungal activities against at least three fungi, and dramatic effects of substituents on the activities were observed. Docking studies were established to explore the potential antifungal mechanism of quinazolinone derivatives as the chitinase inhibitors, and also verified the importance of the amide moiety. PMID:27040656

  17. New Class of Algicidal Compounds and Fungicidal Activities Derived from a Chromene Amide of Amyris texana

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In our continuing search for natural algicides with selective toxicity towards the 2-methyl- isoborneol (MIB) -producing blue-green alga Oscillatoria perornata , the ethyl acetate extract from Amyris texana leaves was investigated by bioassay-guided fractionation. A chromene amide was isolated and i...

  18. Specificity and formation of unusual amino acids of an amide ligation strategy for unprotected peptides.

    PubMed

    Tam, J P; Rao, C; Liu, C F; Shao, J

    1995-03-01

    An important step in the recently developed ligation strategy known as domain ligation strategy to link unprotected peptide segments without activation is the ring formation between the C-terminal ester aldehyde and the N-terminal amino acid bearing a beta-thiol or beta-hydroxide. A new method was developed to define the specificity of this reaction using a dye-labeled alanyl ester aldehyde to react with libraries of 400 dipeptides which contained all dipeptide combinations of the 20 genetically coded amino acids. Three different ester aldehydes of the dye-labeled alanine: alpha-formylmethyl (FM), beta-formylethyl (FE), and beta,beta,beta-dimethyl and formylethyl esters (DFE), were examined. The DFE ester was overly hindered and reacted with N-terminal Cys dipeptides (Cys-X). Interestingly, it also reacted slowly with the sequences of X-Gly where Gly was the second amino acid and the X-Gly amide bond participated in the ring formation. Although the FE ester reacted similarly as the FM ester in the ring formation, the subsequent O,N-acyl transfer was at least 30-fold slower than those of the FM-ester. The FM alpha-formyl methyl ester was the most suitable ester and was reactive with dipeptides of six N-terminal amino acids: Cys, Thr, Trp, Ser, His and Asn. The order and extent of their reactivity were highly dependent on pH, solvent and neighboring participation by the adjacent amino acid. In general, they could be divided into three categories. (1) N-Terminal Cys and Thr were the most reactive.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7775013

  19. Occurrence of N-phenylpropenoyl-L-amino acid amides in different herbal drugs and their influence on human keratinocytes, on human liver cells and on adhesion of Helicobacter pylori to the human stomach.

    PubMed

    Hensel, A; Deters, A M; Müller, G; Stark, T; Wittschier, N; Hofmann, T

    2007-02-01

    Thirty commonly used medicinal plants were screened by a selective and specific LC-MS/MS method for the occurrence of N-phenylpropenoyl- L-amino acid amides, a new homologous class of secondary products. In 15 plants, one or more of the respective derivatives (1 to 12) were found and quantitated. Especially roots from Angelica archangelica, fruits of Cassia angustifolia, C. senna, Coriandrum sativum, leaves from Hedera helix, flowers from Lavandula spec. and from Sambucus nigra contained high amounts (1 to 11 microg/g) of mixtures of the different amides 1 to 12. For functional investigations on potential activity in cellular physiology, two amides with an aliphatic (8) and an aromatic amino acid residue (5) were used. N-(E)-Caffeic acid L-aspartic acid amide (8) and N-(E)-caffeic acid L-tryptophan amide (5) stimulated mitochondrial activity as well as the proliferation rate of human liver cells (HepG2) at 10 microg/mL significantly. When monitoring the influence of selected phase I and II metabolizing enzymes, both compounds did not influence CYP3A4 gene expression, but stimulated CYP1A2 gene expression and inhibited GST expression. Also, the proliferation of human keratinocytes (NHK) was increased up to 150% by both amides 5 and 8; this stimulation was also detectable on the level of gene expression by an up-regulation of the transcription factor STAT6. The aliphatic aspartic compound 8 showed strong antiadhesive properties on the adhesion of Helicobacter pylori to human stomach tissue. PMID:17295182

  20. A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase

    PubMed Central

    Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma; Cornett, Ben; Mackie, Ken; Bradshaw, Heather

    2016-01-01

    Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic

  1. A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase.

    PubMed

    Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma; Cornett, Ben; Mackie, Ken; Bradshaw, Heather; Hohmann, Andrea G

    2016-02-01

    Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic

  2. Direct amidation of carboxylic acids catalyzed by ortho-iodo arylboronic acids: catalyst optimization, scope, and preliminary mechanistic study supporting a peculiar halogen acceleration effect.

    PubMed

    Gernigon, Nicolas; Al-Zoubi, Raed M; Hall, Dennis G

    2012-10-01

    The importance of amides as a component of biomolecules and synthetic products motivates the development of catalytic, direct amidation methods employing free carboxylic acids and amines that circumvent the need for stoichiometric activation or coupling reagents. ortho-Iodophenylboronic acid 4a has recently been shown to catalyze direct amidation reactions at room temperature in the presence of 4A molecular sieves as dehydrating agent. Herein, the arene core of ortho-iodoarylboronic acid catalysts has been optimized with regards to the electronic effects of ring substitution. Contrary to the expectation, it was found that electron-donating substituents are preferable, in particular, an alkoxy substituent positioned para to the iodide. The optimal new catalyst, 5-methoxy-2-iodophenylboronic acid (MIBA, 4f), was demonstrated to be kinetically more active than the parent des-methoxy catalyst 4a, providing higher yields of amide products in shorter reaction times under mild conditions at ambient temperature. Catalyst 4f is recyclable and promotes the formation of amides from aliphatic carboxylic acids and amines, and from heteroaromatic carboxylic acids and other functionalized substrates containing moieties like a free phenol, indole and pyridine. Mechanistic studies demonstrated the essential role of molecular sieves in this complex amidation process. The effect of substrate stoichiometry, concentration, and measurement of the catalyst order led to a possible catalytic cycle based on the presumed formation of an acylborate intermediate. The need for an electronically enriched ortho-iodo substituent in catalyst 4f supports a recent theoretical study (Marcelli, T. Angew. Chem. Int. Ed.2010, 49, 6840-6843) with a purported role for the iodide as a hydrogen-bond acceptor in the orthoaminal transition state. PMID:23013456

  3. Potent and Selective α-Ketoheterocycle-Based Inhibitors of the Anandamide and Oleamide Catabolizing Enzyme, Fatty Acid Amide Hydrolase

    PubMed Central

    Romero, F. Anthony; Du, Wu; Hwang, Inkyu; Rayl, Thomas J.; Kimball, F. Scott; Leung, Donmienne; Hoover, Heather S.; Apodaca, Richard L.; Breitenbucher, J. Guy; Cravatt, Benjamin F.; Boger, Dale L.

    2008-01-01

    A study of the structure–activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12–14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, non-aromatic C5-substituents was also explored and revealed that the Ki follows a well-defined correlation with the Hammett σp constant (ρ = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency leading to inhibitors with Ki’s as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH. PMID:17279740

  4. Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids.

    PubMed

    Magoulas, George E; Rigopoulos, Andreas; Piperigkou, Zoi; Gialeli, Chrysostomi; Karamanos, Nikos K; Takis, Panteleimon G; Troganis, Anastassios N; Chrissanthopoulos, Athanassios; Maroulis, George; Papaioannou, Dionissios

    2016-06-01

    Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256μM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64-70μM) for the MDA-MB-231 cell line after 24-48h of treatment, but they were more selective and much more potent (IC50 4-16μM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1-2μM), probably as the result of slow hydrolysis of their methyl ester functions. PMID:27155809

  5. Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

    PubMed

    Ogawa, Shintaro; Kunugi, Hiroshi

    2015-01-01

    Cannabis and analogs of Δ9-tetrahydrocannabinol have been used for therapeutic purposes, but their therapeutic use remains limited because of various adverse effects. Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD). Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD. Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors). In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors' therapeutic potential. MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2. In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted. PMID:26630956

  6. Amide-conjugated indole-3-acetic acid and adventitious root formation in mung bean cuttings

    SciTech Connect

    Norcini, J.G.

    1986-01-01

    The purpose of this research was to investigate further the relationship between amide-conjugated auxin and adventitious root formation. Indoleacetylaspartic acid (IAA-aspartate) was positively identified as the predominant conjugate isolated from mung bean cuttings after the cuttings has been treated with 10/sup -3/ M IAA. In cuttings treated with (1-/sup 14/C)IAA immediately after excision (0 hr), the percent of extractable /sup 14/C in IAA-aspartate in the hypocotyl sharply increased until 36 hr, then steadily declined. (/sup 14/C)IAA was completely metabolized between 12 and 24 hr. The rooting activities of IAA-L-aspartate, IAA-L-alanine, and IAA-glycine were determined at various stages of root formation; some cuttings were pretreated with 10/sup -3/ M IAA at 0 hr. Pretreated cuttings that were treated with IAA-glycine at 12, 24, 36 hr exhibited the greatest consistency between replications, the greatest number of long roots, and the longest roots. The conjugates did not stimulate rooting as effectively as IAA, yet like IAA, generally enhanced rooting the greatest when applied before the first cell division (24 hr).

  7. Immunohistochemical distribution of the cannabinoid receptor 1 and fatty acid amide hydrolase in the dog claustrum.

    PubMed

    Pirone, Andrea; Cantile, Carlo; Miragliotta, Vincenzo; Lenzi, Carla; Giannessi, Elisabetta; Cozzi, Bruno

    2016-07-01

    Cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) are part of the endocannabinoid system (ECB) which exerts a neuromodulatory activity on different brain functions and plays a key role in neurogenesis. Although many studies have reported FAAH and CB1R expression in the brain of different animal species, to the best of our knowledge they have never been described in the canine claustrum. Claustrum samples, obtained from necropsy of four neurologically normal dogs, were formalin fixed for paraffin embedding. Sections were either stained for morpho-histological analysis or immunostained for CB1R and FAAH. Analysis of adjacent sections incubated with the two antisera showed a complementary labeling pattern in the claustrum, with CB1R antibody staining fibers while anti-FAAH antibody stained cell bodies and the proximal portion of dendrites; this particular anatomical relationship suggests a retrograde endocannabinoid action via CB1R. CB1R and FAAH complementary immunostaining and their cellular localization reported here provide the first anatomical evidence for existence of the ECB in the dog claustrum. PMID:26907575

  8. Fatty-acid amide hydrolase polymorphisms and post-traumatic stress disorder after penetrating brain injury

    PubMed Central

    Pardini, M; Krueger, F; Koenigs, M; Raymont, V; Hodgkinson, C; Zoubak, S; Goldman, D; Grafman, J

    2012-01-01

    The past few years have seen an increase in the clinical awareness of post-traumatic stress disorder (PTSD), one of the most disabling and least understood behavioral disorders. Although the biological bases of PTSD are poorly understood, fatty-acid amide hydrolase (FAAH) activity has been linked with arousability and aversive-memories extinction, that is, two key features of PTSD. In this study, we investigated the association between the FAAH genetic polymorphisms and PTSD development and maintenance. We assessed PTSD frequency in a group of male Vietnam war veterans who suffered combat-related penetrating traumatic brain injury, that is, a relatively homogeneous population regarding the nature of the events that led to PTSD. We showed that rs2295633, a single-nucleotide polymorphism of FAAH, was significantly associated with PTSD diagnosis in subjects without lesions in the ventromedial prefrontal cortex. Moreover, the presence of the C allele was associated with more severe re-experiencing of trauma and more negative reported childhood experiences. In conclusion, our data suggest that FAAH has an important role in PTSD through modulation of aversive memories and point to both a novel therapeutic target and a possible risk marker for this condition. PMID:22832737

  9. Synthesis of Phenoxyacyl-Ethanolamides and Their Effects on Fatty Acid Amide Hydrolase Activity*

    PubMed Central

    Faure, Lionel; Nagarajan, Subbiah; Hwang, Hyeondo; Montgomery, Christa L.; Khan, Bibi Rafeiza; John, George; Koulen, Peter; Blancaflor, Elison B.; Chapman, Kent D.

    2014-01-01

    N-Acylethanolamines (NAEs) are involved in numerous biological activities in plant and animal systems. The metabolism of these lipids by fatty acid amide hydrolase (FAAH) is a key regulatory point in NAE signaling activity. Several active site-directed inhibitors of FAAH have been identified, but few compounds have been described that enhance FAAH activity. Here we synthesized two sets of phenoxyacyl-ethanolamides from natural products, 3-n-pentadecylphenolethanolamide and cardanolethanolamide, with structural similarity to NAEs and characterized their effects on the hydrolytic activity of FAAH. Both compounds increased the apparent Vmax of recombinant FAAH proteins from both plant (Arabidopsis) and mammalian (Rattus) sources. These NAE-like compounds appeared to act by reducing the negative feedback regulation of FAAH activity by free ethanolamine. Both compounds added to seedlings relieved, in part, the negative growth effects of exogenous NAE12:0. Cardanolethanolamide reduced neuronal viability and exacerbated oxidative stress-mediated cell death in primary cultured neurons at nanomolar concentrations. This was reversed by FAAH inhibitors or exogenous NAE substrate. Collectively, our data suggest that these phenoxyacyl-ethanolamides act to enhance the activity of FAAH and may stimulate the turnover of NAEs in vivo. Hence, these compounds might be useful pharmacological tools for manipulating FAAH-mediated regulation of NAE signaling in plants or animals. PMID:24558037

  10. Synthesis of phenoxyacyl-ethanolamides and their effects on fatty acid amide hydrolase activity.

    PubMed

    Faure, Lionel; Nagarajan, Subbiah; Hwang, Hyeondo; Montgomery, Christa L; Khan, Bibi Rafeiza; John, George; Koulen, Peter; Blancaflor, Elison B; Chapman, Kent D

    2014-03-28

    N-Acylethanolamines (NAEs) are involved in numerous biological activities in plant and animal systems. The metabolism of these lipids by fatty acid amide hydrolase (FAAH) is a key regulatory point in NAE signaling activity. Several active site-directed inhibitors of FAAH have been identified, but few compounds have been described that enhance FAAH activity. Here we synthesized two sets of phenoxyacyl-ethanolamides from natural products, 3-n-pentadecylphenolethanolamide and cardanolethanolamide, with structural similarity to NAEs and characterized their effects on the hydrolytic activity of FAAH. Both compounds increased the apparent Vmax of recombinant FAAH proteins from both plant (Arabidopsis) and mammalian (Rattus) sources. These NAE-like compounds appeared to act by reducing the negative feedback regulation of FAAH activity by free ethanolamine. Both compounds added to seedlings relieved, in part, the negative growth effects of exogenous NAE12:0. Cardanolethanolamide reduced neuronal viability and exacerbated oxidative stress-mediated cell death in primary cultured neurons at nanomolar concentrations. This was reversed by FAAH inhibitors or exogenous NAE substrate. Collectively, our data suggest that these phenoxyacyl-ethanolamides act to enhance the activity of FAAH and may stimulate the turnover of NAEs in vivo. Hence, these compounds might be useful pharmacological tools for manipulating FAAH-mediated regulation of NAE signaling in plants or animals. PMID:24558037

  11. Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants

    PubMed Central

    Ogawa, Shintaro; Kunugi, Hiroshi

    2015-01-01

    Cannabis and analogs of Δ9-tetrahydrocannabinol have been used for therapeutic purposes, but their therapeutic use remains limited because of various adverse effects. Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD). Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD. Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors). In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors’ therapeutic potential. MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2. In the hypothalamic–pituitary–adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted. PMID:26630956

  12. Determination of free and amidated bile acids by high-performance liquid chromatography with evaporative light-scattering mass detection.

    PubMed

    Roda, A; Cerrè, C; Simoni, P; Polimeni, C; Vaccari, C; Pistillo, A

    1992-09-01

    A simple reverse phase high-performance liquid chromatographic method for a simultaneous analysis of free, glycine- and taurine-amidated bile acids is described. The resolution of ursodeoxycholic, cholic, chenodeocycholic, deoxycholic, and lithocholic acids, either free or amidated with glycine and taurine, is achieved using a C-18 octadecylsilane column (30 cm length, 4 micron particle size) with a gradient elution of aqueous methanol (65----75%) containing 15 mM ammonium acetate, pH 5.40, at 37 degrees C. The separated bile acids are detected with a new evaporative light-scattering mass detector and by absorbance at 200 nm. A complete resolution of the 16 bile acids, including the internal standard nor-deoxycholic acid, is obtained within 55 min. Using the light-scattering mass detector, amidated bile acids and, for the first time, free bile acids can be detected with similar detection limits in the order of 2-7 nmol. The new detector improves the baseline and the signal-to-noise ratio over the UV detection as it is not affected by impurities present in the samples with higher molar absorptivity than bile acids or by the change in the mobile phase composition during the gradient. The method fulfills all the standard requirements of precision and accuracy and the linearity of the mass detector is over 5 decade the detection limit. The new method has been used for the direct analysis of bile acid in stools and bile with only a preliminary clean-up procedure using a C-18 reverse phase extraction. PMID:1402406

  13. Hepatoprotective properties of betulonic acid amide and heptral in toxic liver injury induced by carbon tetrachloride in combination with ethanol.

    PubMed

    Semenov, D E; Zhukova, N A; Ivanova, E P; Sorokina, I V; Baiev, D S; Nepomnyashchikh, G I; Tolstikova, T G; Biryukova, M S

    2015-01-01

    Toxic liver injury with the development of fibrosis and cirrhosis was modeled in Wistar rats by intragastric administration of 0.1 ml/kg CCl4 in combination with 5% ethanol with glucose 3 times a week for 6 weeks. The animals were treated with betulonic acid amide (50 mg/kg in Tween aqueous solution) and heptral (6 mg/kg) as hepatoprotective compounds. It was found that betulonic acid amide stimulated the regenerative response in hepatocytes under conditions of combined toxic exposure and promoted recovery of their qualitative and quantitative characteristics, which was accompanied by a significant decrease in the severity of liver fibrosis and the absence of cirrhotic transformation of the liver. PMID:25573364

  14. Redox regulation of protein tyrosine phosphatase 1B (PTP1B): Importance of steric and electronic effects on the unusual cyclization of the sulfenic acid intermediate to a sulfenyl amide

    NASA Astrophysics Data System (ADS)

    Sarma, Bani Kanta

    2013-09-01

    The redox regulation of protein tyrosine phosphatase 1B (PTP1B) via the unusual transformation of its sulfenic acid (PTP1B-SOH) to a cyclic sulfenyl amide intermediate is studied by using small molecule chemical models. These studies suggest that the sulfenic acids derived from the H2O2-mediated reactions o-amido thiophenols do not efficiently cyclize to sulfenyl amides and the sulfenic acids produced in situ can be trapped by using methyl iodide. Theoretical calculations suggest that the most stable conformer of such sulfenic acids are stabilized by nO → σ*S-OH orbital interactions, which force the -OH group to adopt a position trans to the S⋯O interaction, leading to an almost linear arrangement of the O⋯S-O moiety and this may be the reason for the slow cyclization of such sulfenic acids to their corresponding sulfenyl amides. On the other hand, additional substituents at the 6-position of o-amido phenylsulfenic acids that can induce steric environment and alter the electronic properties around the sulfenic acid moiety by S⋯N or S⋯O nonbonded interactions destabilize the sulfenic acids by inducing strain in the molecule. This may lead to efficient the cyclization of such sulfenic acids. This model study suggests that the amino acid residues in the close proximity of the sulfenic acid moiety in PTP1B may play an important role in the cyclization of PTP1B-SOH to produce the corresponding sulfenyl amide.

  15. Melonoside A: An ω-Glycosylated Fatty Acid Amide from the Far Eastern Marine Sponge Melonanchora kobjakovae.

    PubMed

    Guzii, Alla G; Makarieva, Tatyana N; Denisenko, Vladimir A; Dmitrenok, Pavel S; Kuzmich, Aleksandra S; Dyshlovoy, Sergey A; von Amsberg, Gunhild; Krasokhin, Vladimir B; Stonik, Valentin A

    2016-07-15

    Melonoside A (1), the first representative of a new class of ω-glycosylated fatty acid amides, was isolated from the Far Eastern marine sponge Melonanchora kobjakovae. The structure of 1, including absolute configuration, was established using detailed analysis of 1D and 2D NMR, CD, and mass spectra as well as chemical transformations. Compound 1 induces autophagy of human cisplatin-resistant germinal tumor cells NCCIT-R. PMID:27358020

  16. A billion-fold range in acidity for the solvent-exposed amides of Pyrococcus furiosus rubredoxin.

    PubMed

    Anderson, Janet S; Hernández, Griselda; Lemaster, David M

    2008-06-10

    The exchange rates of the static solvent-accessible amide hydrogens of Pyrococcus furiosus rubredoxin range from near the diffusion-limited rate to a billion-fold slower for the non-hydrogen-bonded Val 38 (eubacterial numbering). Hydrogen exchange directly monitors the kinetic acidity of the peptide nitrogen. Electrostatic solvation free energies were calculated by Poisson-Boltzmann methods for the individual peptide anions that form during the hydroxide-catalyzed exchange reaction to examine how well the predicted thermodynamic acidities match the experimentally determined kinetic acidities. With the exception of the Ile 12 amide, the differential exchange rate constant for each solvent-exposed amide proton that is not hydrogen bonded to a backbone carbonyl can be predicted within a factor of 6 (10 (0.78)) root-mean-square deviation (rmsd) using the CHARMM22 electrostatic parameter set and an internal dielectric value of 3. Under equivalent conditions, the PARSE parameter set yields a larger rmsd value of 1.28 pH units, while the AMBER parm99 parameter set resulted in a considerably poorer correlation. Either increasing the internal dielectric value to 4 or reducing it to a value of 2 significantly degrades the quality of the prediction. Assigning the excess charge of the peptide anion equally between the peptide nitrogen and the carbonyl oxygen also reduces the correlation to the experimental data. These continuum electrostatic calculations were further analyzed to characterize the specific structural elements that appear to be responsible for the wide range of peptide acidities observed for these solvent-exposed amides. The striking heterogeneity in the potential at sites along the protein-solvent interface should prove germane to the ongoing challenge of quantifying the contribution that electrostatic interactions make to the catalytic acceleration achieved by enzymes. PMID:18479148

  17. Chiral Nanoparticles/Lewis Acids as Cooperative Catalysts for Asymmetric 1,4-Addition of Arylboronic Acids to α,β-Unsaturated Amides.

    PubMed

    Yasukawa, Tomohiro; Saito, Yuuki; Miyamura, Hiroyuki; Kobayashi, Shū

    2016-07-01

    Cooperative catalysts consisting of chiral Rh/Ag nanoparticles and Sc(OTf)3 have been developed that catalyze asymmetric 1,4-addition reactions of arylboronic acids with α,β-unsaturated amides efficiently. The reaction has been considered one of the most challenging reactions because of the low reactivity of the amide substrates. The new catalysts provide the desired products with outstanding enantioselectivities (>98 % ee) in the presence of low loadings (<0.5 mol %) of the catalyst. PMID:27193210

  18. Friedel-Crafts Acylation with Amides

    PubMed Central

    Raja, Erum K.; DeSchepper, Daniel J.; Nilsson Lill, Sten O.; Klumpp, Douglas A.

    2012-01-01

    Friedel-Crafts acylation has been known since the 1870s and it is an important organic synthetic reaction leading to aromatic ketone products. Friedel-Crafts acylation is usually done with carboxylic acid chlorides or anhydrides while amides are generally not useful substrates in these reactions. Despite being the least reactive carboxylic acid derivative, we have found a series of amides capable of providing aromatic ketones in good yields (55–96%, 17 examples). We propose a mechanism involving diminished C-N resonance through superelectrophilic activation and subsequent cleavage to acyl cations. PMID:22690740

  19. Metabolism and toxicological evaluation of the aromatic amide herbicide propanil and its derivatives

    SciTech Connect

    McMillian, D.C.

    1989-01-01

    Since propanil is structurally similar to other carcinogenic arylamides, the potential chronic toxicity of propanil and its derivatives were examined in short-term assays for genotoxicity. Propanil, 3,4-dichloroaniline, and their N-oxidized derivatives were inactive in the Salmonella typhimurium reversion, Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT), and rat hepatocyte/DNA repair assays. The metabolism of propanil and 3,4-dichloroaniline was subsequently examined in liver microsomes from males Sprague-Dawley rats to identify metabolites that may be involved in the acute toxicity of propanil. The major pathway of propanil metabolism was acylamidase-catalyzed hydrolysis to 3,4-dichloroaniline. Oxidized metabolites were isolated by high performance liquid chromatography, and identified as 2{prime}-hydroxy-propanil and 6-hydroxy-propanil by comparison of their mass and nuclear magnetic resonance spectra to synthetic standards. Experiments were performed to determine if propanil exposure could be monitored by the analysis of hemoglobin binding. Administration of (ring-U-{sup 14}C)propanil to rats increased methemoglobin formation in a dose-dependent manner. Concomitant with methemoglobin formation, dose-dependent covalent binding of radiolabeled propanil to hemoglobin was detected. HPLC analysis indicated that the hemoglobin adducts were sulfinic acid esters, and these data suggest that human exposure to propanil may be monitored by the analysis of propanil metabolites bound to hemoglobin.

  20. Fatty acid amide hydrolase inhibitors confer anti-invasive and antimetastatic effects on lung cancer cells

    PubMed Central

    Winkler, Katrin; Ramer, Robert; Dithmer, Sophie; Ivanov, Igor; Merkord, Jutta; Hinz, Burkhard

    2016-01-01

    Inhibition of endocannabinoid degradation has been suggested as tool for activation of endogenous tumor defense. One of these strategies lies in blockade of fatty acid amide hydrolase (FAAH) which catalyzes the degradation of endocannabinoids (anandamide [AEA], 2-arachidonoylglycerol [2-AG]) and endocannabinoid-like substances (N-oleoylethanolamine [OEA], N-palmitoylethanolamine [PEA]). This study addressed the impact of two FAAH inhibitors (arachidonoyl serotonin [AA-5HT], URB597) on A549 lung cancer cell metastasis and invasion. LC-MS analyses revealed increased levels of FAAH substrates (AEA, 2-AG, OEA, PEA) in cells incubated with either FAAH inhibitor. In athymic nude mice FAAH inhibitors were shown to elicit a dose-dependent antimetastatic action yielding a 67% and 62% inhibition of metastatic lung nodules following repeated administration of 15 mg/kg AA-5HT and 5 mg/kg URB597, respectively. In vitro, a concentration-dependent anti-invasive action of either FAAH inhibitor was demonstrated, accompanied with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Using siRNA approaches, a causal link between the TIMP-1-upregulating and anti-invasive action of FAAH inhibitors was confirmed. Moreover, knockdown of FAAH by siRNA was shown to confer decreased cancer cell invasiveness and increased TIMP-1 expression. Inhibitor experiments point toward a role of CB2 and transient receptor potential vanilloid 1 in conferring anti-invasive effects of FAAH inhibitors and FAAH siRNA. Finally, antimetastatic and anti-invasive effects were confirmed for all FAAH substrates with AEA and OEA causing a TIMP-1-dependent anti-invasive action. Collectively, the present study provides first-time proof for an antimetastatic action of FAAH inhibitors. As mechanism of its anti-invasive properties an upregulation of TIMP-1 was identified. PMID:26930716

  1. Synergistic effects in solvent-extraction systems based on alkylsalicylic acids. I. Extraction of trivalent rare-earth metals in the presence of aliphatic amides

    SciTech Connect

    Preston, J.S.; Preez, A.C. du

    1995-07-01

    Aliphatic carboxylic acid amides were found to cause synergistic shifts in the pH{sub 50} values for the extraction of the trivalent rare-earth metals from chloride media by solutions of alkylsalicylic acids in xylene. For the different types of amide examined, the synergistic shifts for the extraction of neodymium by 3,5-diisopropylsalicylic acid (DIPSA) generally decrease in the order: R.CO.NR{sub 2}` > R.CO.NHR` > R.CO.NH{sub 2}, where R and R` are alkyl groups. With the N,N-dialkyl amides (R.CO.NR{sub 2}`) and the N-alkyl amides (R.CO.NHR`), the extent of the synergistic effect decreases with increasing chain-branching in either of the alkyl groups R and R`. For additions to 0.25 M alkylsalicylic acid, the synergistic effect increases with concentrations of up to 0.1 M amide, and decreases with higher concentrations. The extent of the synergistic shift produced by a given amide, as well as the separation in pH{sub 50} values from lanthanum to lutetium, increases with increasing steric bulk of the alkylsalicylic acid used. The separations between adjacent lanthanides are too small to be of any practical interest, however. Measurement of the solubility of salicylic acids (HA) in xylene containing various amounts of N,N-dialkyl amide (L) indicate that essentially complete formation of the HA.L adduct takes place. Treatment of metal-distribution data by slope analysis, and measurement of the solubility of the neodymium-DIPSA complex in xylene in the presence of amide suggest that the mixed-ligand complex has the stoichiometry NdA{sub 3}L{sub 2}. 18 refs., 6 figs., 3 refs.

  2. Synthesis of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4·OEt2 as a mild and versatile reagent and evaluation of their antimicrobial and anti-biofilm activities.

    PubMed

    Ratnakar Reddy, K; Poornachandra, Y; Jitender Dev, G; Mallareddy, G; Nanubolu, Jagadeesh B; Kumar, C Ganesh; Narsaiah, B

    2015-08-01

    A series of novel amide functionalized 2H-chromene derivatives 3 were prepared starting from ethyl-2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate 1 via sodium borohydride reduction followed by Ritter amidation using HBF4·OEt2 as a mild and versatile reagent. All the products 3 were screened for antimicrobial activity against various Gram-positive, Gram-negative bacteria and fungal strain. The promising derivatives such as 3f, 3g, 3k, 3l, 3m, 3n and 3o were further screened for minimum bactericidal concentration and bio-film inhibition activity and identified the potential ones. Among all the promising, compound 3g was more potent for antimicrobial, MBC and anti bio-film activities. The structure verses activity relationship of 3g revealed that the presence of two bromine atoms at sixth and R position promotes high activity. PMID:26048810

  3. Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity.

    PubMed

    Caraci, Filippo; Pappalardo, Giuseppe; Basile, Livia; Giuffrida, Alessandro; Copani, Agata; Tosto, Rita; Sinopoli, Alessandro; Giuffrida, Maria Laura; Pirrone, Emanuele; Drago, Filippo; Pignatello, Rosario; Guccione, Salvatore

    2015-10-01

    Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer's disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-β (Aβ)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Aβ-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 µM. TCP-But was maximally protective in mixed neuronal cultures at 1 µM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Aβ toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Aβ aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Aβ(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Aβ(1-42) oligomers with TCP-Ac was able to almost completely prevent Aβ-induced neurodegeneration. These results suggest that inhibition of Aβ oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD. PMID:26162702

  4. (E)-4-aryl-4-oxo-2-butenoic acid amides, chalcone–aroylacrylic acid chimeras: Design, antiproliferative activity and inhibition of tubulin polymerization

    PubMed Central

    Vitorović-Todorović, Maja D.; Erić-Nikolić, Aleksandra; Kolundžija, Branka; Hamel, Ernest; Ristić, Slavica; Juranić, Ivan O.; Drakulić, Branko J.

    2013-01-01

    Antiproliferative activity of twenty-nine (E)-4-aryl-4-oxo-2-butenoic acid amides against three human tumor cell lines (HeLa, FemX, and K562) is reported. Compounds showed antiproliferative activity in one-digit micromolar to submicromolar concentrations. The most active derivatives toward all the cell lines tested bear alkyl substituents on the aroyl moiety of the molecules. Fourteen compounds showed tubulin assembly inhibition at concentrations <20 μM. The most potent inhibitor of tubulin assembly was unsubstituted compound 1, with IC50 = 2.9 μM. Compound 23 had an oral LD50 in vivo of 45 mg/kg in mice. Cell cycle analysis on K562 cells showed that compounds 1, 2 and 23 caused accumulation of cells in the G2/M phase, but inhibition of microtubule polymerization is not the principal mode of action of the compounds. Nevertheless, they may be useful leads for the design of a new class of antitubulin agents. PMID:23353745

  5. Spectroscopic studies on the interaction of cinnamic acid and its hydroxyl derivatives with human serum albumin

    NASA Astrophysics Data System (ADS)

    Min, Jiang; Meng-Xia, Xie; Dong, Zheng; Yuan, Liu; Xiao-Yu, Li; Xing, Chen

    2004-04-01

    Cinnamic acid and its derivatives possess various biological effects in remedy of many diseases. Interaction of cinnamic acid and its hydroxyl derivatives, p-coumaric acid and caffeic acid, with human serum albumin (HSA), and concomitant changes in its conformation were studied using fluorescence and Fourier transform infrared spectroscopic methods. Fluorescence data revealed the presence of one binding site on HSA for cinnamic acid and its hydroxyl derivatives, and their binding constants ( KA) are caffeic acid> p-coumaric acid> cinnamic acid when Cdrug/ CHSA ranging from 1 to 10. The changes of the secondary structure of HSA after interacting with the three drugs are estimated, respectively by combining the curve-fitting results of amid I and amid III bands. The α-helix structure has a decrease of ≈9, 5 and 3% after HSA interacted with caffeic acid, p-coumaric acid and cinnamic acid, respectively. It was found that the hydroxyls substituted on aromatic ring of the drugs play an important role in the changes of protein's secondary structure. Combining the result of fluorescence quenching and the changes of secondary structure of HSA after interaction with the three drugs, the drug-HSA interaction mode was discussed.

  6. Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

    PubMed

    Dragovich, Peter S; Zhao, Guiling; Baumeister, Timm; Bravo, Brandon; Giannetti, Anthony M; Ho, Yen-Ching; Hua, Rongbao; Li, Guangkun; Liang, Xiaorong; Ma, Xiaolei; O'Brien, Thomas; Oh, Angela; Skelton, Nicholas J; Wang, Chengcheng; Wang, Weiru; Wang, Yunli; Xiao, Yang; Yuen, Po-wai; Zak, Mark; Zhao, Qiang; Zheng, Xiaozhang

    2014-02-01

    The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described. PMID:24433859

  7. Betulinic acid derived hydroxamates and betulin derived carbamates are interesting scaffolds for the synthesis of novel cytotoxic compounds.

    PubMed

    Wiemann, Jana; Heller, Lucie; Perl, Vincent; Kluge, Ralph; Ströhl, Dieter; Csuk, René

    2015-12-01

    The betulinic acid-derived hydroxamates 5-18, the amides 19-24, and betulin-derived bis-carbamates 25-28 as well as the carbamates 31-40 and 44-48 were prepared and evaluated for their antiproliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 μM were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16-20 μM). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 μM for A2780 human ovarian carcinoma cells and EC50 > 30 μM for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19-24 and of betulin derived bis-carbamates 25-28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 μM (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined. PMID:26547057

  8. PET imaging of fatty acid amide hydrolase with [(18)F]DOPP in nonhuman primates.

    PubMed

    Rotstein, Benjamin H; Wey, Hsiao-Ying; Shoup, Timothy M; Wilson, Alan A; Liang, Steven H; Hooker, Jacob M; Vasdev, Neil

    2014-11-01

    Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [(11)C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [(18)F]DOPP ([(18)F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising (18)F-labeled analogue based on rodent studies. The goal of this work is to evaluate [(18)F]DOPP in nonhuman primates to support its clinical translation. High specific activity [(18)F]DOPP (5-6 Ci·μmol(-1)) was administered intravenously (iv) to three baboons (2M/1F, 3-4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [(18)F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [(18)F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [(11)C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [(18)F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm(3)/min; 300 μg/kg URB597: 0.058 mL/cm(3)/min), suggesting that [(18)F]DOPP binding is specific for FAAH, consistent with previous rodent data. PMID:25004399

  9. Quantification and enzyme targets of fatty acid amides from duckweed root exudates involved in the stimulation of denitrification.

    PubMed

    Sun, Li; Lu, Yufang; Kronzucker, Herbert J; Shi, Weiming

    2016-07-01

    Fatty acid amides from plant root exudates, such as oleamide and erucamide, have the ability to participate in strong plant-microbe interactions, stimulating nitrogen metabolism in rhizospheric bacteria. However, mechanisms of secretion of such fatty acid amides, and the nature of their stimulatory activities on microbial metabolism, have not been examined. In the present study, collection, pre-treatment, and determination methods of oleamide and erucamide in duckweed root exudates are compared. The detection limits of oleamide and erucamide by gas chromatography (GC) (10.3ngmL(-1) and 16.1ngmL(-1), respectively) are shown to be much lower than those by liquid chromatography (LC) (1.7 and 5.0μgmL(-1), respectively). Quantitative GC analysis yielded five times larger amounts of oleamide and erucamide in root exudates of Spirodela polyrrhiza when using a continuous collection method (50.20±4.32 and 76.79±13.92μgkg(-1) FW day(-1)), compared to static collection (10.88±0.66 and 15.27±0.58μgkg(-1) FW day(-1)). Furthermore, fatty acid amide secretion was significantly enhanced under elevated nitrogen conditions (>300mgL(-1)), and was negatively correlated with the relative growth rate of duckweed. Mechanistic assays were conducted to show that erucamide stimulates nitrogen removal by enhancing denitrification, targeting two key denitrifying enzymes, nitrate and nitrite reductases, in bacteria. Our findings significantly contribute to our understanding of the regulation of nitrogen dynamics by plant root exudates in natural ecosystems. PMID:27152459

  10. An efficient phase-selective gelator for aromatic solvents recovery based on a cyanostilbene amide derivative.

    PubMed

    Zhang, Yuping; Ma, Yao; Deng, Mengyu; Shang, Hongxing; Liang, Chunshuang; Jiang, Shimei

    2015-07-01

    Two novel low molecular weight organogelators (LMOGs) 1 and 2 composed of a cholesteryl group, an amide group and various terminal cyanostilbene moieties were synthesized. They could form stable gels in p-xylene. In particular, 2 with more extended π-conjugation length showed remarkable gelation ability in many aromatic solvents, chloroform and chloroform-containing mixed solvents at a relatively low concentration. FT-IR and XRD spectra indicated that the difference between 1 and 2 in the gelation properties may result from the deviation of the intermolecular hydrogen bonding and π–π stacking as driving forces for the formation of the gels. Significantly, 2 can function as an efficient room-temperature phase-selective gelator (PSG) for potential application in the separation and recovery of various aromatic solvents from its mixture with water. Meanwhile, the gelator can be easily recovered and reused several times. Furthermore, the phase-selective gelation properties of 2 can provide a simple and feasible approach for the removal of the rhodamine B (RhB) dye from water. PMID:26035825

  11. Synthesis and evaluation of fatty acid amides on the N-oleoylethanolamide-like activation of peroxisome proliferator activated receptor α.

    PubMed

    Takao, Koichi; Noguchi, Kaori; Hashimoto, Yosuke; Shirahata, Akira; Sugita, Yoshiaki

    2015-01-01

    A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor α (PPAR-α) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-α downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-α agonistic activities. We prepared nine oleic acid amides. Their PPAR-α agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Δ(9)-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-α antagonist, GW6471, inhibited the induction of the PPAR-α downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-α agonists. PMID:25832022

  12. Hydrogen-deuterium exchange of aromatic amines and amides using deuterated trifluoroacetic acid

    PubMed Central

    Giles, Richard; Lee, Amy; Jung, Erica; Kang, Aaron; Jung, Kyung Woon

    2014-01-01

    The H-D exchange of aromatic amines and amides, including pharmaceutically relevant compounds such as acetaminophen and diclofenac, was investigated using CF3COOD as both the sole reaction solvent and source of deuterium label. The described method is amenable to efficient deuterium incorporation for a wide variety of substrates possessing both electron-donating and electron-withdrawing substituents. Best results were seen with less basic anilines and highly activated acetanilides, reflecting the likelihood of different mechanistic pathways. PMID:25641994

  13. Lewis Acid Catalyzed Regiospecific Cross-Dehydrative Coupling Reaction of 2-Furylcarbinols with β-Keto Amides or 4-Hydroxycoumarins: A Route to Furyl Enols.

    PubMed

    Miao, Maozhong; Luo, Yi; Li, Hongli; Xu, Xin; Chen, Zhengkai; Xu, Jianfeng; Ren, Hongjun

    2016-06-17

    Lewis acid catalyzed directly dehydrative carbon-carbon bond formation reaction of 2-furylcarbinols with β-keto amides provides a straightforward method for regioselective synthesis of (Z)-furyl enols. Moreover, this Lewis acid catalyzed cross-coupling reaction can be extended to an interesting heterocyclic version featuring a functionalized 3-furyl-4-hydroxycoumarin synthesis. PMID:27224045

  14. X-ray Crystallographic Analysis of α-Ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase

    PubMed Central

    Mileni, Mauro; Garfunkle, Joie; Ezzili, Cyrine; Kimball, F. Scott; Cravatt, Benjamin F.; Stevens, Raymond C.; Boger, Dale L.

    2009-01-01

    Three cocrystal X-ray structures of the α-ketoheterocycle inhibitors 3–5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the α-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure–activity relationships are discussed providing important insights for future design. PMID:19924997

  15. X-ray Crystallographic Analysis of [alpha]-Ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase

    SciTech Connect

    Mileni, Mauro; Garfunkle, Joie; Ezzili, Cyrine; Kimball, F.Scott; Cravatt, Benjamin F.; Stevens, Raymond C.; Boger, Dale L.

    2010-11-03

    Three cocrystal X-ray structures of the {alpha}-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the {alpha}-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design.

  16. Synthesis and structure--activity relationships of substituted cinnamic acids and amide analogues: a new class of herbicides.

    PubMed

    Vishnoi, Shipra; Agrawal, Vikash; Kasana, Virendra K

    2009-04-22

    In the present investigation, substituted cinnamic acids (3-hydroxy, 4-hydroxy, 2-nitro, 3-nitro, 4-nitro, 3-chloro, and 4-methoxy) and their amide analogues with four different types of substituted anilines have been synthesized. The synthesized compounds have been screened for their germination inhibition activity on radish (Raphanus sativus L. var. Japanese White) seeds at 50, 100, and 200 ppm concentrations, and the activity was compared with standard herbicide, metribuzin formulation (sencor). Significant activity was exhibited by all of the compounds. It was observed that with the increase in concentration of the test solution, the activity also increased. All of the compounds showed more than 70% inhibition at 100 ppm concentration except 4-hydroxy cinnamanilide. The compound, 2-chloro (4'-hydroxy) cinnamanilide was the best among the tested compounds, and it was found to be at par with the standard, metribuzin at all concentrations. Thus, it can be concluded that substituted cinnamic acids and their amide analogues may be developed as potential herbicides. PMID:19368353

  17. Drug Nanoparticle Formulation Using Ascorbic Acid Derivatives

    PubMed Central

    Moribe, Kunikazu; Limwikrant, Waree; Higashi, Kenjirou; Yamamoto, Keiji

    2011-01-01

    Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate. PMID:21603195

  18. Nucleosides of 4-methylthio-1,2,3-triazol-5-yl-carboxylic acid derivatives

    SciTech Connect

    Shingarova, I.D.; Yartseva, I.V.; Preobrazhenskaya, M.N.

    1987-08-01

    2-..beta..-D-Ribofuranosyl-4-methylthio-5-methoxycarbonyl-1,2,3-triazole was obtained by fusing 4-methylthio-5-methoxycarbonyl-1,2,3-triazole together with tetraacyl-D-ribofuranose, followed by deacylation, and its amide and hydrazide were prepared. The structures of the new nucleosides were established by converting them into known 2-nucleosides of 1,2,3-triazol-4-yl-carboxylic acid derivatives. By comparing PMR spectra with previously reported PMR spectra for the isomeric 1- and 2-nucleosides of 1,2,3-triazol-4-yl-carboxylic acid derivatives, the synthesized nucleosides could be assigned to 2-substituted triazoles.

  19. Modulation by APGW-amide, an Achatina endogenous inhibitory tetrapeptide, of currents induced by neuroactive compounds on Achatina neurons: amines and amino acids.

    PubMed

    Han, X Y; Salunga, T L; Zhang, W; Takeuchi, H; Matsunami, K

    1997-10-01

    1. Modulatory effects of APGW-amide (Ala-Pro-Gly-Trp-NH2), proposed as an inhibitory neurotransmitter of Achatina neurons, perfused at 3 x 10(-6) M on the currents induced by small-molecule putative neurotransmitters were examined by using Achatina giant neuron types, v-RCDN (ventral-right cerebral distinct neuron), TAN (tonically autoactive neuron) and RAPN (right anterior pallial nerve neuron), under voltage clamp. These putative neurotransmitters were ejected locally to the neuron by brief pneumatic pressure. 2. Outward current (Iout) induced by erythro-beta-hydroxy-L-glutamic acid (erythro-L-BHGA) on v-RCDN, which was probably K+ dependent, was enhanced with membrane conductance (g) increase under APGW-amide. From dose (pressure duration)-response curves of erythro-L-BHGA measured in physiological solution (control curve) and with APGW-amide (drug curve), ED50 values of the two curves were nearly comparable, whereas Emax of the drug curve was significantly larger than that of the other. From a Lineweaver-Burk plot of these data, the cross point of the control line and the drug line was on the abscissa. 3. K(+)-dependent Iout caused by dopamine (DA) on v-RCDN was inhibited with a g increase by APGW-amide. The inhibition of this current caused by APGW-amide was mainly in a noncompetitive and partly uncompetitive manner. 4. 5-Hydroxytryptamine (5-HT) produced an inward current (Iin) with two (fast and slow) components on TAN, which was probably Na+ dependent. The fast component of the Iin was inhibited by APGW-amide. The inhibition was mainly in a noncompetitive manner. 5. The currents induced by acetylcholine, gamma-aminobutyric acid and L-glutamic acid on Achatina neuron types were not affected by APGW-amide. 6. The inhibitory effects of APGW-amide on the Iin (fast component) induced by 5-HT were nearly equipotent or a bit stronger than those on the Iout caused by DA. 7. The g increase produced by APGW-amide would be a cause for inhibiting the Iout induced by DA

  20. Structural characterization of synthetic poly(ester amide) from sebacic acid and 4-amino-1-butanol by matrix-assisted laser desorption ionization time-of-flight/time-of-flight tandem mass spectrometry.

    PubMed

    Rizzarelli, Paola; Puglisi, Concetto

    2008-01-01

    Matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry (MALDI-TOF/TOF-MS/MS) was employed to analyze a poly(ester amide) sample (PEA-Bu) from the melt condensation of sebacic acid and 4-amino-1-butanol. In particular, we investigated the fragmentation pathways, the ester/amide bond sequences and the structure of species derived from side reactions during the synthesis. MALDI-TOF/TOF-MS/MS analysis was performed on cyclic species and linear oligomers terminated by dicarboxyl groups, carboxyl and hydroxyl groups and diamino alcohol groups. The sodium adducts of these oligomers were selected as precursor ions. Different end groups do not influence the fragmentation of sodiated poly(ester amide) oligomers and similar series of product ions were observed in the MALDI-TOF/TOF-MS/MS spectra. According to the structures of the most abundant product ions identified, the main cleavages proceed through a beta-hydrogen-transfer rearrangement, leading to the selective scission of the --O--CH2-- bonds. Abundant product ions originating from --CH2--CH2-- (beta-gamma) bond cleavage in the sebacate moiety were also detected. Their formation should be promoted by the presence of an alpha,beta-unsaturated ester or amide end group. MALDI-TOF/TOF-MS/MS provided structural information concerning the ester/amide sequences in the polymer chains. In the MALDI-TOF/TOF-MS/MS spectra acquired, using argon as the collision gas, of cyclic species and linear oligomers terminated by diamino alcohol groups, product ions in the low-mass range, undetected in the mass spectra acquired using air as the collision gas, proved to be diagnostic and made it possible to establish the presence of random sequences of ester and amide bonds in the poly(ester amide) sample. Furthermore, MALDI-TOF/TOF-MS/MS provided useful information to clarify the structures of precursor ions derived from side reactions during the synthesis. PMID:18278818

  1. Investigations on the synthesis and pharmacological properties of amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4- dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-pyrimidine-5-carboxylic acid.

    PubMed

    Sladowska, H; Sieklucka-Dziuba, M; Rajtar, G; Sadowski, M; Kleinrok, Z

    1999-01-01

    Synthesis of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4- tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (6-10) and their 1-[2-hydroxy-3(4-phenyl-1-piperazinyl)propyl] derivatives (11-15) are described. Some of them displayed strong analgesic activity. PMID:10668178

  2. Intracellular Self-Assembly of Cyclic d-Luciferin Nanoparticles for Persistent Bioluminescence Imaging of Fatty Acid Amide Hydrolase.

    PubMed

    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. PMID:27348334

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

    PubMed Central

    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

  4. Differentiation of skeletal osteogenic progenitor cells to osteoblasts with 3,4-diarylbenzopyran based amide derivatives: Novel osteogenic agents.

    PubMed

    Gupta, Atul; Ahmad, Imran; Kureel, Jyoti; John, Aijaz A; Sultan, Eram; Chanda, Debabrata; Agarwal, Naresh Kumar; Alauddin; Wahajuddin; Prabhaker, S; Verma, Amita; Singh, Divya

    2016-10-01

    A series of 3,4-diarylbenzopyran based amide derivatives was synthesized and evaluated for osteogenic activity in in vitro and in vivo models of osteoporosis. Compounds 17a, 21b-c and 22a-b showed significant osteogenic activity in osteoblast differentiation assay. Among the synthesized compounds, 22b was identified as lead molecule which showed significant osteogenic activity at 1 pM concentration in osteoblast differentiation assay and at 1 mg kg(-1) body weight dose in estrogen deficient balb/c mice model. In vitro bone mineralization and expression of osteogenic marker genes viz BMP-2, RUNX-2, OCN, and collagen type 1 further confirmed the osteogenic potential of 22b. Gene expression study for estrogen receptor α and β (ER-α and ER-β) in mouse calvarial osteoblasts (MCOs) unveiled that possibly 22b exerted osteogenic efficacy via activation of Estrogen receptor-β preferentially. In vivo pharmacokinetic, estrogenicity and acute toxicity studies of 22b showed that it had good bioavailability and was devoid of uterine estrogenicity at 1 mg kg(-1) and inherent toxicity up to 1000 mg kg(-1) body weight dose respectively. PMID:27236065

  5. Comparability of higher order structure in proteins: chemometric analysis of second-derivative amide I Fourier transform infrared spectra.

    PubMed

    Stockdale, Gregory; Murphy, Brian M; D'Antonio, Jennifer; Manning, Mark Cornell; Al-Azzam, Wasfi

    2015-01-01

    Comparing higher order structure (HOS) in therapeutic proteins is a significant challenge. Previously, we showed that changes in solution conditions produced detectable changes in the second-derivative amide I Fourier transform infrared (FTIR) spectra for a variety of model proteins. Those comparisons utilized vector-based approaches, such as spectral overlap and spectral correlation coefficients to quantify differences between spectra. In this study, chemometric analyses of the same data were performed, to classify samples into different groups based on the solution conditions received. The solution conditions were composed of various combinations of temperature, pH, and salt types. At first, principal component analysis (PCA) was used to visually demonstrate that FTIR spectra respond to changes in solution conditions, which, presumably indicates variations in HOS. This observed when samples from the same solution condition form clusters within a PCA score plot. The second approach, called soft independent modeling of class analogy (SIMCA), was conducted to account for the within-class experimental error for the lysozyme spectra. The DModX values, indicative of the distance of each spectra to their respective class models, was found to be a more sensitive quantitative indicator of changes in HOS, when compared with the modified area of overlap algorithm. The SIMCA approach provides a metric to determine whether new observations do, or do not belong to a particular class or group. Thus, SIMCA is the recommended approach when multiple samples from each condition are available. PMID:25382804

  6. A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation.

    PubMed

    Scarpelli, Rita; Sasso, Oscar; Piomelli, Daniele

    2016-06-20

    Pain states that arise from non-resolving inflammation, such as inflammatory bowel disease or arthritis, pose an unusually difficult challenge for therapy because of the complexity and heterogeneity of their underlying mechanisms. It has been suggested that key nodes linking interactive pathogenic pathways of non-resolving inflammation might offer novel targets for the treatment of inflammatory pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the cyclooxygenase (COX)-mediated production of pain- and inflammation-inducing prostanoids, are a common first-line treatment for this condition, but their use is limited by mechanism-based side effects. The endogenous levels of anandamide, an endocannabinoid mediator with analgesic and tissue-protective functions, are regulated by fatty acid amide hydrolase (FAAH). This review outlines the pharmacological and chemical rationale for the simultaneous inhibition of COX and FAAH activities with designed multitarget agents. Preclinical studies indicate that such agents may combine superior anti-inflammatory efficacy with reduced toxicity. PMID:26486424

  7. A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia.

    PubMed

    Morita, Yukitaka; Ujike, Hiroshi; Tanaka, Yuji; Uchida, Naohiko; Nomura, Akira; Ohtani, Kyohei; Kishimoto, Makiko; Morio, Akiko; Imamura, Takaki; Sakai, Ayumu; Inada, Toshiya; Harano, Mutsuo; Komiyama, Tokutaro; Yamada, Mitsuhiko; Sekine, Yoshimoto; Iwata, Nakao; Iyo, Masaomi; Sora, Ichiro; Ozaki, Norio; Kuroda, Shigetoshi

    2005-03-16

    Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia. PMID:15721218

  8. An azobenzene-containing metal-organic framework as an efficient heterogeneous catalyst for direct amidation of benzoic acids: synthesis of bioactive compounds.

    PubMed

    Hoang, Linh T M; Ngo, Long H; Nguyen, Ha L; Nguyen, Hanh T H; Nguyen, Chung K; Nguyen, Binh T; Ton, Quang T; Nguyen, Hong K D; Cordova, Kyle E; Truong, Thanh

    2015-12-14

    An azobenzene-containing zirconium metal-organic framework was demonstrated to be an effective heterogeneous catalyst for the direct amidation of benzoic acids in tetrahydrofuran at 70 °C. This finding was applied to the synthesis of several important, representative bioactive compounds. PMID:26455380

  9. Organocatalytic enantioselective decarboxylative reaction of malonic acid half thioesters with cyclic N-sulfonyl ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides.

    PubMed

    Nakamura, Shuichi; Sano, Masahide; Toda, Ayaka; Nakane, Daisuke; Masuda, Hideki

    2015-03-01

    The organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half thioesters (MAHTs) with cyclic N-sulfonyl ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation. PMID:25614368

  10. Amidation inhibitors 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester are novel HDAC inhibitors with anti-tumorigenic properties.

    PubMed

    Ali, Amna; Burns, Timothy J; Lucrezi, Jacob D; May, Sheldon W; Green, George R; Matesic, Diane F

    2015-08-01

    4-Phenyl-3-butenoic acid (PBA) is an inhibitor of peptidylglycine alpha-amidating monooxygenase with anti-inflammatory properties that has been shown to inhibit the growth of ras-mutated epithelial and human lung carcinoma cells. In this report, we show that PBA also increases the acetylation levels of selected histone subtypes in a dose and time dependent manner, an effect that is attributable to the inhibition of histone deacetylase (HDAC) enzymes. Comparison studies with the known HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) using high resolution two-dimensional polyacrylamide gels and Western analysis provide evidence that PBA acts as an HDAC inhibitor within cells. PBA and a more potent amidation inhibitor, 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester (AOPHA-Me), inhibit HDAC enzymes in vitro at micromolar concentrations, with IC50 values approximately 30 fold lower for AOPHA-Me than PBA for selected HDAC isoforms. Overall, these results indicate that PBA and AOPHA-Me are novel anti-tumorigenic HDAC inhibitors. PMID:26065689

  11. Catalyst-Free Three-Component Tandem CDC Cyclization: Convenient Access to Isoindolinones from Aromatic Acid, Amides, and DMSO by a Pummerer-Type Rearrangement.

    PubMed

    Wang, Peng-Min; Pu, Fan; Liu, Ke-Yan; Li, Chao-Jun; Liu, Zhong-Wen; Shi, Xian-Ying; Fan, Juan; Yang, Ming-Yu; Wei, Jun-Fa

    2016-04-25

    A catalyst-free multicomponent CDC reaction is rarely reported, especially for the intermolecular tandem CDC cyclization, which represents an important strategy for constructing cyclic compounds. Herein, a three-component tandem CDC cyclization by a Pummerer-type rearrangement to afford biologically relevant isoindolinones from aromatic acids, amides, and DMSO, is described. This intermolecular tandem reaction undergoes a C(sp(2) )-H/C(sp(3) )-H cross-dehydrogenative coupling, C-N bond formation, and intramolecular amidation. A notable feature of this novel protocol is avoiding a catalyst and additive (apart from oxidant). PMID:26998754

  12. Synthesis and pharmacological properties of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid.

    PubMed

    Sladowska, Helena; Sabiniarz, Aleksandra; Filipek, Barbara; Kardasz, Małgorzata; Maciag, Dorota

    2003-01-01

    Synthesis of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (5-9) and their 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl] derivatives (10-14) is described. Compounds 10-14 were tested for analgesic and sedative activities as well as for mu-opioid receptors binding affinities. All the amides, being the object of investigation, displayed an interesting analgesic action, which in case of the compounds 10-12 and 14 was superior to that of acetylsalicylic acid in two different tests. Furthermore all the amides (10-14) significantly suppressed the spontaneous locomotor activity, prolonged barbiturate sleep in mice and showed a weak affinity to mu-opioid receptors. PMID:12595034

  13. Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH)

    PubMed Central

    Sałaga, M; Mokrowiecka, A; Zakrzewski, P K; Cygankiewicz, A; Leishman, E; Sobczak, M; Zatorski, H; Małecka-Panas, E; Kordek, R; Storr, M; Krajewska, W M; Bradshaw, H B; Fichna, J

    2014-01-01

    Background and aims Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis. Methods We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation. Results We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon). Conclusions We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation. PMID:24530133

  14. Towards novel 5-HT7versus 5-HT1A receptor ligands among LCAPs with cyclic amino acid amide fragments: design, synthesis, and antidepressant properties. Part II.

    PubMed

    Canale, Vittorio; Kurczab, Rafał; Partyka, Anna; Satała, Grzegorz; Witek, Jagna; Jastrzębska-Więsek, Magdalena; Pawłowski, Maciej; Bojarski, Andrzej J; Wesołowska, Anna; Zajdel, Paweł

    2015-03-01

    A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970. PMID:25555143

  15. Identification of the Amidotransferase AsnB1 as Being Responsible for meso-Diaminopimelic Acid Amidation in Lactobacillus plantarum Peptidoglycan ▿ †

    PubMed Central

    Bernard, Elvis; Rolain, Thomas; Courtin, Pascal; Hols, Pascal; Chapot-Chartier, Marie-Pierre

    2011-01-01

    The peptidoglycan (PG) of Lactobacillus plantarum contains amidated meso-diaminopimelic acid (mDAP). The functional role of this PG modification has never been characterized in any bacterial species, except for its impact on PG recognition by receptors of the innate immune system. In silico analysis of loci carrying PG biosynthesis genes in the L. plantarum genome revealed the colocalization of the murE gene, which encodes the ligase catalyzing the addition of mDAP to UDP-N-muramoyl-d-glutamate PG precursors, with asnB1, which encodes a putative asparagine synthase with an N-terminal amidotransferase domain. By gene disruption and complementation experiments, we showed that asnB1 is the amidotransferase involved in mDAP amidation. PG structural analysis revealed that mDAP amidation plays a key role in the control of the l,d-carboxypeptidase DacB activity. In addition, a mutant strain with a defect in mDAP amidation is strongly affected in growth and cell morphology, with filamentation and cell chaining, while a DacB-negative strain displays a phenotype very similar to that of a wild-type strain. These results suggest that mDAP amidation may play a critical role in the control of the septation process. PMID:21949063

  16. Detection and qualitative analysis of fatty acid amides in the urine of alcoholics using HPLC-QTOF-MS.

    PubMed

    Dabur, Rajesh; Mittal, Ashwani

    2016-05-01

    Fatty acid amides (FAAs) in alcoholism lead to liver diseases. These amides have been reported in plasma and in other organs of the body, while their detection or presence in the urine is still unknown. Therefore, the focus of the current study was to detect and analyze FAAs qualitatively in urine samples of alcoholics. Furthermore, the effects of Tinospora cordifolia (hepatoprotective medicinal plant) intervention on FAA levels in moderate alcoholics were also analyzed. In the study, asymptomatic chronic alcoholics (n = 22) without chronic liver disease and nonalcoholic healthy volunteers (n = 24) with a mean age of 39 ± 2.0 years were selected. The first-pass urine and fasting blood samples were collected in the morning on day 0 and day 14 after T. cordifolia water extract (TCE) treatment and analyzed using automated biochemistry analyzer and HPLC-QTOF-MS. Results indicated the increased levels of serum triglycerides, cholesterol, and liver function enzymes in alcoholic subjects, which were significantly down-regulated by TCE intervention. Multivariate discrimination analysis of QTOF-MS data showed increased urinary levels of oleoamide (2.55-fold), palmitamide (5.6-fold), and erucamide (1.6-fold) in alcoholics as compared to control subjects. Levels of oleamide (1.8-fold), palmitamide (1.7-fold), and linoleamide (1.5-fold) were found to be increased in plasma. Treatment with TCE in alcoholics (3.0 g lyophilized water extract/day) significantly decreased the plasma and urinary levels of all FAAs except linoleamide. The HPLC-QTOF-MS approach for FAAs analysis in both urinary and plasma samples of alcoholics worked very well. Moreover, findings (i.e., increased levels of FAAs in urine and in plasma) further support other findings that these amides play a very important role in alcoholism. Further, like our previous findings, TCE proved its hepatoprotective effect against alcoholism not only by lowering the levels of these detected FAAs, but also by decreasing the

  17. The Influence of the Amide Linkage in the Fe(III) -Binding Properties of Catechol-Modified Rosamine Derivatives.

    PubMed

    Queirós, Carla; Leite, Andreia; G M Couto, Maria; Cunha-Silva, Luís; Barone, Giampaolo; de Castro, Baltazar; Rangel, Maria; M N Silva, André; M G Silva, Ana

    2015-10-26

    The two new fluorescent ligands RosCat1 and RosCat2 contain catechol receptors connected to rosamine platforms through an amide linkage and were synthesized by using microwave-assisted coupling reactions of carboxyl- or amine-substituted rosamines with the corresponding catechol units and subsequent deprotection. RosCat1 possesses a reverse amide, whereas RosCat2 has the usual oriented amide bond (HNCO vs. CONH, respectively). The ligands were characterized by means of NMR spectroscopy, mass-spectrometry, and DFT calculations and X-ray crystallography studies for RosCat1. The influence of the amide linkage on the photophysical properties of the fluorescent ligands was assessed in different solvents and showed a higher fluorescence quantum yield for RosCat1. The coordination chemistry of these ligands with a Fe(III) center has been rationalized by mass-spectrometric analysis and semiempirical calculations. Octahedral Fe(III) complexes were obtained by the chelation of three RosCat1 or RosCat2 ligands. Interestingly, the unconventional amide connectivity in RosCat1 imposes the formation of an eight-membered ring on the chelate complex through a "salicylate-type" mode of coordination. PMID:26493881

  18. Ab initio molecular orbital and infrared spectroscopic study of the conformation of secondary amides: derivatives of formanilide, acetanilide and benzylamides

    NASA Astrophysics Data System (ADS)

    Ilieva, S.; Hadjieva, B.; Galabov, B.

    1999-09-01

    Ab initio molecular orbital calculations at HF/4-31G level and infrared spectroscopic data for the frequencies are applied to analyse the grouping in a series model aromatic secondary amides: formanilide; acetanilide; o-methylacetanilide; 2,6-dimethylformanilide, 2,6-dimethylacetanilide; N-benzylacetamide and N-benzylformamide. The theoretical and experimental data obtained show that the conformational state of the molecules studied is determined by the fine balance of several intramolecular factors: resonance effect between the amide group and the aromatic ring, steric interaction between various substituents around the -NH-CO- grouping in the aromatic ring, conjugation between the carbonyl bond and the nitrogen lone pair as well as direct field influences inside the amide group.

  19. Interactions of amino acids, carboxylic acids, and mineral acids with different quinoline derivatives

    NASA Astrophysics Data System (ADS)

    Kalita, Dipjyoti; Deka, Himangshu; Samanta, Shyam Sundar; Guchait, Subrata; Baruah, Jubaraj B.

    2011-03-01

    A series of quinoline containing receptors having amide and ester bonds are synthesized and characterised. The relative binding abilities of these receptors with various amino acids, carboxylic acids and mineral acids are determined by monitoring the changes in fluorescence intensity. Among the receptors bis(2-(quinolin-8-yloxy)ethyl) isophthalate shows fluorescence enhancement on addition of amino acids whereas the other receptors shows fluorescence quenching on addition of amino acids. The receptor N-(quinolin-8-yl)-2-(quinolin-8-yloxy) propanamide has higher binding affinity for amino acids. However, the receptor N-(quinolin-8-yl)-2-(quinolin-8-yloxy)acetamide having similar structure do not bind to amino acids. This is attributed to the concave structure of the former which is favoured due to the presence of methyl substituent. The receptor bis(2-(quinolin-8-yloxy)ethyl) isophthalate do not bind to hydroxy carboxylic acids, but is a good receptor for dicarboxylic acids. The crystal structure of bromide and perchlorate salts of receptor 2-bromo-N-(quinolin-8-yl)-propanamide are determined. In both the cases the amide groups are not in the plane of quinoline ring. The structure of N-(quinolin-8-yl)-2-(quinolin-8-yloxy)acetamide, N-(2-methoxyphenethyl)-2-(quinolin-8-yloxy)acetamide and their salts with maleic acid as well as fumaric acid are determined. It is observed that the solid state structures are governed by the double bond geometry of these two acid. Maleic acid forms salt in both the cases, whereas fumaric acid forms either salt or co-crystals.

  20. Enantioresolution of five β-blockers by reversed-phase high-performance liquid chromatography using fifteen chiral derivatizing reagents having amino acids or their amides as chiral auxiliaries on a cyanuric chloride platform.

    PubMed

    Bhushan, Ravi; Dixit, Shuchi

    2012-02-01

    Enantioseparation of five β-blockers, namely, (R,S)-atenolol, (R,S)-propranolol, (R,S)-bisoprolol, (R,S)-metoprolol and (R,S)-carvedilol, was achieved as their diastereomers prepared with chiral derivatizing reagents (CDRs) synthesized on a cyanuric chloride platform. Fifteen CDRs were synthesized by nucleophilic substitution of the Cl atom in cyanuric chloride or its 6-methoxy derivative with amino acids (namely, L-Leu, L-Val, D-Phg, L-Met and L-Ala) or their amides as chiral auxiliaries. The diastereomers were synthesized under microwave irradiation for 70 or 100 s at 85% power. Separation of diastereomers was carried out on a C(18) column and gradient eluting mixtures of methanol with aqueous trifluoroacetic acid with UV detection at 230 nm. Separation efficiencies of the reagents were compared on the basis of effect of chiral auxiliaries (i.e. amino acids or amino acid amides) and achiral substituents (i.e. chlorine or methoxy group) in the CDRs. The method was validated for detection limit, linearity, accuracy and precision. PMID:21678456

  1. Application of cyanuric chloride-based six new chiral derivatizing reagents having amino acids and amino acid amides as chiral auxiliaries for enantioresolution of proteinogenic amino acids by reversed-phase high-performance liquid chromatography.

    PubMed

    Bhushan, Ravi; Dixit, Shuchi

    2012-04-01

    Six dichloro-s-triazine (DCT) reagents having L-Leu, D-Phg, L-Val, L-Met, L-Ala and L-Met-NH(2) as chiral auxiliaries in cyanuric chloride were introduced for enantioseparation of 13 proteinogenic amino acids. Four other DCTs and six monochloro-s-triazine (MCT) reagents having amino acid amides as chiral auxiliaries were also synthesized. These 16 chiral derivatizing reagents (CDRs) were used for synthesis of diastereomers of all the 13 analytes using microwave irradiation, which were resolved by reversed-phase high-performance liquid chromatography (RP-HPLC) using C18 column and gradient eluting mixture of aqueous TFA and acetonitrile with UV detection at 230 nm. It required only 60-90 s for derivatization using microwave irradiation. Better resolution and lower retention times were observed for the diastereomers prepared with CDRs having amino acids as chiral auxiliaries as compared to counterparts prepared with reagents having amino acid amides as chiral auxiliaries. As the best resolution of all the 13 analytes was observed for their diastereomers prepared using the DCT reagent having L-Leu as chiral auxiliary, this CDR was further employed for derivatization of Lys, Tyr, His and Arg followed by RP-HPLC analysis of resulting diastereomers. The results are discussed in light of acid and amide groups of chiral auxiliaries constituting CDRs, electronegativities of the atoms of achiral moieties constituting CDRs and hydrophobicities of side chains of amino acids constituting CDRs and analytes. PMID:21246226

  2. Identification of N-acylethanolamines in Dictyostelium discoideum and confirmation of their hydrolysis by fatty acid amide hydrolase[S

    PubMed Central

    Hayes, Alexander C.; Stupak, Jacek; Li, Jianjun; Cox, Andrew D.

    2013-01-01

    N-acylethanolamines (NAEs) are endogenous lipid-based signaling molecules best known for their role in the endocannabinoid system in mammals, but they are also known to play roles in signaling pathways in plants. The regulation of NAEs in vivo is partly accomplished by the enzyme fatty acid amide hydrolase (FAAH), which hydrolyses NAEs to ethanolamine and their corresponding fatty acid. Inhibition of FAAH has been shown to increase the levels of NAEs in vivo and to produce desirable phenotypes. This has led to the development of pharmaceutical-based therapies for a variety of conditions targeting FAAH. Recently, our group identified a functional FAAH homolog in Dictyostelium discoideum, leading to our hypothesis that D. discoideum also possesses NAEs. In this study, we provide a further characterization of FAAH and identify NAEs in D. discoideum for the first time. We also demonstrate the ability to modulate their levels in vivo through the use of a semispecific FAAH inhibitor and confirm that these NAEs are FAAH substrates through in vitro studies. We believe the demonstration of the in vivo modulation of NAE levels suggests that D. discoideum could be a good simple model organism in which to study NAE-mediated signaling. PMID:23187822

  3. Cholic acid derivatives: novel antimicrobials.

    PubMed

    Savage, P B; Li, C

    2000-02-01

    Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding new antimicrobial agents. The squalamine mimics include the polyamine and sulphate functionalities found in the parent antibiotic, however, the positions relative to the steroid nucleus have been exchanged. The PMB mimics include the conservation of functionality among the polymyxin family of antibiotics, the primary amine groups and a hydrophobic chain. Although the squalamine and PMB mimics are morphologically dissimilar, they display similar activities. Both are simple to prepare and demonstrate broad spectrum antimicrobial activity against Gram-negative and Gram-positive organisms. Specific examples may be inactive alone, yet effectively permeabilise the outer membranes of Gram-negative bacteria rendering them sensitive to hydrophobic antibiotics. Problems associated with some of the squalamine and PMB mimics stem from their haemolytic activity and interactions with serum proteins, however, examples exist without these side effects which can sensitise Gram-negative bacteria to hydrophobic antibiotics. PMID:11060676

  4. [The Qualitative Analysis of the Amide Derivative of HLDF-6 Peptide and Its Metabolites with the Use of Tritium- and Deuterium-Labeled Derivatives].

    PubMed

    Zolotarev, A; Dadayan, A K; Kost, N V; Voevodina, M E; Sokolov, O Y; Kozik, V S; Shram, S I; Azev, V N; Bocharov, E V; Bogachouk, A P; Lipkin, V M; Myasoedov, N F

    2015-01-01

    The goal of the study was to elaborate the pharmacokinetics methods of the amide derivative of peptide HLDF-6 (TGENHR-NH2) and its range of nootropic and neuroprotective activity is wide. The hexapeptide 41TGENHR46 is a fragment of the HDLF differentiation factor. It forms the basis for the development of preventive and therapeutic preparations for treating cerebrovascular and neurodegenerative conditions. Pharmacokinetic and molecular mechanisms of the action of the HLDF-6 peptide were studied using tritium- and deuterium-labeled derivatives of this peptide, produced with the use of the high-temperature solid-state catalytic isotope exchange reaction (HSCIE). This reaction was employed to produce the tritium-labeled peptide [3H]TGENHR-NH2 with a molar radioactivity of 230 Ci/mmol and the deuterium-labeled peptide [2H]TGENHR-NH2 with an average deuterium incorporation equal to 10.5 atoms. It was shown by the NMR spectroscopy that the isotope label distribution over the labeled peptide's molecule was uniform, which allowed qualitative analysis ofboth the peptide itself and its fragments in the organism's tissues to be conducted. The newly developed pharmacokinetics method makes it possible to avoid almost completely losses of the peptides under study due to biodegradation during the analysis of tissues. These labeled peptides were used in mice, rats and rabbits to study the pharmacokinetics of the peptide and to calculate the values of its principal pharmacokinetic parameters. Characteristics of its pharmacokinetic profile in the blood were obtained, the hypothesis of pharmacokinetics linearity tested, its metabolism analyzed and its bioavailability value, 34%, calculated. It has been shown that the studied TGENHR-NH2 peptide shows high resistance to hydrolysis in the blood plasma, with dipeptidyl aminopeptidases making the largest contribution to its hydrolysis. PMID:27125017

  5. Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands –in vitro and in vivo characterization

    PubMed Central

    Khom, S; Strommer, B; Ramharter, J; Schwarz, T; Schwarzer, C; Erker, T; Ecker, GF; Mulzer, J; Hering, S

    2010-01-01

    BACKGROUND AND PURPOSE Subunit-specific modulators of γ-aminobutyric acid (GABA) type A (GABAA) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a β2/3 subunit-specific modulator of GABAA receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABAA receptor modulators and to gain insight into the structure–activity relation of this molecule. EXPERIMENTAL APPROACH The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABAA receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (IGABA) through GABAA receptors (EC50) and efficacies (maximal stimulation of IGABA) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. KEY RESULTS Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater IGABA enhancement than VA) and highest potency (EC50= 13.7 ± 2.3 µM) on α1β3 receptors. Higher efficacy and potency of VA-A were also observed on α1β2γ2s and α3β3γ2s receptors. Anxiolytic effects were most pronounced for VA-A. CONCLUSIONS AND IMPLICATIONS Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting β3 subunit containing GABAA receptors for development of anxiolytics. PMID:20718740

  6. Characterisation of (R)-2-(2-Fluorobiphenyl-4-yl)-N-(3-Methylpyridin-2-yl)Propanamide as a Dual Fatty Acid Amide Hydrolase: Cyclooxygenase Inhibitor

    PubMed Central

    Gouveia-Figueira, Sandra; Karlsson, Jessica; Deplano, Alessandro; Hashemian, Sanaz; Svensson, Mona; Fredriksson Sundbom, Marcus; Congiu, Cenzo; Onnis, Valentina; Fowler, Christopher J.

    2015-01-01

    Background Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate selective cyclooxygenase (COX-2) inhibitors is a promising approach for pain-relief. One such compound with this profile is 2-(2-fluorobiphenyl-4-yl)-N-(3-methylpyridin-2-yl)propanamide (Flu-AM1). These activities are shown by Flu-AM1 racemate, but it is not known whether its two single enantiomers behave differently, as is the case towards COX-2 for the parent flurbiprofen enantiomers. Further, the effects of the compound upon COX-2-derived lipids in intact cells are not known. Methodology/Principal Findings COX inhibition was determined using an oxygraphic method with arachidonic acid and 2-arachidonoylglycerol (2-AG) as substrates. FAAH was assayed in mouse brain homogenates using anandamide (AEA) as substrate. Lipidomic analysis was conducted in unstimulated and lipopolysaccharide + interferon γ- stimulated RAW 264.7 macrophage cells. Both enantiomers inhibited COX-2 in a substrate-selective and time-dependent manner, with IC50 values in the absence of a preincubation phase of: (R)-Flu-AM1, COX-1 (arachidonic acid) 6 μM; COX-2 (arachidonic acid) 20 μM; COX-2 (2-AG) 1 μM; (S)-Flu-AM1, COX-1 (arachidonic acid) 3 μM; COX-2 (arachidonic acid) 10 μM; COX-2 (2-AG) 0.7 μM. The compounds showed no enantiomeric selectivity in their FAAH inhibitory properties. (R)-Flu-AM1 (10 μM) greatly inhibited the production of prostaglandin D2 and E2 in both unstimulated and lipopolysaccharide + interferon γ- stimulated RAW 264.7 macrophage cells. Levels of 2-AG were not affected either by (R)-Flu-AM1 or by 10 μM flurbiprofen, either alone or in combination with the FAAH inhibitor URB597 (1 μM). Conclusions/Significance Both enantiomers of Flu-AM1 are more potent inhibitors of 2-AG compared to arachidonic acid oxygenation by COX-2. Inhibition of COX in lipopolysaccharide + interferon γ- stimulated RAW 264.7 cells is insufficient to affect 2-AG levels despite the

  7. Role of amidation in bile acid effect on DNA synthesis by regenerating mouse liver.

    PubMed

    Barbero, E R; Herrera, M C; Monte, M J; Serrano, M A; Marin, J J

    1995-06-01

    Effect of bile acids on DNA synthesis by the regenerating liver was investigated in mice in vivo after partial hepatectomy (PH). Radioactivity incorporation into DNA after [14C]thymidine intraperitoneal administration peaked at 48 h after PH. At this time a significant taurocholate-induced dose-dependent reduction in DNA synthesis without changes in total liver radioactivity content was found (half-maximal effect at approximately 0.1 mumol/g body wt). Effect of taurocholate (0.5 mumol/g body wt) was mimicked by chocolate, ursodeoxycholate, deoxycholate, dehydrocholate, tauroursodeoxycholate, taurochenodeoxycholate, and taurodeoxycholate. In contrast, chenodeoxycholate, glycocholate, glycochenodeoxycholate, glycoursodeoxycholate, glycodeoxycholate, 5 beta-cholestane, bromosulfophthalein, and free taurine lacked this effect. No relationship between hydrophobic-hydrophilic balance and inhibitory effect was observed. Analysis by high-performance liquid chromatography indicated that inhibition of thymidine incorporation into DNA was not accompanied by an accumulation of phosphorylated DNA precursors in the liver but rather by a parallel increase in nucleotide catabolism. Bile acid-induced modifications in DNA synthesis were observed in vivo even in the absence of changes in toxicity tests, which suggests that the inhibitory effect shared by most unconjugated and tauroconjugated bile acids but not by glycoconjugated bile acids should be accounted for by mechanisms other than nonselective liver cell injury. PMID:7611405

  8. Inhibition of LN-308 glioma cell proliferation and migration by retinoic acid amide through activation of Akt pathway

    PubMed Central

    Zhu, Jun; Lu, Xiang-Dong; Si, Feng; Song, Chun-Yu; Meng, Qing-Hai

    2015-01-01

    The present study was performed to investigate the effect of retinoic acid amide (RAA) on the expression of integrin α3β1, rate of cell proliferation and migration in p53-deficient glioma cell line, LN-308. The results revealed promotion of integrin α3 expression, reduction in proliferation and migration in RAA treated cells compared to the control LN-308 glioma cells. Promotion of RAA induced integrin α3β1 expression led to the enhancement in cyclin-dependent kinase nuclear localization and activation of Akt pathway. In addition, RAA treatment inhibited the expression of nuclear factor-κB, Bcl-2 and epidermal growth factor receptor (EGFR). These factors are responsible for promoting the rate of cell proliferation and survival in the carcinoma cells. Thus RAA treatment inhibits rate of LN-308 glioma cell proliferation and migration through increase in integrin α3β1 expression and activation of Akt pathway. Therefore, RAA can be of therapeutic importance for the treatment of glioma. PMID:26823704

  9. The macamide N-3-methoxybenzyl-linoleamide is a time-dependent fatty acid amide hydrolase (FAAH) inhibitor.

    PubMed

    Almukadi, Haifa; Wu, Hui; Böhlke, Mark; Kelley, Charles J; Maher, Timothy J; Pino-Figueroa, Alejandro

    2013-10-01

    The Peruvian plant Lepidium meyenii (Maca) has been shown to possess neuroprotective activity both in vitro and in vivo. Previous studies have also demonstrated the activity of the pentane extract and its macamides, the most representative lipophilic constituents of Maca, in the endocannabinoid system as fatty acid amide hydrolase (FAAH) inhibitors. One of the most active macamides, N-3-methoxybenzyl-linoleamide, was studied to determine its mechanism of interaction with FAAH and whether it has inhibitory activity on mono-acyl glycerol lipase (MAGL), the second enzyme responsible for endocannabinoid degradation. Macamide concentrations from 1 to 100 μM were tested using FAAH and MAGL inhibitor assay methods and showed no effect on MAGL. Tests with other conditions were performed in order to characterize the inhibitory mechanism of FAAH inhibition. N-3-methoxybenzyl-linoleamide displayed significant time-dependent and dose-dependent FAAH inhibitory activity. The mechanism of inhibition was most likely irreversible or slowly reversible. These results suggest the potential application of macamides isolated from Maca as FAAH inhibitors, as they might act on the central nervous system to provide analgesic, anti-inflammatory, or neuroprotective effects, by modulating the release of neurotransmitters. PMID:23853040

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

    PubMed Central

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

    2015-01-01

    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. PMID:26656183

  11. [The influence of docosahexaenoic acid moiety on cytotoxic activity of 1,2,4-thiadiazole derivatives].

    PubMed

    Akimov, M G; Gretskaia, N M; Karnoukhova, V A; Serkov, I V; Proshin, A N; Shtratnikova, V Iu; Bezuglov, V V

    2014-01-01

    Among 3-(2-aminopropyl)-1,2,4-thiadiazole derivatives contatining substitution-ready secondary amino group and exhibiting cytotoxic towards rat C 6 glioma cells three compounds with LD 50 values ranged from 6 to 48 мM were chosen. For these compounds amides with docosahexaenoic acid were synthetised and their cytotoxic activity was studied. It was shown that, although docosahexaenoic acid itself was not toxic for C 6 glioma cells, its addition to the amino derivatives of 1,2,4-thiadiazole increased or decreased resultant cytotoxicity. The effect depended on the structure of 1,2,4-thiadiazole substituents. The obtained data show that the acylation of cytotoxic compounds with docosahexaenoic acid does not necessarily lead to the increase of their activity, but sometimes can inactivate a compound. This fact should be taken into account, especially in the case of anti-cancer drug development. PMID:25249531

  12. Dianthosaponins G-I, triterpene saponins, an anthranilic acid amide glucoside and a flavonoid glycoside from the aerial parts of Dianthus japonicus and their cytotoxicity.

    PubMed

    Kanehira, Yuka; Kawakami, Susumu; Sugimoto, Sachiko; Matsunami, Katsuyoshi; Otsuka, Hideaki

    2016-10-01

    Extensive isolation work on the 1-BuOH-soluble fraction of a MeOH extract of the aerial parts of Dianthus japonicus afforded three further triterpene glycosyl estsers, termed dianthosaponins G-I, an anthranilic acid amide glucoside and a C-glycosyl flavonoid along with one known triterpene saponin. Their structures were elucidated from spectroscopic evidence. The cytotoxicity of the isolated compounds toward A549 cells was evaluated. PMID:27351981

  13. Possible Evidence of Amide Bond Formation Between Sinapinic Acid and Lysine-Containing Bacterial Proteins by Matrix-Assisted Laser Desorption/Ionization (MALDI) at 355 nm

    NASA Astrophysics Data System (ADS)

    Fagerquist, Clifton K.; Sultan, Omar; Carter, Michelle Q.

    2012-12-01

    We previously reported the apparent formation of matrix adducts of 3,5-dimethoxy-4-hydroxy-cinnamic acid (sinapinic acid or SA) via covalent attachment to disulfide bond-containing proteins (HdeA, Hde, and YbgS) from bacterial cell lysates ionized by matrix-assisted laser desorption/ionization (MALDI) time-of-flight-time-of-flight tandem mass spectrometry (TOF-TOF-MS/MS) and post-source decay (PSD). We also reported the absence of adduct formation when using α-cyano-4-hydroxycinnamic acid (CHCA) matrix. Further mass spectrometric analysis of disulfide-intact and disulfide-reduced over-expressed HdeA and HdeB proteins from lysates of gene-inserted E. coli plasmids suggests covalent attachment of SA occurs not at cysteine residues but at lysine residues. In this revised hypothesis, the attachment of SA is preceded by formation of a solid phase ammonium carboxylate salt between SA and accessible lysine residues of the protein during sample preparation under acidic conditions. Laser irradiation at 355 nm of the dried sample spot results in equilibrium retrogradation followed by nucleophilic attack by the amine group of lysine at the carbonyl group of SA and subsequent amide bond formation and loss of water. The absence of CHCA adducts suggests that the electron-withdrawing effect of the α-cyano group of this matrix may inhibit salt formation and/or amide bond formation. This revised hypothesis is supported by dissociative loss of SA (-224 Da) and the amide-bound SA (-206 Da) from SA-adducted HdeA and HdeB ions by MS/MS (PSD). It is proposed that cleavage of the amide-bound SA from the lysine side-chain occurs via rearrangement involving a pentacyclic transition state followed by hydrogen abstraction/migration and loss of 3-(4-hydroxy-3,5-dimethoxyphenyl)prop-2-ynal (-206 Da).

  14. Synthesis and characterisation of bismacrocyclic DO3A-amide derivatives - an approach towards metal-responsive PARACEST agents.

    PubMed

    Cakić, Nevenka; Verbić, Tatjana Ž; Jelić, Ratomir M; Platas-Iglesias, Carlos; Angelovski, Goran

    2016-04-12

    Three new bismacrocyclic Ln(3+) chelates consisting of triamide derivatives of cyclen with glycine, methyl and tert-butyl substituents (, respectively) linked to an acyclic EGTA-derived calcium chelator were synthesised as potential MRI contrast agents (EGTA - ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid). Eu(3+) and Yb(3+) complexes of were investigated as chemical exchange saturation transfer (CEST) agents. Moderate to minor CEST effects were observed for , and complexes in the absence of Ca(2+), with negligible changes upon addition of this metal ion. Luminescence steady-state emission and lifetime experiments did not reveal any changes in the coordination environment of the complexes, while the number of inner-sphere water molecules remained constant in the absence and presence of Ca(2+). The protonation constants of and and stability constants of their complexes with Ca(2+), Mg(2+) and Zn(2+) were determined by means of potentiometric titrations. The results show that the charge of the complex dramatically affects the protonation constants of the EGTA-binding unit. The stability constants of the complexes formed with Ca(2+), Mg(2+) and Zn(2+) are several orders of magnitude lower than those of EGTA. These findings indicate that the nature of Ln(3+) chelates and their charge are the main reasons for the observed results and weaker response of these EGTA-derived triamide derivatives compared to their tricarboxylate analogues. PMID:26956151

  15. K-Nutrition, Growth Bud Formation, and Amine and Hydroxycinnamic Acid Amide Contents in Leaf Explants of Nicotiana tabacum Variety Xanthi n.c. Cultivated in Vitro1

    PubMed Central

    Klinguer, Serge; Martin-Tanguy, Josette; Martin, Claude

    1986-01-01

    The effects of K-nutrition on growth (increase of fresh weight), bud formation (time of emergence, number of buds), and amine and hydroxycinnamic acid amide contents in foliar explants of Nicotiana tabacum cv Xanthi n.c. cultivated in vitro were examined. In K-deficient medium and in high K medium growth and bud formation were markedly inhibited. Marked changes of amine content (a diamine, putrescine; a phenolic amine, phenethylamine) were observed after a few days of culture. No apparent relationship was found between these amines and growth or bud differentiation. In contrast, changes in hydroxycinnamic acid levels were shown to correlate well with growth and bud formation. The greatest stimulation of budding and growth was correlated with the greatest accumulation of these amides. The highest contents of hydroxycinnamic acid amides were found during the first 15 days in culture when intensive cell division took place. Then they declined sharply after 26 days in culture as the rate of cell division decreased and differentiation occurred. PMID:16665067

  16. Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets

    PubMed Central

    Palermo, Giulia; Bauer, Inga; Campomanes, Pablo; Cavalli, Andrea; Armirotti, Andrea; Girotto, Stefania; Rothlisberger, Ursula; De Vivo, Marco

    2015-01-01

    The fatty acid amide hydrolase (FAAH) regulates the endocannabinoid system cleaving primarily the lipid messenger anandamide. FAAH has been well characterized over the years and, importantly, it represents a promising drug target to treat several diseases, including inflammatory-related diseases and cancer. But its enzymatic mechanism for lipid selection to specifically hydrolyze anandamide, rather than similar bioactive lipids, remains elusive. Here, we clarify this mechanism in FAAH, examining the role of the dynamic paddle, which is formed by the gating residues Phe432 and Trp531 at the boundary between two cavities that form the FAAH catalytic site (the “membrane-access” and the “acyl chain-binding” pockets). We integrate microsecond-long MD simulations of wild type and double mutant model systems (Phe432Ala and Trp531Ala) of FAAH, embedded in a realistic membrane/water environment, with mutagenesis and kinetic experiments. We comparatively analyze three fatty acid substrates with different hydrolysis rates (anandamide > oleamide > palmitoylethanolamide). Our findings identify FAAH’s mechanism to selectively accommodate anandamide into a multi-pocket binding site, and to properly orient the substrate in pre-reactive conformations for efficient hydrolysis that is interceded by the dynamic paddle. Our findings therefore endorse a structural framework for a lipid selection mechanism mediated by structural flexibility and gating residues between multiple binding cavities, as found in FAAH. Based on the available structural data, this exquisite catalytic strategy for substrate specificity seems to be shared by other lipid-degrading enzymes with similar enzymatic architecture. The mechanistic insights for lipid selection might assist de-novo enzyme design or drug discovery efforts. PMID:26111155

  17. Impaired neurogenesis by HIV-1-Gp120 is rescued by genetic deletion of fatty acid amide hydrolase enzyme

    PubMed Central

    Avraham, H K; Jiang, S; Fu, Y; Rockenstein, E; Makriyannis, A; Wood, J; Wang, L; Masliah, E; Avraham, S

    2015-01-01

    Background and Purpose The HIV-envelope glycoprotein Gp120 is involved in neuronal injury and is associated with neuro-AIDS pathogenesis in the brain. Endocannabinoids are important lipid ligands in the CNS regulating neural functions, and their degeneration is controlled by hydrolysing enzymes such as the fatty acid amide hydrolase (FAAH). Here, we examined whether in vivo genetic deletion of Faah gene prevents HIV-1 Gp120-mediated effects on neurogenesis. Experimental Approach We generated new GFAP/Gp120 transgenic (Tg) mice that have genetic deletion of Faah gene by mating glial fribillary acidic protein (GFAP)/Gp120 Tg mice with Faah−/− mice. Neurogenesis and cell death were assessed by immunocytochemical analysis. Key Results Endocannabinoid levels in the brain of the double GFAP/Gp120//Faah−/− mice were similar to those observed in Faah−/− mice. However, unlike the impaired neurogenesis observed in GFAP/Gp120 Tg mice and Faah−/− mice, these GFAP/Gp120//Faah-/ mice showed significantly improved neurogenesis in the hippocampus, indicated by a significant increase in neuroblasts and neuronal cells, an increase in BrdU+ cells and doublecortin positive cells (DCX+), and an increase in the number of PCNA. Furthermore, a significant decrease in astrogliosis and gliogenesis was observed in GFAP/Gp120//Faah−/−mice and neurogenesis was stimulated by neural progenitor cells (NPCs) and/or the newly formed NPC niches characterized by increased COX-2 expression and elevated levels of PGE2. Conclusions and Implications In vivo genetic ablation of Faah, resulted in enhanced neurogenesis through modulation of the newly generated NPC niches in GFAP/Gp120//Faah−/− mice. This suggests a novel approach of using FAAH inhibitors to enhance neurogenesis in HIV-1 infected brain. PMID:24571443

  18. Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.

    PubMed

    Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo; Redhi, Godfrey H; Auber, Alessia; Secci, Maria E; Mascia, Paola; Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Chefer, Svetlana I; Barnes, Chanel; Yasar, Sevil; Piomelli, Daniele; Goldberg, Steven R

    2015-08-01

    Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement. PMID:25754762

  19. Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

    PubMed Central

    Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo; Redhi, Godfrey H; Auber, Alessia; Secci, Maria E; Mascia, Paola; Bandiera, Tiziano; Armirotti, Andrea; Bertorelli, Rosalia; Chefer, Svetlana I; Barnes, Chanel; Yasar, Sevil; Piomelli, Daniele; Goldberg, Steven R

    2015-01-01

    Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose–response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell—consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement. PMID:25754762

  20. Halochromism, ionochromism, solvatochromism and density functional study of a synthesized copper(II) complex containing hemilabile amide derivative ligand

    NASA Astrophysics Data System (ADS)

    Golchoubian, Hamid; Moayyedi, Golasa; Reisi, Neda

    2015-03-01

    This study investigates chromotropism of newly synthesized 3,3‧-(ethane-1,2-diylbis(benzylazanediyl))dipropanamide copper(II) perchlorate complex. The compound was structurally characterized by physico-chemical and spectroscopic methods. X-ray crystallography of the complex showed that the copper atom achieved a distorted square pyramidal environment through coordination of two amine N atoms and two O atoms of the amide moieties. The pH effect on the visible absorption spectrum of the complex was studied which functions as pH-induced "off-on-off" switches through protonation and deprotonation of amide moieties along with the Cusbnd O to Cusbnd N bond rearrangement at room temperature. The complex was also observed to show solvatochromism and ionochromism. The distinct solution color changes mainly associated with hemilability of the amide groups. The solvatochromism of the complex was investigated with different solvent parameter models using stepwise multiple linear regression method. The results suggested that the basicity power of the solvent has a dominant contribution to the shift of the d-d absorption band of the complex. Density functional theory, DFT calculations were performed in order to study the electronic structure of the complex, the relative stabilities of the Cusbnd N/Cusbnd O isomers, and to understand the nature of the halochromism processes taking place. DFT computational results buttressed the experimental observations indicating that in the natural pH (5.8) the Cusbnd O isomer is more stable than its linkage isomer and conversely in alkaline aqueous solution.

  1. The Effect of the Amide Substituent on the Biodistribution and Tolerance of Lanthanide(III) DOTA-Tetraamide Derivatives

    PubMed Central

    Woods, Mark; Caravan, Peter; Geraldes, Carlos F. G. C.; Greenfield, Matthew T.; Kiefer, Garry E.; Lin, Mai; McMillan, Kenneth; Prata, M. Isabel M.; Santos, Ana C.; Sun, Xiankai; Wang, Jufeng; Zhang, Shanrong; Zhao, Piyu; Sherry, A. Dean

    2009-01-01

    Objectives Recent advances in the design of MRI contrast agents have rendered the lanthanide complexes of DOTA-tetraamide ligands of considerable interest, both as responsive MR agents and paramagnetic chemical exchange saturation transfer agents. The potential utility of these complexes for in vivo applications is contingent upon them being well tolerated by the body. The purpose of this study was to examine how the nature of the amide substituent, and in particular its charge, affected the fate of these chelates postinjection. Materials and Methods Complexes of 6 DOTA-tetraamide ligands were prepared in which the nature of the amide substituent was systematically altered. The 6 ligands formed 3 series: a phosphonate series that included tri-cationic, mono-anionic, and polyanionic complexes; a carboxylate series made up of a tri-cationic complex and a mono-anionic complex; and lastly, a tri-cationic complex with an aromatic amide substituent. These complexes were labeled with an appropriate radioisotope, either 153Gd or 177Lu, and the biodistribution profiles in rats recorded 2 hours postinjection. Results Biodistribution profiles were initially acquired at low doses to minimize adverse effects. All the complexes studied were found to be excreted primarily through the renal system, with the majority of the dose being found in the urine. None of the complexes exhibited substantial uptake by bone, liver, and spleen, except for a complex with 4 phosphonate groups that exhibited significant bone targeting capabilities. Increasing the dose of each complex to that of a typical MR contrast agent was found to render all 3 tri-cationic complexes studied here acutely toxic. In contrast, no ill effects were observed after administration of similar doses of the corresponding anionic complexes. Conclusions The absence of uptake by the liver and spleen indicate that irrespective of the ligand structure and charge, these complexes are not prone to dissociation in vivo. This is

  2. Linear and cyclic aliphatic carboxamides of the Murchison meteorite: Hydrolyzable derivatives of amino acids and other carboxylic acids

    NASA Astrophysics Data System (ADS)

    Cooper, G. W.; Cronin, J. R.

    1995-03-01

    Analyses of fractionated aqueous extracts of the Murchison meteorite by gas chromatographymass spectrometry after silylation with N-methyl-N ( tert-butyldimethylsilyl) trifluoroacetamide have revealed an extensive series of linear and cyclic aliphatic amides. These include monocarboxylic acid amides, dicarboxylic acid monoamides, hydroxy acid amides, lactams, carboxy lactams, lactims, N-acetyl amino acids, and substituted hydantoins. Numerous isomers and homologues through at least C 8 were observed in all cases, except for the N-acetyl amino acids and hydantoins. Carboxy lactams, lactams, hydantoins, and N-acetyl amino acids are converted to amino acids by acid hydrolysis, thus, these compounds qualitatively account for the earlier observation of acid-labile amino acid precursors in meteoritic extracts. Laboratory studies of the spontaneous decomposition of N-carbamyl-α-amino acids and their dehydration products, the 5-substituted hydantoins, have led to the recognition of a series of aqueous phase reactions by which amino acids and cyanic acid/cyanate ion in the primitive parent body might have given rise to several of the observed classes of amides, as well as to monocarboxylic acids, dicarboxylic acids, and hydroxy acids. A previously undescribed reaction of 5-substituted hydantoins with cyanic acid/cyanate ion to give carboxamides of the 5-substituent groups was observed in the course of these studies. The presence of an extensive suite of amides in a CM chondrite appears to be consistent with the interstellar-parent body formation hypothesis for the organic compounds of these meteorites. The presence of carboxy lactams and lactams along with free amino acids suggests the possibility of further chemical evolution of meteorite amino acids by thermal polymerization. The cyclic amides, given their potential for hydrogen-bonded pair formation, might be considered candidate bases for a primitive sequence coding system.

  3. [Amides of creatine: perspectives of neuroprotection].

    PubMed

    Vlasov, T D; Chefu, S G; Baĭsa, A E; Leko, M V; Burov, S V; Veselkina, O S

    2011-07-01

    We evaluated the efficacy of derivatives of creatine and amino acids (CrAA) for decreasing cerebral injury in rats with transient middle cerebral artery occlusion (MCAO). Neuroprotective effects of amides of creatine and glycine (CrGlyOEt), phenylalanine (CrPheNH2), thyrosine (CrTyrNH2), and GABA (CrGABAOEt) were investigated. Brain injury was evaluated on day 2 after transient MCAO using a TTC staining of brain slices. Compared with the MCAO control group, all the CrAms showed decreased cerebral injury (p < 0.05). However CrPheNH2, CrTyrNH2, and CrGABAOEt were toxic after intravenous administration and investigated only after intraperitoneal injection. CrGlyOEt did not show any toxicity at dose of 1 mmol/kg. These data evidenced that creatinyl amides can represent promising candidates for the development of new drugs useful in brain ischemia treatment. PMID:21961295

  4. The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase

    PubMed Central

    Patel, Sachin; Wohlfeil, Eric R; Rademacher, David J; Carrier, Erica J; Perry, LaToya J; Kundu, Abhijit; Falck, J R; Nithipatikom, Kasem; Campbell, William B; Hillard, Cecilia J

    2003-01-01

    Propofol (2,6-diisopropylphenol) is widely used as a general anesthetic and for the maintenance of long-term sedation. We have tested the hypothesis that propofol alters endocannabinoid brain content and that this effect contributes to its sedative properties. A sedating dose of propofol in mice produced a significant increase in the whole-brain content of the endocannabinoid, N-arachidonylethanolamine (anandamide), when administered intraperitoneally in either Intralipid or emulphor-ethanol vehicles. In vitro, propofol is a competitive inhibitor (IC50 52 μM; 95% confidence interval 31, 87) of fatty acid amide hydrolase (FAAH), which catalyzes the degradation of anandamide. Within a series of propofol analogs, the critical structural determinants of FAAH inhibition and sedation were found to overlap. Other intravenous general anesthetics, including midazolam, ketamine, etomidate, and thiopental, do not affect FAAH activity at sedative-relevant concentrations. Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM. Pretreatment of mice with the CB1 receptor antagonist SR141716 (1 mg kg−1, i.p.) significantly reduced the number of mice that lost their righting reflex in response to propofol. Pretreatment of mice with the CB1 receptor agonist, Win 55212-2 (1 mg kg−1, i.p.), significantly potentiated the loss of righting reflex produced by propofol. These data indicate that CB1 receptor activity contributes to the sedative properties of propofol. These data suggest that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol and that FAAH could be a novel target for anesthetic development. PMID:12839875

  5. Binding and Inactivation Mechanism of a Humanized Fatty Acid Amide Hydrolase by [alpha]-Ketoheterocycle Inhibitors Revealed from Cocrystal Structures

    SciTech Connect

    Mileni, Mauro; Garfunkle, Joie; DeMartino, Jessica K.; Cravatt, Benjamin F.; Boger, Dale L.; Stevens, Raymond C.

    2010-08-17

    The cocrystal X-ray structures of two isomeric {alpha}-ketooxazole inhibitors (1 (OL-135) and 2) bound to fatty acid amide hydrolase (FAAH), a key enzymatic regulator of endocannabinoid signaling, are disclosed. The active site catalytic Ser241 is covalently bound to the inhibitors electrophilic carbonyl groups, providing the first structures of FAAH bound to an inhibitor as a deprotonated hemiketal mimicking the enzymatic tetrahedral intermediate. The work also offers a detailed view of the oxyanion hole and an exceptional 'in-action' depiction of the unusual Ser-Ser-Lys catalytic triad. These structures capture the first picture of inhibitors that span the active site into the cytosolic port providing new insights that help to explain FAAH's interaction with substrate leaving groups and their role in modulating inhibitor potency and selectivity. The role for the activating central heterocycle is clearly defined and distinguished from that observed in prior applications with serine proteases, reconciling the large electronic effect of attached substituents found unique to this class of inhibitors with FAAH. Additional striking active site flexibility is seen upon binding of the inhibitors, providing insights into the existence of a now well-defined membrane access channel with the disappearance of a spatially independent portion of the acyl chain-binding pocket. Finally, comparison of the structures of OL-135 (1) and its isomer 2 indicates that they bind identically to FAAH, albeit with reversed orientations of the central activating heterocycle, revealing that the terminal 2-pyridyl substituent and the acyl chain phenyl group provide key anchoring interactions and confirming the distinguishing role of the activating oxazole.

  6. Effect of cannabidiol on sepsis-induced motility disturbances in mice: involvement of CB receptors and fatty acid amide hydrolase.

    PubMed

    de Filippis, D; Iuvone, T; d'amico, A; Esposito, G; Steardo, L; Herman, A G; Pelckmans, P A; de Winter, B Y; de Man, J G

    2008-08-01

    Sepsis is an inflammatory condition that is associated with reduced propulsive gastrointestinal motility (ileus). A therapeutic option to treat sepsis is to promote intestinal propulsion preventing bacterial stasis, overgrowth and translocation. Recent evidence suggests that anti-oxidants improve sepsis-induced ileus. Cannabidiol, a non-psychotropic component of Cannabis sativa, exerts strong anti-oxidant and anti-inflammatory effects without binding to cannabinoid CB(1) or CB(2) receptors. Cannabidiol also regulates the activity of fatty acid amide hydrolase (FAAH) which is the main enzyme involved in endocannabinoid breakdown and which modulates gastrointestinal motility. Because of the therapeutic potential of cannabidiol in several pathologies, we investigated its effect on sepsis-induced ileus and on cannabinoid receptor and FAAH expression in the mouse intestine. Sepsis was induced by treating mice with lipopolysaccharides for 18 h. Sepsis led to a decrease in gastric emptying and intestinal transit. Cannabidiol further reduced gastrointestinal motility in septic mice but did not affect gastrointestinal motility in control mice. A low concentration of the CB(1) antagonist AM251 did not affect gastrointestinal motility in control mice but reversed the effect of cannabidiol in septic mice. Sepsis was associated with a selective upregulation of intestinal CB(1) receptors without affecting CB(2) receptor expression and with increased FAAH expression. The increase in FAAH expression was completely reversed by cannabidiol but not affected by AM251. Our results show that sepsis leads to an imbalance of the endocannabinoid system in the mouse intestine. Despite its proven anti-oxidant and anti-inflammatory properties, cannabidiol may be of limited use for the treatment of sepsis-induced ileus. PMID:18373655

  7. Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase.

    PubMed

    Sadovski, Oleg; Hicks, Justin W; Parkes, Jun; Raymond, Roger; Nobrega, José; Houle, Sylvain; Cipriano, Mariateresa; Fowler, Christopher J; Vasdev, Neil; Wilson, Alan A

    2013-07-15

    Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an (18)F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [(18)F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [(18)F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [(18)F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [(18)F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [(18)F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding. PMID:23712084

  8. Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode

    PubMed Central

    Deplano, Alessandro; Smaldone, Giovanni; Pedone, Emilia; Luque, F. Javier; Svensson, Mona; Novellino, Ettore; Congiu, Cenzo; Onnis, Valentina; Catalanotti, Bruno; Fowler, Christopher J.

    2015-01-01

    Background Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here. Methodology/Principal Findings FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAHT488A-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)- and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 μM, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 μM) was more potent than the (R)-enantiomer (IC50 5.7 μM). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH. Conclusions/Significance The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors. PMID:26565710

  9. Evaluation of ascorbic acid in protecting labile folic acid derivatives.

    PubMed Central

    Wilson, S D; Horne, D W

    1983-01-01

    The use of ascorbic acid as a reducing agent to protect labile, reduced derivatives of folic acid has been evaluated by high-performance liquid chromatographic separations and Lactobacillus casei microbiological assay of eluate fractions. Upon heating for 10 min at 100 degrees C, solutions of tetrahydropteroylglutamic acid (H4PteGlu) in 2% sodium ascorbate gave rise to 5,10-methylene-H4PteGlu and 5-methyl-H4PteGlu. H2PteGlu acid gave rise to 5-methyl-H4PteGlu and PteGlu. 10-Formyl-H4PteGlu gave rise to 5-formyl-H4PteGlu and 10-formyl-PteGlu. 5-Formyl-H4-PteGlu gave rise to a small amount of 10-formyl-PteGlu. 5-Methyl-H4PteGlu and PteGlu appeared stable to these conditions. These interconversions were not seen when solutions of these folate derivatives were kept at 0 degrees C in 1% ascorbate. These observations indicate that elevated temperatures are necessary for the interconversions of folates in ascorbate solutions. Assays of ascorbic acid solutions indicated the presence of formaldehyde (approximately equal to 6 mM). This was confirmed by the identification of 3,5-diacetyl-1,4-dihydrolutidine by UV, visible, and fluorescence spectroscopy and by thin-layer chromatography of chloroform extracts of the reaction mixture of ascorbic acid solutions, acetylacetone, and ammonium acetate. These results indicate that solutions of sodium ascorbate used at elevated temperatures are not suitable for extracting tissue for the subsequent assay of the individual folic acid derivatives. PMID:6415653

  10. Fatty Acid Amide Hydrolase-Dependent Generation of Antinociceptive Drug Metabolites Acting on TRPV1 in the Brain

    PubMed Central

    Blomgren, Anders; Simonsen, Charlotte; Daulhac, Laurence; Libert, Frédéric; Chapuy, Eric; Etienne, Monique; Högestätt, Edward D.; Zygmunt, Peter M.; Eschalier, Alain

    2013-01-01

    The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol’s antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z-octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively. The order of potency of these lipid metabolites as TRPV1 activators was arvanil = olvanil>>AM404> HPODA. Both 4-aminophenol and HMBA displayed antinociceptive activity in various rodent pain tests. The formation of AM404, arvanil and olvanil, but not HPODA, and the antinociceptive effects of 4-aminophenol and HMBA were substantially reduced or disappeared in FAAH null mice. The activity of 4-aminophenol in the mouse formalin, von Frey and tail immersion tests was also lost in TRPV1 null mice. Intracerebroventricular injection of the TRPV1 blocker capsazepine eliminated the antinociceptive effects of 4-aminophenol and HMBA in the mouse formalin test. In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol’s analgesic activity via activation

  11. Zinc(II) complexes with heterocyclic ether, acid and amide. Crystal structure, spectral, thermal and antibacterial activity studies

    NASA Astrophysics Data System (ADS)

    Jabłońska-Wawrzycka, Agnieszka; Rogala, Patrycja; Czerwonka, Grzegorz; Hodorowicz, Maciej; Stadnicka, Katarzyna

    2016-02-01

    The reaction of zinc salts with heterocyclic ether (1-ethoxymethyl-2-methylimidazole (1-ExMe-2-MeIm)), acid (pyridine-2,3-dicarboxylic acid (2,3-pydcH2)) and amide (3,5-dimethylpyrazole-1-carboxamide (3,5-DMePzCONH2)) yielded three new zinc complexes formulated as [Zn(1-ExMe-2-MeIm)2Cl2] 1, fac-[Zn(H2O)6][Zn(2,3-pydcH)3]22 and [Zn(3,5-DMePz)2(NCO)2] 3. Complexes of 1 and 3 are four-coordinated with a tetrahedron as coordination polyhedron. However, compound 2 forms an octahedral cation-anion complex. The complex 3 was prepared by eliminating of the carboxamide group from the ligand and then the 3,5-dimethylpyrazole (3,5-DMePz) and isocyanates formed were employed as new ligands. The IR and X-ray studies have confirmed a bidentate fashion of coordination of the 2,3-pydcH and monodentate fashion of coordination of the 1-ExMe-2-MeIm and 3,5-DMePz to the Zn(II) ions. The crystal packing of Zn(II) complexes are stabilized by intermolecular classical hydrogen bonds of O-H⋯O and N-H⋯O types. The most interesting feature of the supramolecular architecture of complexes is the existence of C-H⋯O, C-H⋯Cl and C-H⋯π interactions and π⋯π stacking, which also contributes to structural stabilisation. The correlation between crystal structure and thermal stability of zinc complexes is observed. In all compounds the fragments of ligands donor-atom containing go in the last steps. Additionally, antimicrobial activities of compounds were carried out against certain Gram-positive and Gram-negative bacteria and counts of CFU (colony forming units) were also determined. The achieved results confirmed a significant antibacterial activity of some tested zinc complexes. On the basis of the Δ log CFU values the antibacterial activity of zinc complexes follows the order: 3 > 2 > 1. Influence a number of N-donor atoms in zinc environment on antibacterial activity is also observed.

  12. Simultaneous Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Shares Discriminative Stimulus Effects with Δ9-Tetrahydrocannabinol in Mice

    PubMed Central

    Hruba, Lenka; Seillier, Alexandre; Zaki, Armia; Cravatt, Benjamin F.; Lichtman, Aron H.; Giuffrida, Andrea

    2015-01-01

    Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibitors exert preclinical effects indicative of therapeutic potential (i.e., analgesia). However, the extent to which MAGL and FAAH inhibitors produce unwanted effects remains unclear. Here, FAAH and MAGL inhibition was examined separately and together in a Δ9-tetrahydrocannabinol (Δ9-THC; 5.6 mg/kg i.p.) discrimination assay predictive of subjective effects associated with cannabis use, and the relative contribution of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the prefrontal cortex, hippocampus, and caudate putamen to those effects was examined. Δ9-THC dose-dependently increased Δ9-THC appropriate responses (ED50 value = 2.8 mg/kg), whereas the FAAH inhibitors PF-3845 [N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide] and URB597 [(3′-​(aminocarbonyl)[1,​1′-​biphenyl]-​3-​yl)-​cyclohexylcarbamate] or a MAGL inhibitor JZL184 [4-​nitrophenyl-​4-​(dibenzo[d][1,​3]dioxol-​5-​yl(hydroxy)methyl)piperidine-​1-​carboxylate] alone did not substitute for the Δ9-THC discriminative stimulus. The nonselective FAAH/MAGL inhibitors SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] and JZL195 [4-​nitrophenyl 4-​(3-​phenoxybenzyl)piperazine-​1-​carboxylate] fully substituted for Δ9-THC with ED50 values equal to 2.4 and 17 mg/kg, respectively. Full substitution for Δ9-THC was also produced by a combination of JZL184 and PF-3845, but not by a combination of JZL184 and URB597 (i.e., 52% maximum). Cannabinoid receptor type 1 antagonist rimonabant attenuated the discriminative stimulus effects of Δ9-THC, SA-57, JZL195, and the combined effects of JZL184 and PF-3845. Full substitution for the Δ9-THC discriminative stimulus occurred only when both 2-AG and AEA were significantly elevated, and the patterns of increased endocannabinoid content were

  13. Antidepressant activity of aspartic acid derivatives.

    PubMed

    Petrov, V I; Sergeev, V S; Onishchenko, N V; Piotrovskii, L B

    2001-04-01

    Antidepressant activity of N-phenyl(benzyl)amino derivatives of aspartic acid was studied on various experimental models of depression. IEM-1770 (30 mg/kg) and IEM-1944 (20 mg/kg) exhibited antidepressant activity after single injection in the forced swimming and tail suspension tests. Antidepressant effect of 14-day administration of these compounds and reference drugs maprotiline (10 mg/kg) and citalopram (10 mg/kg) was confirmed on the model of learned helplessness. PMID:11550022

  14. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  15. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  16. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  17. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and...

  18. Immobilization of alpha-[di-(beta-chloroethyl)-amide]-N-(m-nitrobenzoyl)-D,L-asparagic acid on xanthan.

    PubMed

    Marcel, Popa; Lăcrămioara, Bălăită Rusu; Valeriu, Sunel

    2003-10-01

    The paper studies the coupling reaction, through ester-type covalent bonds, of an oxazolone derived from the N-(m-nitrobenzoyl)-L-asparagic acid, the cycle of which is opened with an N-mustard derivative, on xanthan (a polysaccharide of microbian synthesis), in conditions of activation with dicyclohexyl carbodiimide. The coupling product has been characterized through elemental analysis and IR spectroscopy. For the establishment of the capacity of the active principle's controlled release by the polymer-active principle system thus obtained, active principle's release kinetics from the polysaccharide support, in conditions of basic hydrolysis, is studied. In vivo tests realized on mice proved the antitumoral activity of the compounds resulted by chemical bonding of the N-mustard derivative on xanthan. PMID:14621335

  19. Caffeic acid phenethyl amide improves glucose homeostasis and attenuates the progression of vascular dysfunction in Streptozotocin-induced diabetic rats

    PubMed Central

    2013-01-01

    Background Glucose intolerance and cardiovascular complications are major symptoms in patients with diabetes. Many therapies have proven beneficial in treating diabetes in animals by protecting the cardiovascular system and increasing glucose utilization. In this study, we evaluated the effects of caffeic acid phenethyl amide (CAPA) on glucose homeostasis and vascular function in streptozotocin (STZ)-induced type 1 diabetic rats. Methods Diabetes (blood glucose levels > 350 mg/dL), was induced in Wistar rats by a single intravenous injection of 60 mg/kg STZ. Hypoglycemic effects were then assessed in normal and type 1 diabetic rats. In addition, coronary blood flow in Langendorff-perfused hearts was evaluated in the presence or absence of nitric oxide synthase (NOS) inhibitor. The thoracic aorta was used to measure vascular response to phenylephrine. Finally, the effect of chronic treatment of CAPA and insulin on coronary artery flow and vascular response to phenylephrine were analyzed in diabetic rats. Results Oral administration of 0.1 mg/kg CAPA decreased plasma glucose in normal (32.9 ± 2.3% decrease, P < 0.05) and diabetic rats (11.8 ± 5.5% decrease, P < 0.05). In normal and diabetic rat hearts, 1–10 μM CAPA increased coronary flow rate, and this increase was abolished by 10 μM NOS inhibitor. In the thoracic aorta, the concentration/response curve of phenylephrine was right-shifted by administration of 100 μM CAPA. Coronary flow rate was reduced to 7.2 ± 0.2 mL/min at 8 weeks after STZ-induction. However, 4 weeks of treatment with CAPA (3 mg/kg, intraperitoneal, twice daily) started at 4 weeks after STZ induction increased flow rate to 11.2 ± 0.5 mL/min (P < 0.05). In addition, the contractile response induced by 1 μM phenylephrine increased from 6.8 ± 0.6 mN to 11.4 ± 0.4 mN (P < 0.05) and 14.9 ± 1.4 mN (P < 0.05) by insulin (1 IU/kg, intraperitoneal) or CAPA treatment, respectively. Conclusions CAPA induced hypoglycemic activity, increased

  20. Synthesis of Glycosyl Amides Using Selenocarboxylates as Traceless Reagents for Amide Bond Formation.

    PubMed

    Silva, Luana; Affeldt, Ricardo F; Lüdtke, Diogo S

    2016-07-01

    Carbohydrate-derived amides were successfully prepared in good yields from a broad range of substrates, including furanosyl and pyranosyl derivatives. The methodology successfully relied on the in situ generation of lithium selenocarboxylates from Se/LiEt3BH and acyl chlorides or carboxylic acids and their reaction with sugar azides. A key aspect of the present protocol is that we start from elemental selenium; isolation and handling of all reactive and sensitive selenium-containing intermediates is avoided, therefore providing the selenocarboxylate the status of a traceless reagent. PMID:27275515

  1. Structure-activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps.

    PubMed

    Sundermann, Tom; Hanekamp, Walburga; Lehr, Matthias

    2016-08-01

    Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are serine hydrolases. cPLA2α is involved in the generation of pro-inflammatory lipid mediators, FAAH terminates the anti-inflammatory effects of endocannabinoids. Therefore, inhibitors of these enzymes may represent new drug candidates for the treatment of inflammation. We have reported that certain 1-heteroarylpropan-2-ones are potent inhibitors of cPLA2α and FAAH. The serine reactive ketone group of these compounds, which is crucial for enzyme inhibition, is readily metabolized resulting in inactive alcohol derivatives. In order to obtain metabolically more stable inhibitors, we replaced this moiety by α-ketoheterocyle, cyanamide and nitrile serine traps. Investigations on activity and metabolic stability of these substances revealed that in all cases an increased metabolic stability was accompanied by a loss of inhibitory potency against cPLA2α and FAAH, respectively. PMID:26153239

  2. Aminocarbonylation of 4-iodo-1H-imidazoles with an amino acid amide nucleophile: synthesis of constrained H-Phe-Phe-NH2 analogues.

    PubMed

    Skogh, Anna; Fransson, Rebecca; Sköld, Christian; Larhed, Mats; Sandström, Anja

    2013-12-01

    A simple and an expedient process to prepare 5-aryl-1-benzyl-1H-imidazole-4-carboxamides by the aminocarbonylation of 5-aryl-4-iodo-1H-imidazoles using ex situ generation of CO from Mo(CO)6 with an amino acid amide nucleophile is reported. Furthermore, a microwave-assisted protocol for the direct C-5 arylation of 1-benzyl-1H-imidazole and a regioselective C-4 iodination method to acquire starting material for our aminocarbonylation are presented. The method can be used to prepare imidazole based peptidomimetics, herein exemplified by the synthesis of constrained H-Phe-Phe-NH2 analogues. PMID:24171628

  3. Amide bond direction modulates G-quadruplex recognition and telomerase inhibition by 2,6 and 2,7 bis-substituted anthracenedione derivatives.

    PubMed

    Zagotto, Giuseppe; Sissi, Claudia; Moro, Stefano; Dal Ben, Diego; Parkinson, Gary N; Fox, Keith R; Neidle, Stephen; Palumbo, Manlio

    2008-01-01

    G-quadruplex structures of DNA represent a potentially useful target for anticancer drugs. Stabilisation of this arrangement at the ends of chromosomes may inhibit the action of telomerase, an enzyme involved in immortalization of cancer cells. Appropriately substituted amido anthracenediones are effective G-quadruplex stabilizers, but no information is available as yet on the possible modulation of G-quadruplex recognition and telomerase inhibition produced by the direction of the amide bond. To understand the basis of amido anthracenedione selectivity, we have synthesized a number of derivatives bearing the -CO-NH- or -NH-CO- group linked to the planar anthraquinone (AQ) moiety at 2,6 and 2,7 positions. The various isomers were tested in terms of telomerase inhibition, determined by the TRAP assay, G-quadruplex stabilisation measured by the increase in melting temperature of the appropriately folded oligonucleotide using FRET, and conformational and G4 binding properties examined by molecular modelling techniques. In all cases, enzymatic inhibition and G-quadruplex stabilization were directly related, which strongly supports the proposed molecular mechanism of telomerase interference. Interestingly, the AQ-NH-CO- arrangement performs invariantly better than the AQ-CO-NH- arrangement, showing a clear preference among isomeric derivatives. Theoretical calculations suggest that the former amide arrangement is co-planar with the aromatic system, whereas the latter is tilted by about 30 degrees when considering the most stable conformation. A more extended planar surface would allow more efficient stacking interactions with the quadruplex structure, hence more effective telomerase inhibition. PMID:17936629

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

    PubMed

    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. PMID:26988305

  5. Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors.

    PubMed

    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

    2013-07-25

    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

  6. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  7. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  8. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  9. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  10. 40 CFR 721.6097 - Phosphoric acid derivative (generic name).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphoric acid derivative (generic... Specific Chemical Substances § 721.6097 Phosphoric acid derivative (generic name). (a) Chemical substance... phosphoric acid derivative (PMN P-95-284) is subject to reporting under this section for the significant...

  11. Novel endogenous N-acyl amides activate TRPV1-4 receptors, BV-2 microglia, and are regulated in brain in an acute model of inflammation

    PubMed Central

    Raboune, Siham; Stuart, Jordyn M.; Leishman, Emma; Takacs, Sara M.; Rhodes, Brandon; Basnet, Arjun; Jameyfield, Evan; McHugh, Douglas; Widlanski, Theodore; Bradshaw, Heather B.

    2014-01-01

    A family of endogenous lipids, structurally analogous to the endogenous cannabinoid, N-arachidonoyl ethanolamine (Anandamide), and called N-acyl amides have emerged as a family of biologically active compounds at TRP receptors. N-acyl amides are constructed from an acyl group and an amine via an amide bond. This same structure can be modified by changing either the fatty acid or the amide to form potentially hundreds of lipids. More than 70 N-acyl amides have been identified in nature. We have ongoing studies aimed at isolating and characterizing additional members of the family of N-acyl amides in both central and peripheral tissues in mammalian systems. Here, using a unique in-house library of over 70 N-acyl amides we tested the following three hypotheses: (1) Additional N-acyl amides will have activity at TRPV1-4, (2) Acute peripheral injury will drive changes in CNS levels of N-acyl amides, and (3) N-acyl amides will regulate calcium in CNS-derived microglia. Through these studies, we have identified 20 novel N-acyl amides that collectively activate (stimulating or inhibiting) TRPV1-4. Using lipid extraction and HPLC coupled to tandem mass spectrometry we showed that levels of at least 10 of these N-acyl amides that activate TRPVs are regulated in brain after intraplantar carrageenan injection. We then screened the BV2 microglial cell line for activity with this N-acyl amide library and found overlap with TRPV receptor activity as well as additional activators of calcium mobilization from these lipids. Together these data provide new insight into the family of N-acyl amides and their roles as signaling molecules at ion channels, in microglia, and in the brain in the context of inflammation. PMID:25136293

  12. Metallo-beta-lactamase inhibitory activity of phthalic acid derivatives.

    PubMed

    Hiraiwa, Yukiko; Morinaka, Akihiro; Fukushima, Takayoshi; Kudo, Toshiaki

    2009-09-01

    4-Butyl-3-methylphthalic acid was recognized as a metallo-beta-lactamase inhibitor. The structure-activity relationship study of substituted phthalic acids afforded 3-phenylphthalic acid derivatives as potent IMP-1 inhibitors. On the other hand, 3-substituted with 4-hydroxyphenyl phthalic acid derivative displayed a potent combination effect with biapenem (BIPM) against Pseudomonas aeruginosa that produce IMP-1. PMID:19632114

  13. Antiparasitic evaluation of betulinic acid derivatives reveals effective and selective anti-Trypanosoma cruzi inhibitors.

    PubMed

    Meira, Cássio Santana; Barbosa-Filho, José Maria; Lanfredi-Rangel, Adriana; Guimarães, Elisalva Teixeira; Moreira, Diogo Rodrigo Magalhães; Soares, Milena Botelho Pereira

    2016-07-01

    Betulinic acid is a pentacyclic triterpenoid with several biological properties already described, including antiparasitic activity. Here, the anti-Trypanosoma cruzi activity of betulinic acid and its semi-synthetic amide derivatives (BA1-BA8) was investigated. The anti-Trypanosoma cruzi activity and selectivity were enhanced in semi-synthetic derivatives, specially on derivatives BA5, BA6 and BA8. To understand the mechanism of action underlying betulinic acid anti-T. cruzi activity, we investigated ultrastructural changes by electron microscopy. Ultrastructural studies showed that trypomastigotes incubated with BA5 had membrane blebling, flagella retraction, atypical cytoplasmic vacuoles and Golgi cisternae dilatation. Flow cytometry analysis showed that parasite death is mainly caused by necrosis. Treatment with derivatives BA5, BA6 or BA8 reduced the invasion process, as well as intracellular parasite development in host cells, with a potency and selectivity similar to that observed in benznidazole-treated cells. More importantly, the combination of BA5 and benznidazole revealed synergistic effects on trypomastigote and amastigote forms of T. cruzi. In conclusion, we demonstrated that BA5 compound is an effective and selective anti-T. cruzi agent. PMID:27080160

  14. Structure-property relationships of a class of carbamate-based Fatty Acid Amide Hydrolase (FAAH) inhibitors: chemical and biological stability

    PubMed Central

    Vacondio, Federica; Silva, Claudia; Lodola, Alessio; Fioni, Alessandro; Rivara, Silvia; Duranti, Andrea; Tontini, Andrea; Sanchini, Silvano; Clapper, Jason; Piomelli, Daniele; Tarzia, Giorgio

    2012-01-01

    Cyclohexylcarbamic acid aryl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which includes the reference compound URB597. The reactivity of their carbamate fragment is involved in pharmacological activity and may affect pharmacokinetic and toxicological properties. We conducted in vitro stability experiments in chemical and biological environments to investigate the structure-stability relationships in this class of compounds. The results show that electrophilicity of the carbamate influences its chemical stability, as suggested by the relation between the rate constant of alkaline hydrolysis (log kpH9) and the energy of lowest unoccupied molecular orbital (LUMO). Introduction of small, electron donor substituents at conjugated positions of the O-aryl moiety increased overall hydrolytic stability of the carbamate group without affecting FAAH inhibitory potency, whereas peripheral nonconjugated hydrophilic groups, which favor FAAH recognition, helped reducing oxidative metabolism in the liver. PMID:19554599

  15. A two-step approach to achieve secondary amide transamidation enabled by nickel catalysis

    PubMed Central

    Baker, Emma L.; Yamano, Michael M.; Zhou, Yujing; Anthony, Sarah M.; Garg, Neil K.

    2016-01-01

    A long-standing challenge in synthetic chemistry is the development of the transamidation reaction. This process, which involves the conversion of one amide to another, is typically plagued by unfavourable kinetic and thermodynamic factors. Although some advances have been made with regard to the transamidation of primary amide substrates, secondary amide transamidation has remained elusive. Here we present a simple two-step approach that allows for the elusive overall transformation to take place using non-precious metal catalysis. The methodology proceeds under exceptionally mild reaction conditions and is tolerant of amino-acid-derived nucleophiles. In addition to overcoming the classic problem of secondary amide transamidation, our studies expand the growing repertoire of new transformations mediated by base metal catalysis. PMID:27199089

  16. Scanning Tunneling Imaging of Bio-Organic Molecules and Their Tunneling Properties: Fatty Acids, Their Derivatives and Cholesteryl Stearate

    NASA Astrophysics Data System (ADS)

    Yoshimura, Kousei; Arakawa, Hideo; Ikai, Atsushi

    1995-06-01

    Scanning tunneling microscopy imaging was applied to long-chain fatty acids, their derivatives and cholesteryl stearate in the adsorbed state at the liquid-solid interface between phenyloctane and highly oriented pyrolytic graphite. Cerotic acid, lignoceric acid, stearic acid, sodium stearate, stearoyl amide, and stearoyl anilide all produced regular arrays of dark and bright bands. Bright bands in the images of all execept the last compound were assigned as side-by-side alignment of hydrocarbon chains based on the variation of the band width between the three fatty acids. In the case of stearoyl anilide, the bright part was assigned to aromatic ring structure and the wider dark area to the hydrocarbon part.

  17. Synthesis, structural, conformational and pharmacological study of some amides derived from 3 -methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9α-amine

    NASA Astrophysics Data System (ADS)

    Iriepa, I.; Bellanato, J.; Gálvez, E.; Gil-Alberdi, B.

    2010-07-01

    Some mono-substituted amides ( 2- 5) derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9α-amine were synthesized and studied by IR, 1H and 13C NMR spectroscopy. The crystal structure of 3-methyl-2,4-diphenyl-9α-(3,5-dichlorobenzamido)-3-azabicyclo[3.3.1]nonane ( 3) was determined by X-ray diffraction. NMR data showed that all compounds adopt in CDCl 3 a preferred flattened chair-chair conformation with the N-CH 3 group in equatorial disposition. X-ray data agreed with this conformation in the case of compound 3. IR data revealed that compounds 2 and 3 present a C dbnd O⋯HN intermolecular bond in the solid state. This conclusion was also confirmed by X-ray data of compound 3. In the case of compound 5, IR results suggested intermolecular NH⋯N-heterocyclic bonding. On the contrary, in the pyrazine derivative ( 4), IR, 1H and 13C NMR data showed the presence of an intramolecular NH⋯N1″-heterocyclic hydrogen bond in the solid state and solution. Moreover, NMR and IR data showed a preferred trans disposition for the NH-C dbnd O group. NMR also revealed free rotation of the -NH-CO-R group around C9-NH bond. Pharmacological assays on mice were drawn to evaluate analgesic activity.

  18. Synthesis and Anchoring of Antineoplastic Ferrocene and Phthalocyanine Derivatives on Water-Soluble Polymeric Drug Carriers Derived from Lysine and Aspartic Acid

    PubMed Central

    Maree, M. David; Neuse, Eberhard W.; Erasmus, Elizabeth; Swarts, Jannie C.

    2008-01-01

    The general synthetic strategy towards water-soluble biodegradable drug carriers and the properties that they must have are discussed. The syntheses of water-soluble biodegradable copolymers of lysine and aspartic acid as potential drug-delivering devices, having amine-functionalised side chains are then described. Covalent anchoring of carboxylic acid derivatives of the antineoplastic ferrocene and photodynamically active phthalocyanine moieties to the amine-containing drug carrier copolymers under mild coupling conditions has been achieved utilising the coupling reagent O-benzotriazolyl-N,N,N′,N′-tetramethyluronium hexafluorophosphate to promote formation of the biodegradable amide bond. Even though the parent antineoplastic ferrocene and phthalocyanine derivatives are themselves insoluble in water at pH < 7, the new carrier-drug conjugates that were obtained are well water-soluble. PMID:18288243

  19. Microbiological degradation of bile acids. Nitrogenous hexahydroindane derivatives formed from cholic acid by Streptomyces rubescens.

    PubMed Central

    Hayakawa, S; Hashimoto, S; Onaka, T

    1976-01-01

    The metabolism of cholic acid (I) by Streptomyces rubescens was investigated. This organism effected ring A cleavage, side-chain shortening and amide bond formation and gave the following metabolites: (4R)-4-[4alpha-(2-carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1 beta-yl]valeric acid (IIa) and its mono-amide (valeramide) (IIb); and 2,3,4,6, 6abeta,7,8,9,9aalpha,9bbeta-decahydro-6abeta-methyl-1H-cyclopenta[f]quinoline-3,7-dione(IIIe)and its homologues with the beta-oriented side chains, valeric acid, valeramide, butanone and propionic acid, in the place of the oxo group at C-7, i.e.compounds (IIIa), (IIIb), (IIIc) and (IIId) respectively. All the nitrogenous metabolites were new compounds, and their structures were established by partial synthesis except for the metabolite (IIIc). The mechanism of formation of these metabolites is considered. A degradative pathway of cholic acid (I) into the metabolites is also tentatively proposed. PMID:1016253

  20. Caffeic acid derivatives in the roots of yacon (Smallanthus sonchifolius).

    PubMed

    Takenaka, Makiko; Yan, Xiaojun; Ono, Hiroshi; Yoshida, Mitsuru; Nagata, Tadahiro; Nakanishi, Tateo

    2003-01-29

    Five caffeic acid derivatives were found in the roots of yacon, Smallanthus sonchifolius (Poepp. and Endl.) H. Robinson, Asteraceae, as the major water-soluble phenolic compounds. The structures of these compounds were determined by analysis of spectroscopic data. Two of these were chlorogenic acid (3-caffeoylquinic acid) and 3,5-dicaffeoylquinic acid, common phenolic compounds in plants of the family Asteraceae. Three were esters of caffeic acid with the hydroxy groups of aldaric acid, derived from hexose. The structure of the aldaric moiety was determined by hydrolysis and comparison of NMR spectra with those of standard aldaric acids. The compounds were novel caffeic acid esters of altraric acid: 2,4- or 3,5-dicaffeoylaltraric acid, 2,5-dicaffeoylaltraric acid, and 2,3,5- or 2,4,5-tricaffeoylaltraric acid. PMID:12537459

  1. Synthesis and characterization of new optically active poly(amide-imide)s derived from N,N'-(pyromellitoyl) bis-L-tyrosine and various diamines

    NASA Astrophysics Data System (ADS)

    Khalaf, H. I.; Wady, A. N.; Daham, H. K.

    2013-01-01

    Five new optically active poly(amide-imide)s(PAIs) 5a-e were prepared by direct polycondensation reaction of N,N'- (pyromellitoyl) bis-L-tyrosine 3 as chiral dicarboxylic acid with various aromatic diamines 4a-e. Triphenylphosphite(TPP)/pyridine(py) in the presence of calcium chloride (CaCl2) and N-methyl-2-pyrrolidone (NMP) were successfully applied to direct polycondensation reaction. The resulting new polymers were obtained in good yields with inherent viscosities ranging between 0.48 dL/g and 0.6 dL/g. They were analyzed with a C.H.N. elemental analyzer, FTIR, 1H-NMR, UV-VIS spectroscopy and polarimeter (specific rotation measurement, [α]{D/25}). Thermogravimetric analysis (TGA) indicated that the residual weight percentage of polymers at 600 °C were between 48.66 % and 64.21 %, which showed their thermal stability. These polymers are attractive to be used as packing materials in chromatography columns for separation of enantiomers.

  2. Optically active poly(amide-imide)/TiO2 nanocomposites containing amino acid moieties: synthesis and properties.

    PubMed

    Rafiee, Zahra; Zare, Elham

    2015-11-01

    The novel optically active poly(amide-imide) (PAI)/TiO2 nanocomposites containing fluorene moieties have been successfully synthesized through ultrasonic irradiation. The surface of nanoparticles was chemically modified with γ-aminopropyltriethoxyl silane to enhance the compatibility with polymeric matrix and to avoid the aggregation of nanoparticles. The dispersion of surface-modified TiO2 in PAI film was confirmed by the transmission electron microscope (TEM) analysis showing the well-dispersed nanosized TiO2 nanoparticles. The thermal stabilities and optical properties of PAI/surface-modified TiO2 nanocomposite films were also investigated. The thermogravimetric analysis data showed an improvement of thermal stability of novel nanocomposite films as compared to the pure polymer. PMID:26002811

  3. Quantitation of the area of overlap between second-derivative amide I infrared spectra to determine the structural similarity of a protein in different states.

    PubMed

    Kendrick, B S; Dong, A; Allison, S D; Manning, M C; Carpenter, J F

    1996-02-01

    Maintaining a native-like structure of protein pharmaceuticals during lyophilization is an important aspect of formulation. Infrared spectroscopy can be used to evaluate the effectiveness of formulations in protecting the secondary structural integrity of proteins in the dried solid. This necessitates making quantitative comparisons of the overall similarity of infrared spectra in the conformationally sensitive amide I region. We initially used the correlation coefficient r, as defined by Prestrelski et al. (Biophys. J. 1993, 65, 661-671), for this quantitation. Occasionally, we noticed that the r value did not agree with a visual assessment of the spectral similarity. In some cases this was due to an offset in baselines, which led artifactually to an unreasonably low r value. Conversely, if the spectra were baseline corrected and there existed a large similarity between peak positions, but differences in relative peak heights, the r value would be unreasonably high. Our approach to avoiding these problems is to use area-normalized second-derivative spectra. We have found that quantitating the area of overlap between area-normalized spectra provides a reliable, objective method to compare overall spectral similarity. In the current report, we demonstrate this method with selected protein spectra, which were taken from experiments where unfolding was induced by lyophilization or guanidine hydrochloride, and artificial data sets. With this analysis, we document how problems associated with calculation of the correlation coefficient, r, are avoided. PMID:8683440

  4. The fatty acid amide hydrolase C385A variant affects brain binding of the positron emission tomography tracer [11C]CURB

    PubMed Central

    Boileau, Isabelle; Tyndale, Rachel F; Williams, Belinda; Mansouri, Esmaeil; Westwood, Duncan J; Foll, Bernard Le; Rusjan, Pablo M; Mizrahi, Romina; De Luca, Vincenzo; Zhou, Qian; Wilson, Alan A; Houle, Sylvain; Kish, Stephen J; Tong, Junchao

    2015-01-01

    The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [11C]CURB ([11C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n=24) completed one [11C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [11C]CURB binding (λk3) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [11C]CURB measurement. PMID:26036940

  5. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage

    PubMed Central

    Sasso, Oscar; Migliore, Marco; Habrant, Damien; Armirotti, Andrea; Albani, Clara; Summa, Maria; Moreno-Sanz, Guillermo; Scarpelli, Rita; Piomelli, Daniele

    2015-01-01

    The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4 (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.—Sasso, O., Migliore, M., Habrant, D., Armirotti, A., Albani, C., Summa, M., Moreno-Sanz, G., Scarpelli, R., Piomelli, D. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage. PMID:25757568

  6. Synthesis of Hydroxymethylenebisphosphonic Acid Derivatives in Different Solvents.

    PubMed

    Nagy, Dávid Illés; Grün, Alajos; Garadnay, Sándor; Greiner, István; Keglevich, György

    2016-01-01

    The syntheses of hydroxymethylenebisphosphonic acid derivatives (dronic acid derivatives) starting from the corresponding substituted acetic acids and P-reagents, mainly phosphorus trichloride and phosphorous acid are surveyed according to the solvents applied. The nature of the solvent is a critical point due to the heterogeneity of the reaction mixtures. This review sheds light on the optimum choice and ratio of the P-reactants, and on the optimum conditions. PMID:27529200

  7. Effects of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor URB597 on Pain-Stimulated and Pain-Depressed Behavior in Rats

    PubMed Central

    Kwilasz, Andrew J.; Abdullah, Rehab A.; Poklis, Justin L.; Lichtman, Aron H.; Negus, S. Stevens

    2014-01-01

    Cannabinoid receptor (CBR) agonists produce antinociception in conventional preclinical assays of pain-stimulated behavior but are not effective in preclinical assays of pain-depressed behavior. Fatty acid amide hydrolase (FAAH) inhibitors increase physiological levels of the endocannabinoid anandamide (AEA), which may confer improved efficacy and/or safety relative to direct CBR agonists. To further evaluate FAAH inhibitors as candidate analgesics, this study assessed effects of the FAAH inhibitor URB597 in assays of acute pain-stimulated and pain-depressed behavior in male Sprague Dawley rats. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response or depress positively reinforced operant behavior (intracranial self-stimulation; ICSS), and URB597 was tested 1 and 4 h after administration. Consistent with FAAH inhibitor effects in other assays of pain-stimulated behavior, URB597 (1–10 mg/kg IP) produced dose-related and CB1R-mediated decreases in acid-stimulated stretching. Conversely, in the assay of acid-depressed ICSS, URB597 produced a delayed, partial and non-CBR-mediated antinociceptive effect. The antinociceptive dose of URB597 (10 mg/kg) increased plasma and brain AEA levels. These results suggest that URB597 produces antinociception in these models of “pain stimulated” and “pain depressed” behavior, but with different rates of onset and differential involvement of CBRs. PMID:24583930

  8. Quantum entanglement between amide-I and amide-site in Davydov-Scott model

    NASA Astrophysics Data System (ADS)

    Liang, Xian-Ting; Fan, Heng

    2014-01-01

    In this paper, we firstly derive non-Markovian operator Langevin equations of the Davydov monomer in its environment. Next, we replace the equations with the c-number quantum general Langevin equations (QGLEs) by calculating statistical and quantum averages of the operator Langevin equations. Then, by using the c-number QGLEs we investigate the evolutions of the subsystems amide-I and amide-site. The evolution of a parameter θ describing quantum entanglement of the coupling subsystems with continuous variable Hamiltonian has also been investigated. It is shown that there is certain entanglement between the amide-I and amide-site in the Davydov-Scott monomer.

  9. Polyhydroxy Fatty Acids Derived from Sophorolipids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Starting from 17-hydroxyoleic acid, which is readily available from acid alcoholysis of sophorolipids, several new polyhydroxy fatty acids have been synthesized. These compounds contain from 2 to 5 hydroxy groups, in some instances combined with other functional groups. The added hydroxy groups ca...

  10. Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense.

    PubMed

    Patrick, Donald A; Wenzler, Tanja; Yang, Sihyung; Weiser, Patrick T; Wang, Michael Zhuo; Brun, Reto; Tidwell, Richard R

    2016-06-01

    2-(2-Benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concentrations below 3.6μM and non-toxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compound 1 and 72 analogues were synthesized in this lab by one of two general pathways. These plus 10 commercially available analogues were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivatives were more potent than 1, including eight with IC50 values below 100nM. The most potent and most selective for the parasite was the urea analogue 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole (70, IC50=9nM, SI>18,000). None of 33 compounds tested were able to cure mice infected with the parasite; however, seven compounds caused temporary reductions of parasitemia (⩾97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogues against mouse and human liver microsomes. PMID:27102161

  11. 40 CFR 721.10410 - Polyether ester acid compound with a polyamine amide (generic) (P-05-714).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Polyether ester acid compound with a... Significant New Uses for Specific Chemical Substances § 721.10410 Polyether ester acid compound with a.... (1) The chemical substance identified generically as polyether ester acid compound with a...

  12. 40 CFR 721.10410 - Polyether ester acid compound with a polyamine amide (generic) (P-05-714).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Polyether ester acid compound with a... Significant New Uses for Specific Chemical Substances § 721.10410 Polyether ester acid compound with a.... (1) The chemical substance identified generically as polyether ester acid compound with a...

  13. 40 CFR 721.10410 - Polyether ester acid compound with a polyamine amide (generic) (P-05-714).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Polyether ester acid compound with a... Significant New Uses for Specific Chemical Substances § 721.10410 Polyether ester acid compound with a.... (1) The chemical substance identified generically as polyether ester acid compound with a...

  14. Synthesis and Structure–Activity Relationships of N-(2-Oxo-3-oxetanyl)amides as N-Acylethanolamine-hydrolyzing Acid Amidase Inhibitors

    PubMed Central

    Solorzano, Carlos; Antonietti, Francesca; Duranti, Andrea; Tontini, Andrea; Rivara, Silvia; Lodola, Alessio; Vacondio, Federica; Tarzia, Giorgio; Piomelli, Daniele; Mor, Marco

    2010-01-01

    The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator-activated receptor-α, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine-hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a a series of β-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC50 = 420 nM; 7h, IC50 = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo. PMID:20604568

  15. Crystal structures of two hydrazinecarbo­thio­amide derivatives: (E)-N-ethyl-2-[(4-oxo-4H-chromen-3-yl)methyl­idene]hydrazinecarbo­thio­amide hemi­hydrate and (E)-2-[(4-chloro-2H-chromen-3-yl)methyl­idene]-N-phenyl­hydrazinecarbo­thio­amide

    PubMed Central

    Gangadharan, Rajeswari; Haribabu, Jebiti; Karvembu, Ramasamy; Sethusankar, K.

    2015-01-01

    The title compounds, C13H13N3O2S·0.5H2O, (I), and C17H14ClN3OS, (II), are hydrazinecarbo­thio­amide derivatives. Compound (I) crystallizes with two independent mol­ecules (A and B) and a water mol­ecule of crystallization in the asymmetric unit. The chromene moiety is essentially planar in mol­ecules A and B, with maximum deviations of 0.028 (3) and 0.016 (3) Å, respectively, for the carbonyl C atoms. In (II), the pyran ring of the chromene moiety adopts a screw-boat conformation and the phenyl ring is inclined by 61.18 (9)° to its mean plane. In the crystal of (I), bifurcated N—H⋯O and C—H⋯O hydrogen bonds link the two independent mol­ecules forming A–B dimers with two R 2 1(6) ring motifs, and R 2 2(10) and R 2 2(14) ring motifs. In addition to these, the water mol­ecule forms tetra­furcated hydrogen bonds which alternately generate R 4 4(12) and R 6 6(22) graph-set ring motifs. There are also π–π [inter-centroid distances = 3.5648 (14) and 3.6825 (15) Å] inter­actions present, leading to the formation of columns along the c-axis direction. In the crystal of (II), mol­ecules are linked by pairs of N—H⋯S hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif. The dimers are linked by C—H⋯π inter­actions, forming ribbons lying parallel to (210). PMID:25844194

  16. Acetylcholinesterase inhibitory properties of some benzoic acid derivatives

    NASA Astrophysics Data System (ADS)

    Yildiz, Melike; Kiliç, Deryanur; Ünver, Yaǧmur; Şentürk, Murat; Askin, Hakan; Küfrevioǧlu, Ömer Irfan

    2016-04-01

    Acetylcholinesterase (AChE) hydrolyses the neurotransmitter acetylcholine to acetic acid and choline. AChE inhibitors are used in treatment of several neurodegeneartive disorder and Alzheimer's disease. In the present study, inhibition of AChE with some benzoic acid derivatives were investigated. 3-Chloro-benzoic acid (1), 2-hydroxy-5-sulfobenzoic acid (2), 2-(sulfooxy) benzoic acid (3), 2-hydroxybenzoic acid (4), 2,3-dimethoxybenzoic (5), and 3,4,5-trimethoxybenzoic (6) were calculated IC50 values AChE enzyme. Kinetic investigations showed that similarly to AChE inhibitors. Benzoic acid derivatives (1-6) investigated are encouraging agents which may be used as lead molecules in order to derivative novel AChE inhibitors that might be useful in medical applications.

  17. Reversed-phase high-performance liquid chromatographic separation of diastereomers of (R,S)-mexiletine prepared by microwave irradiation with four new chiral derivatizing reagents based on trichloro-s-triazine having amino acids as chiral auxiliaries and 10 others having amino acid amides.

    PubMed

    Bhushan, Ravi; Dixit, Shuchi

    2010-12-01

    A new series of chiral derivatizing reagents (CDRs) consisting of four dichloro-s-triazine reagents was synthesized by nucleophilic substitution of one chlorine atom in trichloro-s-triazine with amino acids, namely L-Leu, D-Phg, L-Val and L-Ala as chiral auxiliaries. Two other sets of CDRs consisting of four dichloro-s-triazine (DCT) and six monochloro-s-triazine (MCT) reagents were also prepared by nucleophilic substitution of chlorine atom(s) with different amino acid amides as chiral auxiliaries in trichloro-s-triazine and its 6-methoxy derivative, respectively. These 14 CDRs were used for the synthesis of diastereomers of (R,S)-mexiletine under microwave irradiation (i.e. 60s and 90 s at 85% power (of 800 W) using DCT and MCT reagents, respectively), which were resolved by reversed-phase high-performance liquid chromatography using C18 column and gradient eluting mixtures of methanol with aqueous trifluoroacetic acid (TFA) with UV detection at 230 nm. The resolution (R(s)), difference between retention times of resolved diastereomers (Δt) and retention factors (k) obtained for the three sets of diastereomers were compared among themselves and among the three groups. Explanations have been offered for longer retention times and better resolution of diastereomers prepared with DCT reagents in comparison of their MCT counterparts and, for the influence of hydrophobicity of the side chain R of the amino acid in the CDRs on retention times and resolution. The newly synthesized CDRs were observed to be superior as compared to their amide counterparts in terms of providing better resolution and cost effectiveness. The method was validated for limit of detection, linearity, accuracy and precision. PMID:21035811

  18. Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation.

    PubMed

    Bildziukevich, Uladzimir; Vida, Norbert; Rárová, Lucie; Kolář, Milan; Šaman, David; Havlíček, Libor; Drašar, Pavel; Wimmer, Zdeněk

    2015-08-01

    β-Sitosterol and betulinic acid were used in designing their conjugates with selected polyamines bearing either an amide bond, or an ester and an amide bond simultaneously in the target molecule. The synthesized compounds were subjected to basic cytotoxic and antimicrobial tests. The synthetic protocol is described separately for each of the three series of the target amides, because each series of compounds required a different synthetic approach. The cytotoxicity was tested on cells derived from human T-lymphoblastic leukemia, breast adenocarcinoma and cervical cancer, and compared with the tests on normal human fibroblasts. Most of the target compounds (5a-5c, 11a-11c and 16a-16c) showed medium to high cytotoxicity (0.7-7.8 μM), however, in some cases the compounds showed high cytotoxicity even toward normal human fibroblasts (11a-11c). Two compounds of this series (11c and 16c) also displayed antimicrobial activity with high and selective microbe specificity. The compound 11c was potent against Escherichia coli (minimal inhibition concentration (MIC) 6.25 μg mL(-1), i.e. 9.75 nM mL(-1)) and Staphylococcus aureus (MIC 12.5 μg mL(-1), i.e. 19.5 nM mL(-1)), and showed medium activity against Pseudomonas aeruginosa. The compound 16c was highly active against Enterococcus faecalis and S. aureus (both, MIC 3.125 μg mL(-1), i.e. 4.22 nM mL(-1)), both Gram-positive bacteria, however showed only weak activity against E. coli and no activity against P. aeruginosa, both Gram-negative bacteria, which indicates possible microbe specificity of 16c. Comparing β-sitosterol-based series (5a-5c) and betulinic acid series (11a-11c and 16a-16c) of the target compounds, the latter one gave more promising structures. The compounds 11c and 16c showed effects which may be described as multifarious activity (pleiotropic effects). PMID:25963549

  19. Effect of propane-2-sulfonic acid octadec-9-enyl-amide on the expression of adhesion molecules in human umbilical vein endothelial cells.

    PubMed

    Chen, Cai-Xia; Yang, Li-Chao; Xu, Xu-Dong; Wei, Xiao; Gai, Ya-Ting; Peng, Lu; Guo, Han; Hao-Zhou; Wang, Yi-Qing; Jin, Xin

    2015-06-01

    Oleoylethanolamide (OEA), an endogenous agonist of PPARα, has been reported to have anti-atherosclerotic properties. However, OEA can be enzymatically hydrolyzed to oleic acid and ethanolamine and, thus, is not expected to be orally active. In the present study, we designed and synthesized an OEA analog, propane-2-sulfonic acid octadec-9-enyl-amide (N15), which is resistant to enzymatic hydrolysis. The purpose of this study was to investigate the effects of N15 on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). The results showed that N15 inhibited TNFα-induced production of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and the adhesion of monocytes to TNFα-induced HUVECs. Furthermore, the protective effect of N15 on inflammation is dependent upon a PPAR-α/γ-mediated mechanism. In conclusion, N15 protects against TNFα-induced vascular endothelial inflammation. This anti-inflammatory effect of N15 is dependent on PPAR-α/γ dual targets. PMID:25797284

  20. Biomarkers of myeloperoxidase-derived hypochlorous acid.

    PubMed

    Winterbourn, C C; Kettle, A J

    2000-09-01

    Hypochlorous acid is the major strong oxidant generated by neutrophils. The heme enzyme myeloperoxidase catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride. Although myeloperoxidase has been implicated in the tissue damage that occurs in numerous diseases that involve inflammatory cells, it has proven difficult to categorically demonstrate that it plays a crucial role in any pathology. This situation should soon be rectified with the advent of sensitive biomarkers for hypochlorous acid. In this review, we outline the advantages and limitations of chlorinated tyrosines, chlorohydrins, 5-chlorocytosine, protein carbonyls, antibodies that recognize HOCl-treated proteins, and glutathione sulfonamide as potential biomarkers of hypochlorous acid. Levels of 3-chlorotyrosine and 3,5-dichlorotyrosine are increased in proteins after exposure to low concentrations of hypochlorous acid and we conclude that their analysis by gas chromatography and mass spectrometry is currently the best method available for probing the involvement of oxidation by myeloperoxidase in the pathology of particular diseases. The appropriate use of other biomarkers should provide complementary information.Keywords-Free radicals, Myeloperoxidase, Neutrophil oxidant, Hypochlorous acid, Chlorotyrosine, Chlorohydrin, Oxidant biomarker PMID:11020661

  1. Design of an Amide N-glycoside Derivative of β-Glucogallin: A Stable, Potent, and Specific Inhibitor of Aldose Reductase

    PubMed Central

    Li, Linfeng; Chang, Kun-Che; Zhou, Yaming; Shieh, Biehuoy; Ponder, Jessica; Abraham, Adedoyin D.; Ali, Hadi; Snow, Anson; Petrash, J. Mark; LaBarbera, Daniel V.

    2014-01-01

    β-glucogallin (BGG), a major component of the Emblica officinalis medicinal plant, is a potent and selective inhibitor of aldose-reductase (AKR1B1). New linkages (ether/triazole/amide) were introduced via high yielding, efficient syntheses to replace the labile ester, and an original 2-step (90%) preparation of BGG was developed. Inhibition of AKR1B1was assessed in vitro and using transgenic lens organ cultures, which identified the amide linked glucoside (BGA) as a stable, potent and selective lead therapeutic toward the treatment of diabetic eye disease. PMID:24341381

  2. Structural, conformational and pharmacological study of some amides derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9 β-amine as potential analgesics

    NASA Astrophysics Data System (ADS)

    Iriepa, I.; Gil-Alberdi, B.; Gálvez, E.; Herranz, M. J.; Bellanato, J.; Carmona, P.; Orjales, A.; Berisa, A.; Labeaga, L.

    1999-05-01

    A series of amides derived from 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9 β-amine were synthesized and studied by IR, Raman, 1H and 13C NMR spectroscopy. The compounds studied displayed in CDCl 3 a preferred flattened chair-chair conformation. IR (at room and variable temperature) and 1H and 13C NMR data showed the presence of an intramolecular NH⋯N-heterocyclic hydrogen bond in the pirazine derivative ( IV). Pharmacological assays on mice were drawn to evaluate drug-induced behavioral alteration peripheral or central acute toxicity and analgesic activity.

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

    PubMed

    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. PMID:22967461

  4. Sm(II)-Mediated Electron Transfer to Carboxylic Acid Derivatives: Development of Complexity-Generating Cascades.

    PubMed

    Just-Baringo, Xavier; Procter, David J

    2015-05-19

    exploited productively in efficient new processes. First, we have used internal directing groups in substrates to "switch on" productive ET to esters and amides and have exploited such an approach in tag-removal cyclization processes that deliver molecular scaffolds of significance in biology and materials science. Second, we have exploited external ligands to facilitate ET to carboxylic acid derivatives and have applied the strategy in telescoped reaction sequences. Finally, we have employed follow-up cyclizations with alkenes, alkynes, and allenes to intercept radical anion intermediates formed along the reaction path and have employed this strategy in complexity-generating cascade approaches to biologically significant molecular architectures. From our studies, it is now clear that Sm(II)-mediated ET to carboxylic acid derivatives constitutes a general strategy for inverting the polarity of the carbonyl, allowing nucleophilic carbon-centered radicals to be formed and exploited in novel chemical processes. PMID:25871998

  5. A 2:1 co-crystal of p-nitro­benzoic acid and N,N′-bis­(pyridin-3-ylmeth­yl)ethanedi­amide: crystal structure and Hirshfeld surface analysis

    PubMed Central

    Syed, Sabrina; Halim, Siti Nadiah Abdul; Jotani, Mukesh M.; Tiekink, Edward R. T.

    2016-01-01

    The title 2:1 co-crystal, 2C7H5NO4·C14H14N4O2, in which the complete di­amide mol­ecule is generated by crystallographic inversion symmetry, features a three-mol­ecule aggregate sustained by hydroxyl-O—H⋯N(pyrid­yl) hydrogen bonds. The p-nitro­benzoic acid mol­ecule is non-planar, exhibiting twists of both the carb­oxy­lic acid and nitro groups, which form dihedral angles of 10.16 (9) and 4.24 (4)°, respectively, with the benzene ring. The di­amide mol­ecule has a conformation approximating to a Z shape, with the pyridyl rings lying to either side of the central, almost planar di­amide residue (r.m.s. deviation of the eight atoms being 0.025 Å), and forming dihedral angles of 77.22 (6)° with it. In the crystal, three-mol­ecule aggregates are linked into a linear supra­molecular ladder sustained by amide-N—H⋯O(nitro) hydrogen bonds and orientated along [10-4]. The ladders are connected into a double layer via pyridyl- and benzene-C—H⋯O(amide) inter­actions, which, in turn, are connected into a three-dimensional architecture via π–π stacking inter­actions between pyridyl and benzene rings [inter-centroid distance = 3.6947 (8) Å]. An evaluation of the Hirshfeld surfaces confirm the importance of inter­molecular inter­actions involving oxygen atoms as well as the π–π inter­actions. PMID:26870591

  6. A 2:1 co-crystal of p-nitro-benzoic acid and N,N'-bis-(pyridin-3-ylmeth-yl)ethanedi-amide: crystal structure and Hirshfeld surface analysis.

    PubMed

    Syed, Sabrina; Halim, Siti Nadiah Abdul; Jotani, Mukesh M; Tiekink, Edward R T

    2016-01-01

    The title 2:1 co-crystal, 2C7H5NO4·C14H14N4O2, in which the complete di-amide mol-ecule is generated by crystallographic inversion symmetry, features a three-mol-ecule aggregate sustained by hydroxyl-O-H⋯N(pyrid-yl) hydrogen bonds. The p-nitro-benzoic acid mol-ecule is non-planar, exhibiting twists of both the carb-oxy-lic acid and nitro groups, which form dihedral angles of 10.16 (9) and 4.24 (4)°, respectively, with the benzene ring. The di-amide mol-ecule has a conformation approximating to a Z shape, with the pyridyl rings lying to either side of the central, almost planar di-amide residue (r.m.s. deviation of the eight atoms being 0.025 Å), and forming dihedral angles of 77.22 (6)° with it. In the crystal, three-mol-ecule aggregates are linked into a linear supra-molecular ladder sustained by amide-N-H⋯O(nitro) hydrogen bonds and orientated along [10-4]. The ladders are connected into a double layer via pyridyl- and benzene-C-H⋯O(amide) inter-actions, which, in turn, are connected into a three-dimensional architecture via π-π stacking inter-actions between pyridyl and benzene rings [inter-centroid distance = 3.6947 (8) Å]. An evaluation of the Hirshfeld surfaces confirm the importance of inter-molecular inter-actions involving oxygen atoms as well as the π-π inter-actions. PMID:26870591

  7. Arachidonoyl ethanolamide (AEA)-induced Apoptosis is Mediated by J-series Prostaglandins and is Enhanced by Fatty Acid Amide Hydrolase (FAAH) Blockade

    PubMed Central

    Kuc, Christian; Jenkins, Audrey; Van Dross, R. T.

    2011-01-01

    The endocannabinoid arachidonoyl ethanolamide (AEA) is a potent inducer of tumor cell apoptosis however its mechanism of cytotoxicity is unclear. A previous report from our laboratory showed that AEA induced cell death in a COX-2-dependent manner and in this report our data indicate that AEA-induced apoptosis is mediated by COX-2 metabolic products of the J-series. In experiments conducted with JWF2 keratinocytes which overexpress COX-2, AEA caused a concentration-regulated increase in J-series prostaglandin production and apoptosis. Similarly, cell treatment with exogenously added J-series prostaglandins (15-deoxy, Δ12,14 PGJ2 and PGJ2) induced apoptosis. AEA-induced apoptosis was inhibited by the antioxidant, N-acetyl cysteine, indicating that reactive oxygen species generation was required for apoptosis. Using antagonists of cannabinoid receptor 1, cannabinoid receptor 2, or TRPV1, it was observed that cannabinoid receptor inhibition did not block AEA-mediated cell death. In contrast, an inhibitor of fatty acid amide hydrolase (FAAH) potentiated AEA-induced J-series PG synthesis and apoptosis. These results suggest that the metabolism of AEA to J-series PGs regulates the induction of apoptosis in cells with elevated COX-2 levels. Our data further indicate that the proapoptotic activity of AEA can be enhanced by combining it with an inhibitor of FAAH. As such, AEA may be an effective agent to eliminate tumor cells that overexpress COX-2. PMID:21432910

  8. The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1

    PubMed Central

    Fowler, CJ; Naidu, PS; Lichtman, A; Onnis, V

    2009-01-01

    Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory ‘load’. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs. PMID:19226258

  9. ω-Imidazolyl- and ω-Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability.

    PubMed

    Terwege, Tobias; Hanekamp, Walburga; Garzinsky, David; König, Simone; Koch, Oliver; Lehr, Matthias

    2016-02-17

    Fatty acid amide hydrolase (FAAH) is a serine hydrolase that terminates the analgesic and anti-inflammatory effects of endocannabinoids such as anandamide. Herein, structure-activity relationship studies on a new series of aryl N-(ω-imidazolyl- and ω-tetrazolylalkyl)carbamate inhibitors of FAAH were investigated. As one result, a pronounced increase in inhibitory potency was observed if a phenyl residue attached to the carbamate oxygen atom was replaced by a pyridin-3-yl moiety. The most active compounds exhibited IC50 values in the low nanomolar range. In addition, investigations on the metabolic properties of these inhibitors were performed. In rat liver homogenate and in porcine plasma, the extent of their degradation was shown to be strongly dependent on the kind of aryl residue bound to the carbamate as well as on the length and type of the alkyl spacer connecting the carbamate group with the heterocyclic system. With the aid of esterase inhibitors it was shown that in porcine plasma, carboxylesterase-like enzymes and paraoxonase are involved in carbamate cleavage. Moreover, it was found that highly active pyridin-3-yl carbamates reacted with albumin, which led to covalent albumin adducts. PMID:26732805

  10. Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172

    PubMed Central

    Fegley, D.; Kathuria, S.; Mercier, R.; Li, C.; Goutopoulos, A.; Makriyannis, A.; Piomelli, D.

    2004-01-01

    The endogenous cannabinoid anandamide is removed from the synaptic space by a high-affinity transport system present in neurons and astrocytes, which is inhibited by N-(4-hydroxyphenyl)-arachidonamide (AM404). After internalization, anandamide is hydrolyzed by fatty-acid amide hydrolase (FAAH), an intracellular membrane-bound enzyme that also cleaves AM404. Based on kinetic evidence, it has recently been suggested that anandamide internalization may be mediated by passive diffusion driven by FAAH activity. To test this possibility, in the present study, we have investigated anandamide internalization in wild-type and FAAH-deficient (FAAH–/–) mice. Cortical neurons from either mouse strain internalized [3H]anandamide through a similar mechanism, i.e., via a rapid temperature-sensitive and saturable process, which was blocked by AM404. Moreover, systemic administration of AM404 to either wild-type or FAAH–/– mice enhanced the hypothermic effects of exogenous anandamide, a response that was prevented by the CB1 cannabinoid antagonist rimonabant (SR141716A). The results indicate that anandamide internalization in mouse brain neurons is independent of FAAH activity. In further support of this conclusion, the compound N-(5Z, 8Z, 11Z, 14Z eicosatetraenyl)-4-hydroxybenzamide (AM1172) blocked [3H]anandamide internalization in rodent cortical neurons and human astrocytoma cells without acting as a FAAH substrate or inhibitor. AM1172 may serve as a prototype for novel anandamide transport inhibitors with increased metabolic stability. PMID:15138300

  11. Crystal Structure of Fatty Acid Amide Hydrolase Bound to the Carbamate Inhibitor URB597: Discovery of a Deacylating Water Molecule and Insight into Enzyme Inactivation

    SciTech Connect

    Mileni, Mauro; Kamtekar, Satwik; Wood, David C.; Benson, Timothy E.; Cravatt, Benjamin F.; Stevens, Raymond C.

    2010-08-12

    The endocannabinoid system regulates a wide range of physiological processes including pain, inflammation, and cognitive/emotional states. URB597 is one of the best characterized covalent inhibitors of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH). Here, we report the structure of the FAAH-URB597 complex at 2.3 {angstrom} resolution. The structure provides insights into mechanistic details of enzyme inactivation and experimental evidence of a previously uncharacterized active site water molecule that likely is involved in substrate deacylation. This water molecule is part of an extensive hydrogen-bonding network and is coordinated indirectly to residues lining the cytosolic port of the enzyme. In order to corroborate our hypothesis concerning the role of this water molecule in FAAH's catalytic mechanism, we determined the structure of FAAH conjugated to a urea-based inhibitor, PF-3845, to a higher resolution (2.4 {angstrom}) than previously reported. The higher-resolution structure confirms the presence of the water molecule in a virtually identical location in the active site. Examination of the structures of serine hydrolases that are non-homologous to FAAH, such as elastase, trypsin, or chymotrypsin, shows a similarly positioned hydrolytic water molecule and suggests a functional convergence between the amidase signature enzymes and serine proteases.

  12. Design and synthesis of phosphonoacetic acid (PPA) ester and amide bioisosters of ribofuranosylnucleoside diphosphates as potential ribonucleotide reductase inhibitors and evaluation of their enzyme inhibitory, cytostatic and antiviral activity.

    PubMed

    Manfredini, Stefano; Solaroli, Nicola; Angusti, Angela; Nalin, Federico; Durini, Elisa; Vertuani, Silvia; Pricl, Sabrina; Ferrone, Marco; Spadari, Silvio; Focher, Federico; Verri, Annalisa; De Clercq, Erik; Balzarini, Jan

    2003-07-01

    Continuing our investigations on inhibitors of ribonucleotide reductase (RNR), the crucial enzyme that catalyses the reduction of ribonucleotides to deoxyribonucleotides, we have now prepared and evaluated 5'-phosphonoacetic acid, amide and ester analogues of adenosine, uridine and cytidine with the aim to verify both substrate specificity and contribution to biological activity of diphosphate mimic moieties. A molecular modelling study has been conducted on the RNR R1 subunit, in order to verify the possible interaction of the proposed bioisosteric moieties. The study compounds were finally tested on the recombinant murine RNR showing a degree of inhibition that ranged from 350 microM for the UDP analogue 5'-deoxy-5'-N-(phosphon-acetyl)uridine sodium salt (amide) to 600 microM for the CDP analogue 5'-O-[(diethyl-phosphon)acetyl]cytidine (ester). None of the tested compounds displayed noteworthy cytostatic activity at 100-500 microM concentrations, whereas ADP analogue 5'-N-[(diethyl-phosphon) acetyl]adenosine (amide) and 5'-deoxy-5'-N-(phosphon-acetyl)adenosine sodium salt (amide) showed a moderate inhibitory activity (EC50: 48 microM) against HSV-2 and a modest inhibitory activity (EC50: 110 microM) against HIV-1, respectively. PMID:14582847

  13. Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via N-Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer

    PubMed Central

    2015-01-01

    The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity. PMID:25050843

  14. Synthesis of bile acid derivatives and in vitro cytotoxic activity with pro-apoptotic process on multiple myeloma (KMS-11), glioblastoma multiforme (GBM), and colonic carcinoma (HCT-116) human cell lines.

    PubMed

    Brossard, Dominique; El Kihel, Laïla; Clément, Monique; Sebbahi, Walae; Khalid, Mohamed; Roussakis, Christos; Rault, Sylvain

    2010-07-01

    The novelty of this work derives from the use of nitrogenous heterocycles as building block in the synthesis of conjugate bile acid derivatives. New piperazinyl bile acid derivatives were synthesized and tested in vitro against various human cancer cells (GBM, KMS-11, HCT-116). The best pro-apoptotic activity was obtained with N-[4N-cinnamylpiperazin-1-yl)-3alpha,7beta-dihydroxy-5beta-cholan-24-amide (7b) and N-[4N-cinnamyllpiperazin-1-yl)- 3alpha,7alpha-dihydroxy-5beta-cholan-24-amide (7c) on these human cancer cell lines (IC(50): 8.5-31.4microM). This activity was associated with nuclear and DNA fragmentation, demonstrating that 7b induces cell death by an apoptotic process as 7c. This study shows the possibility of hydrid heterocycle-steroids as new anticancer agents with improved bioactivity and easy to synthesize. PMID:20381215

  15. Caffeic Acid Derivatives in Dried Lamiaceae and Echinacea purpurea Products

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The concentrations of caffeic acid derivatives within Lamiaceae and Echinacea (herb, spice, tea, and dietary supplement forms) readily available in the U.S. marketplace (n=72) were determined. After the first identification of chicoric acid in Ocimum basilicum (basil), the extent to which chicoric a...

  16. Recognition of the folded conformation of plant hormone (auxin, IAA) conjugates with glutamic and aspartic acids and their amides

    NASA Astrophysics Data System (ADS)

    Antolić, S.; Kveder, M.; Klaić, B.; Magnus, V.; Kojić-Prodić, B.

    2001-01-01

    The molecular structure of the endogenous plant hormone (auxin) conjugate, N-(indol-3-ylacetyl)- L-glutamic acid, is deduced by comparison with N2-(indol-3-ylacetyl)glutamine (IAA-Gln), N2-(indol-3-ylacetyl)asparagine (IAA-Asn) and N-(indol-3-ylacetyl)- L-aspartic acid using X-ray structure analysis, 1H-NMR spectroscopy (NOE measurements) and molecular modelling. The significance of the overall molecular shape, and of the resulting amphiphilic properties, of the compounds studied are discussed in terms of possible implications for trafficking between cell compartments. Both in the solid state and in solution, the molecules are in the hair-pin (folded) conformation in which the side chain is folded over the indole ring. While extended conformations can be detected by molecular dynamics simulations, they are so short-lived that any major influence on the biological properties of the compounds studied is unlikely.

  17. Design, Synthesis and Antibacterial Evaluation of Some New 2-Phenyl-quinoline-4-carboxylic Acid Derivatives.

    PubMed

    Wang, Xiaoqin; Xie, Xiaoyang; Cai, Yuanhong; Yang, Xiaolan; Li, Jiayu; Li, Yinghan; Chen, Wenna; He, Minghua

    2016-01-01

    A series of new 2-phenyl-quinoline-4-carboxylic acid derivatives was synthesized starting from aniline, 2-nitrobenzaldehyde, pyruvic acid followed by Doebner reaction, amidation, reduction, acylation and amination. All of the newly-synthesized compounds were characterized by ¹H-NMR, (13)C-NMR and HRMS. The antibacterial activities of these compounds against Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), as well as one strain of methicillin-resistant Staphylococcus aureus (MRSA) bacteria were evaluated by the agar diffusion method (zone of inhibition) and a broth dilution method (minimum inhibitory concentration (MIC)), and their structure-activity relationships were obtained and discussed. The results revealed that some compounds displayed good antibacterial activity against Staphylococcus aureus, and Compounds 5a₄ and 5a₇ showed the best inhibition with an MIC value of 64 μg/mL against Staphylococcus aureus and with an MIC value of 128 μg/mL against Escherichia coli, respectively. The results of the MTT assay illustrated the low cytotoxicity of Compound 5a₄. PMID:26978336

  18. Synthesis and biological evaluation of novel lipoamino acid derivatives.

    PubMed

    Kaki, Shiva Shanker; Arukali, Sammaiah; Korlipara, Padmaja V; Prasad, R B N; Yedla, Poornachandra; Ganesh Kumar, C

    2016-01-01

    Seven novel lipoamino acid conjugates were synthesized from methyl oleate and amino acids. Methyl oleate was grafted to different amino acids using thioglycolic acid as a spacer group. Seven derivatives (3a-g) were prepared and characterized by spectral data (NMR, IR and MS spectral studies). All the derivatives were studied for their antimicrobial, anti-biofilm and anticancer activities. Among all the derivatives, it was found that compound 3b was the most potent antibacterial compound which showed good activity against four Gram positive bacterial strains and also exhibited excellent antifungal activity against a fungal strain. In the anti-biofilm assay, compound 3b showed promising activity with IC50 value of 2.8μM against Bacillus subtilis MTCC 121. All the compounds showed anticancer activities with 3c showing promising anticancer activity (IC50=15.3-22.4μM) against the four cell lines tested. PMID:26586599

  19. Synthesis of structurally defined scaffolds for bivalent ligand display based on glucuronic acid anilides. The degree of tertiary amide isomerism and folding depends on the configuration of a glycosyl azide.

    PubMed

    Tosin, Manuela; Murphy, Paul V

    2005-05-13

    [structures: see text] Syntheses and structural analyses of bivalent carbohydrates based on anilides of glucuronic acid are described. Secondary anilides predominantly adopted the Z-anti structure; there is also evidence for population of the Z-syn isomer. Bivalent tertiary anilides displayed two signal sets in their NMR spectra, consistent with the presence of (i) a major isomer where both amides have E configurations (EE) and (ii) a minor isomer where one amide is E and the other Z (EZ). Qualitative NOE/ROE spectroscopic studies in solution support the proposal that the anti conformation is preferred for E amides. The crystal structure of one bivalent tertiary anilide showed E-anti and E-syn structural isomers; intramolecular carbohydrate-carbohydrate stacking was observed and mediated by carbonyl-pyranose, azide-azide, and pyranose-aromatic interactions. The EE to EZ isomer ratio, or the degree of folding, for tertiary amides, was greatest for a bivalent compound containing two alpha-glycosyl azide groups; this was enhanced in water, suggesting that hydrophobic interactions are partially but not wholly responsible. Computational methods predicted azide-aromatic (N...H-C interaction) and azide-azide interactions for folded isomers. The close contact of the azide and aromatic protons (N...H-C interaction) was observed upon examination of the close packing in the crystal structure of a related monomer. It is proposed that the alpha-azide group is more optimally aligned, compared to the beta-azide, to facilitate interaction and minimize the surface area of the hydrophobic groups exposed to water, and this leads to the increased folding. The alkylation of bivalent secondary anilides induces a switch from Z to E amide that alters the scaffold orientation. The synthesis of a bivalent mannoside, based on a secondary anilide scaffold, for investigation of mannose-binding receptor cross-linking and lattice formation is described. PMID:15876103

  20. Catalytic conversion of lactic acid and its derivatives

    SciTech Connect

    Kokitkar, P.B.; Langford, R.; Miller, D.J.; Jackson, J.E.

    1993-12-31

    The catalytic upgrading of lactic acid and methyl lactate is being investigated. With the commercialization of inexpensive starch fermentation technologies, US production of lactic acid is undergoing a surge. Dropping cost and increased availability offer a major opportunity to develop lactic acid as a renewable feedstock for chemicals production. IT can be catalytically converted into several important chemical intermediates currently derived from petroleum including acrylic acid, propanoic acid, and 2,3-pentanedione. The process can expand the potential of biomass as a substitute feedstock for petroleum and can benefit both the US chemical process industry and US agriculture via increased production of high-value, non-food products from crops and crop byproducts. Reaction studies of lactic acid and its ester are conducted in fixed bed reactors at 250-380{degrees}C and 0.1-0.5 MPa (1-5 atm) using salt catalysts on low surface area supports. Highest selectivities achieved are 42% to acrylic acid and 55% to 2,3-pentanedione from lactic acid over NaNO{sub 3} catalyst on low surface area silica support. High surface area (microporous) or highly acidic supports promote fragmentation to acetaldehyde and thus reduce yields of desirable products. The support acidity gives rice to lactic acid from neat methyl lactate feed but the lactic acid yield goes down after the nitrate salt is impregnated on the support. Both lactic acid and methyl lactate form 2,3-pentanedione. Methyl lactate reactions are more complex since it forms all the products obtained from lactic acid as well as many corresponding esters of the acids obtained from lactic acid (mainly methyl acrylate, methyl propionate, methyl acetate). At high temperatures, methyl acetate and acetic acid yields become significant from methyl lactate whereas lactic acid gives significant amount of acetol at high temperatures.

  1. A 2:1 co-crystal of 2-methyl­benzoic acid and N,N′-bis­(pyridin-4-ylmeth­yl)ethanedi­amide: crystal structure and Hirshfeld surface analysis

    PubMed Central

    Syed, Sabrina; Jotani, Mukesh M.; Halim, Siti Nadiah Abdul; Tiekink, Edward R. T.

    2016-01-01

    The asymmetric unit of the title 2:1 co-crystal, 2C8H8O2·C14H14N4O2, comprises an acid mol­ecule in a general position and half a di­amide mol­ecule, the latter being located about a centre of inversion. In the acid, the carb­oxy­lic acid group is twisted out of the plane of the benzene ring to which it is attached [dihedral angle = 28.51 (8)°] and the carbonyl O atom and methyl group lie approximately to the same side of the mol­ecule [hy­droxy-O—C—C—C(H) torsion angle = −27.92 (17)°]. In the di­amide, the central C4N2O2 core is almost planar (r.m.s. deviation = 0.031 Å), and the pyridyl rings are perpendicular, lying to either side of the central plane [central residue/pyridyl dihedral angle = 88.60 (5)°]. In the mol­ecular packing, three-mol­ecule aggregates are formed via hy­droxy-O—H⋯N(pyrid­yl) hydrogen bonds. These are connected into a supra­molecular layer parallel to (12) via amide-N—H⋯O(carbon­yl) hydrogen bonds, as well as methyl­ene-C—H⋯O(amide) inter­actions. Significant π–π inter­actions occur between benzene/benzene, pyrid­yl/benzene and pyrid­yl/pyridyl rings within and between layers to consolidate the three-dimensional packing. PMID:27006815

  2. A 2:1 co-crystal of 2-methyl-benzoic acid and N,N'-bis-(pyridin-4-ylmeth-yl)ethanedi-amide: crystal structure and Hirshfeld surface analysis.

    PubMed

    Syed, Sabrina; Jotani, Mukesh M; Halim, Siti Nadiah Abdul; Tiekink, Edward R T

    2016-03-01

    The asymmetric unit of the title 2:1 co-crystal, 2C8H8O2·C14H14N4O2, comprises an acid mol-ecule in a general position and half a di-amide mol-ecule, the latter being located about a centre of inversion. In the acid, the carb-oxy-lic acid group is twisted out of the plane of the benzene ring to which it is attached [dihedral angle = 28.51 (8)°] and the carbonyl O atom and methyl group lie approximately to the same side of the mol-ecule [hy-droxy-O-C-C-C(H) torsion angle = -27.92 (17)°]. In the di-amide, the central C4N2O2 core is almost planar (r.m.s. deviation = 0.031 Å), and the pyridyl rings are perpendicular, lying to either side of the central plane [central residue/pyridyl dihedral angle = 88.60 (5)°]. In the mol-ecular packing, three-mol-ecule aggregates are formed via hy-droxy-O-H⋯N(pyrid-yl) hydrogen bonds. These are connected into a supra-molecular layer parallel to (12[Formula: see text]) via amide-N-H⋯O(carbon-yl) hydrogen bonds, as well as methyl-ene-C-H⋯O(amide) inter-actions. Significant π-π inter-actions occur between benzene/benzene, pyrid-yl/benzene and pyrid-yl/pyridyl rings within and between layers to consolidate the three-dimensional packing. PMID:27006815

  3. Oleanolic acid and related derivatives as medicinally important compounds.

    PubMed

    Sultana, Nighat; Ata, Athar

    2008-12-01

    Oleanolic acid has been isolated from chloroform extract of Olea ferruginea Royle after removal of organic bases and free acids. The literature survey revealed it to be biologically very important. In this review the biological significance of oleanolic acid and its derivatives has been discussed. The aim of this review is to update current knowledge on oleanolic acid and its natural and semisynthetic analogs, focussing on its cytotoxic, antitumer, antioxidant, anti-inflamatory, anti-HIV, acetyl cholinesterase, alpha-glucosidase, antimicrobial, hepatoprotective, anti-inflammatory, antipruritic, spasmolytic activity, anti-angiogenic, antiallergic, antiviral and immunomodulatory activities. We present in this review, for the first time, a compilation of the most relevant scientific papers and technical reports of the chemical, pre-clinical and clinical research on the properties of oleanolic acid and its derivatives. PMID:18618318

  4. Conformational Interconversions of Amino Acid Derivatives.

    PubMed

    Kaminský, Jakub; Jensen, Frank

    2016-02-01

    Exhaustive conformational interconversions including transition structure analyses of N-acetyl-l-glycine-N-methylamide as well as its alanine, serine, and cysteine analogues have been investigated at the MP2/6-31G** level, yielding a total of 142 transition states. Improved estimates of relative energies were obtained by separately extrapolating the Hartree-Fock and MP2 energies to the basis set limit and adding the difference between CCSD(T) and MP2 results with the cc-pVDZ basis set to the extrapolated MP2 results. The performance of eight empirical force fields (AMBER94, AMBER14SB, MM2, MM3, MMFFs, CHARMM22_CMAP, OPLS_2005, and AMOEBAPRO13) in reproducing ab initio energies of transition states was tested. Our results indicate that commonly used class I force fields employing a fixed partial charge model for the electrostatic interaction provide mean errors in the ∼10 kJ/mol range for energies of conformational transition states for amino acid conformers. Modern reparametrized versions, such as CHARMM22_CMAP, and polarizable force fields, such as AMOEBAPRO13, have slightly lower mean errors, but maximal errors are still in the 35 kJ/mol range. There are differences between the force fields in their ability for reproducing conformational transitions classified according to backbone/side-chain or regions in the Ramachandran angles, but the data set is likely too small to draw any general conclusions. Errors in conformational interconversion barriers by ∼10 kJ/mol suggest that the commonly used force field may bias certain types of transitions by several orders of magnitude in rate and thus lead to incorrect dynamics in simulations. It is therefore suggested that information for conformational transition states should be included in parametrizations of new force fields. PMID:26691979

  5. Nutritional value of D-amino acids, D-peptides, and amino acid derivatives in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper describes a method for determining the nutritional value of D-amino acids, D-peptides, and amino acid derivatives using a growth assay in mice fed a synthetic all-amino acid diet. A large number of experiments were carried out in which a molar equivalent of the test compound replaced a n...

  6. Reductively degradable α-amino acid-based poly(ester amide)-graft-galactose copolymers: facile synthesis, self-assembly, and hepatoma-targeting doxorubicin delivery.

    PubMed

    Lv, Jiaolong; Sun, Huanli; Zou, Yan; Meng, Fenghua; Dias, Aylvin A; Hendriks, Marc; Feijen, Jan; Zhong, Zhiyuan

    2015-07-01

    Novel reductively degradable α-amino acid-based poly(ester amide)-graft-galactose (SSPEA-Gal) copolymers were designed and developed to form smart nano-vehicles for active hepatoma-targeting doxorubicin (DOX) delivery. SSPEA-Gal copolymers were readily synthesized via solution polycondensation reaction of di-p-toluenesulfonic acid salts of bis-l-phenylalanine 2,2-thiodiethanol diester and bis-vinyl sulfone functionalized cysteine hexanediol diester with dinitrophenyl ester of adipic acid, followed by conjugating with thiol-functionalized galactose (Gal-SH) via the Michael addition reaction. SSPEA-Gal formed unimodal nanoparticles (PDI = 0.10 - 0.12) in water, in which average particle sizes decreased from 138 to 91 nm with increasing Gal contents from 31.6 wt% to 42.5 wt%. Notably, in vitro drug release studies showed that over 80% DOX was released from SSPEA-Gal nanoparticles within 12 h under an intracellular mimicking reductive conditions, while low DOX release (<20%) was observed for reduction-insensitive PEA-Gal nanoparticles under otherwise the same conditions and SSPEA-Gal nanoparticles under non-reductive conditions. Notably, SSPEA-Gal nanoparticles exhibited high specificity to asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells. MTT assays using HepG2 cells showed that DOX-loaded SSPEA-Gal had a low half maximal inhibitory concentration (IC50) of 1.37 μg mL(-1), approaching that of free DOX. Flow cytometry and confocal laser scanning microscopy studies confirmed the efficient uptake of DOX-loaded SSPEA-Gal nanoparticles by HepG2 cells as well as fast intracellular DOX release. Importantly, SSPEA-Gal and PEA-Gal nanoparticles were non-cytotoxic to HepG2 and MCF-7 cells up to a tested concentration of 1.0 mg mL(-1). These tumor-targeting and reduction-responsive degradable nanoparticles have appeared as an interesting multi-functional platform for advanced drug delivery. PMID:26221946

  7. Prolonged Monoacylglycerol Lipase Blockade Causes Equivalent Cannabinoid Receptor Type 1 Receptor–Mediated Adaptations in Fatty Acid Amide Hydrolase Wild-Type and Knockout Mice

    PubMed Central

    Kinsey, Steven G.; Ignatowska-Jankowska, Bogna; Ramesh, Divya; Abdullah, Rehab A.; Tao, Qing; Booker, Lamont; Long, Jonathan Z.; Selley, Dana E.; Cravatt, Benjamin F.; Lichtman, Aron H.

    2014-01-01

    Complementary genetic and pharmacological approaches to inhibit monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, enable the exploration of potential therapeutic applications and physiologic roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond those seen with inhibition of either enzyme alone. While cannabinoid receptor type 1 (CB1) function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence. Here, we evaluated the consequences of a high dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate; 40 mg/kg] given acutely or for 6 days in FAAH(−/−) and (+/+) mice. While acute administration of JZL184 to FAAH(−/−) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of Δ9-tetrahydrocannabinol, decreases in CB1 receptor agonist–stimulated guanosine 5′-O-(3-[35S]thio)triphosphate binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype. Together, these data suggest that simultaneous elevation of both endocannabinoids elicits enhanced cannabimimetic activity but MAGL inhibition drives CB1 receptor functional tolerance and cannabinoid dependence. PMID:24849924

  8. Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of 1-arachidonoylglycerol with monoacylglycerol lipase and fatty acid amide hydrolase

    SciTech Connect

    Vandevoorde, Severine; Saha, Bijali; Mahadevan, Anu; Razdan, Raj K.; Pertwee, Roger G.; Martin, Billy R.; Fowler, Christopher J. . E-mail: cf@pharm.umu.se

    2005-11-11

    Little is known as to the structural requirements of the acyl side chain for interaction of acylglycerols with monoacylglycerol lipase (MAGL), the enzyme chiefly responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain. In the present study, a series of twelve analogues of 1-AG (the more stable regioisomer of 2-AG) were investigated with respect to their ability to inhibit the metabolism of 2-oleoylglycerol by cytosolic and membrane-bound MAGL. In addition, the ability of the compounds to inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) was investigated. For cytosolic MAGL, compounds with 20 carbon atoms in the acyl chain and 2-5 unsaturated bonds inhibited the hydrolysis of 2-oleoylglycerol with similar potencies (IC{sub 50} values in the range 5.1-8.2 {mu}M), whereas the two compounds with a single unsaturated bond were less potent (IC{sub 50} values 19 and 21 {mu}M). The fully saturated analogue 1-monoarachidin did not inhibit the enzyme, whereas the lower side chain analogues 1-monopalmitin and 1-monomyristin inhibited the enzyme with IC{sub 50} values of 12 and 32 {mu}M, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC{sub 50} value 4.5 {mu}M). Introduction of an {alpha}-methyl group for the C20:4, C20:3, and C22:4 compounds did not affect potency in a consistent manner. For the FAAH and the membrane-bound MAGL, there was no obvious relationship between the degree of unsaturation of the acyl side chain and the ability to inhibit the enzymes. It is concluded that increasing the number of unsaturated bonds on the acyl side chain of 1-AG from 1 to 5 has little effect on the affinity of acylglycerols for cytosolic MAGL.

  9. Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice

    PubMed Central

    Ghosh, Sudeshna; Kinsey, Steven G.; Liu, Qing-song; Hruba, Lenka; McMahon, Lance R.; Grim, Travis W.; Merritt, Christina R.; Wise, Laura E.; Abdullah, Rehab A.; Selley, Dana E.; Sim-Selley, Laura J.; Cravatt, Benjamin F.

    2015-01-01

    Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-​3-​pyridinyl-​4-​[[3-​[[5-​(trifluoromethyl)-​2-​pyridinyl]oxy]phenyl]methyl]-​1-​piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ9-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition combined

  10. Antidepressant-like activity and cardioprotective effects of fatty acid amide hydrolase inhibitor URB694 in socially stressed Wistar Kyoto rats.

    PubMed

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

    2015-11-01

    In humans, depression is often triggered by prolonged exposure to psychosocial stressors and is often associated with cardiovascular comorbidity. Mounting evidence suggests a role for endocannabinoid signaling in the regulation of both emotional behavior and cardiovascular function. Here, we examined cardiac activity in a rodent model of social stress-induced depression and investigated whether pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid anandamide, exerts antidepressant-like and cardioprotective effects. Male Wistar Kyoto rats were exposed to five weeks of repeated social stress or control procedure. Starting from the third week, they received daily administration of the selective FAAH inhibitor URB694 (0.1 mg/kg, i.p.) or vehicle. Cardiac electrical activity was recorded by radiotelemetry. Repeated social stress triggered biological and behavioral changes that mirror symptoms of human depression, such as (i) reductions in body weight gain and sucrose solution preference, (ii) hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and (iii) increased immobility in the forced swim test. Moreover, stressed rats showed (i) alterations in heart rate daily rhythm and cardiac autonomic neural regulation, (ii) a larger incidence of spontaneous arrhythmias, and (iii) signs of cardiac hypertrophy. Daily treatment with URB694 (i) increased central and peripheral anandamide levels, (ii) corrected stress-induced alterations of biological and behavioral parameters, and (iii) protected the heart against the adverse effects of social stress. Repeated social stress in Wistar Kyoto rats reproduces aspects of human depression/cardiovascular comorbidity. Pharmacological enhancement of anandamide signaling might be a promising strategy for the treatment of these comorbid conditions. PMID:26391492

  11. Localization of the endocannabinoid-degrading enzyme fatty acid amide hydrolase in rat dorsal root ganglion cells and its regulation after peripheral nerve injury.

    PubMed

    Lever, Isobel J; Robinson, Michelle; Cibelli, Mario; Paule, Cleoper; Santha, Peter; Yee, Louis; Hunt, Stephen P; Cravatt, Benjamin F; Elphick, Maurice R; Nagy, Istvan; Rice, Andrew S C

    2009-03-25

    Fatty acid amide hydrolase (FAAH) is a degradative enzyme for a group of endogenous signaling lipids that includes anandamide (AEA). AEA acts as an endocannabinoid and an endovanilloid by activating cannabinoid and vanilloid type 1 transient receptor potential (TRPV1) receptors, respectively, on dorsal root ganglion (DRG) sensory neurons. Inhibition of FAAH activity increases AEA concentrations in nervous tissue and reduces sensory hypersensitivity in animal pain models. Using immunohistochemistry, Western blotting, and reverse transcription-PCR, we demonstrate the location of the FAAH in adult rat DRG, sciatic nerve, and spinal cord. In naive rats, FAAH immunoreactivity localized to the soma of 32.7 +/- 0.8% of neurons in L4 and L5 DRG. These were small-sized (mean soma area, 395.96 +/- 5.6 mum(2)) and predominantly colabeled with peripherin and isolectin B4 markers of unmyelinated C-fiber neurons; 68% colabeled with antibodies to TRPV1 (marker of nociceptive DRG neurons), and <2% colabeled with NF200 (marker of large myelinated neurons). FAAH-IR was also present in small, NF200-negative cultured rat DRG neurons. Incubation of these cultures with the FAAH inhibitor URB597 increased AEA-evoked cobalt uptake in a capsazepine-sensitive manner. After sciatic nerve axotomy, there was a rightward shift in the cell-size distribution of FAAH-immunoreactive (IR) DRG neurons ipsilateral to injury: FAAH immunoreactivity was detected in larger-sized cells that colabeled with NF200. An ipsilateral versus contralateral increase in both the size and proportion of FAAH-IR DRG occurred after spinal nerve transection injury but not after chronic inflammation of the rat hindpaw 2 d after injection of complete Freund's adjuvant. This study reveals the location of FAAH in neural tissue involved in peripheral nociceptive transmission. PMID:19321773

  12. Pharmacological blockade of the fatty acid amide hydrolase (FAAH) alters neural proliferation, apoptosis and gliosis in the rat hippocampus, hypothalamus and striatum in a negative energy context

    PubMed Central

    Rivera, Patricia; Bindila, Laura; Pastor, Antoni; Pérez-Martín, Margarita; Pavón, Francisco J.; Serrano, Antonia; de la Torre, Rafael; Lutz, Beat; Rodríguez de Fonseca, Fernando; Suárez, Juan

    2015-01-01

    Endocannabinoids participate in the control of neurogenesis, neural cell death and gliosis. The pharmacological effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which limits the endocannabinoid degradation, was investigated in the present study. Cell proliferation (phospho-H3+ or BrdU+ cells) of the main adult neurogenic zones as well as apoptosis (cleaved caspase-3+), astroglia (GFAP+), and microglia (Iba1+ cells) were analyzed in the hippocampus, hypothalamus and striatum of rats intraperitoneally treated with URB597 (0.3 mg/kg/day) at one dose/4-days resting or 5 doses (1 dose/day). Repeated URB597 treatment increased the plasma levels of the N-acylethanolamines oleoylethanolamide, palmitoylethanolamide and arachidonoylethanolamine, reduced the plasma levels of glucose, triglycerides and cholesterol, and induced a transitory body weight decrease. The hippocampi of repeated URB597-treated rats showed a reduced number of phospho-H3+ and BrdU+ subgranular cells as well as GFAP+, Iba1+ and cleaved caspase-3+ cells, which was accompanied with decreased hippocampal expression of the cannabinoid CB1 receptor gene Cnr1 and Faah. In the hypothalami of these rats, the number of phospho-H3+, GFAP+ and 3-weeks-old BrdU+ cells was specifically decreased. The reduced striatal expression of CB1 receptor in repeated URB597-treated rats was only associated with a reduced apoptosis. In contrast, the striatum of acute URB597-treated rats showed an increased number of subventricular proliferative, astroglial and apoptotic cells, which was accompanied with increased Faah expression. Main results indicated that FAAH inhibitor URB597 decreased neural proliferation, glia and apoptosis in a brain region-dependent manner, which were coupled to local changes in Faah and/or Cnr1 expression and a negative energy context. PMID:25870539

  13. The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury

    PubMed Central

    Tchantchou, Flaubert; Tucker, Laura B.; Fu, Amanda H.; Bluett, Rebecca J.; McCabe, Joseph T.; Patel, Sachin; Zhang, Yumin

    2015-01-01

    Traumatic brain injury (TBI) is the leading cause of death in young adults in the United States, but there is still no effective agent for treatment. N-arachidonoylethanolamine (anandamide, AEA) is a major endocannabinoid in the brain. Its increase after brain injury is believed to be protective. However, the compensatory role of AEA is transient due to its rapid hydrolysis by the fatty acid amide hydrolase (FAAH). Thus, inhibition of FAAH can boost the endogenous levels of AEA and prolong its protective effect. Using a TBI mouse model, we found that post-injury chronic treatment with PF3845, a selective and potent FAAH inhibitor, reversed TBI-induced impairments in fine motor movement, hippocampus dependent working memory and anxiety-like behavior. Treatment with PF3845 inactivated FAAH activity and enhanced the AEA levels in the brain. It reduced neurodegeneration in the dentate gyrus, and up-regulated the expression of Bcl-2 and Hsp70/72 in both cortex and hippocampus. PF3845 also suppressed the increased production of amyloid precursor protein, prevented dendritic loss and restored the levels of synaptophysin in the ipsilateral dentate gyrus. Furthermore, PF3845 suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 post-TBI, suggesting a shift of microglia/macrophages from M1 to M2 phenotype. The effects of PF3845 on TBI-induced behavioral deficits and neurodegeneration were mediated by activation of cannabinoid type 1 and 2 receptors and might be attributable to the phosphorylation of ERK1/2 and AKT. These results suggest that selective inhibition of FAAH is likely to be beneficial for TBI treatment. PMID:24937045

  14. Involvement of endocannabinoids in alcohol “binge” drinking: studies of mice with human fatty acid amide hydrolase genetic variation and after CB1 receptor antagonists

    PubMed Central

    Zhou, Yan; Huang, Ted; Lee, Francis; Kreek, Mary Jeanne

    2016-01-01

    Background The endocannabinoid system has been found to play an important role in modulating alcohol intake. Inhibition or genetic deletion of fatty acid amide hydrolase (FAAH, a key catabolic enzyme for endocannabinoids) leads to increased alcohol consumption and preference in rodent models. A common human single-nucleotide polymorphism (SNP; C385A, rs324420) in the FAAH gene is associated with decreased enzymatic activity of FAAH, resulting in increased anandamide levels in both humans and FAAH C385A knock-in mice. Methods As this FAAH SNP has been reported to be associated with altered alcohol abuse, the present study used these genetic knock-in mice containing the human SNP C385A to determine the impact of variant FAAH gene on alcohol “binge” drinking in the drinking-in-the-dark (DID) model. Results We found that the FAAHA/A mice had greater alcohol intake and preference than the wild-type FAAHC/C mice, suggesting that increased endocannabinoid signaling in FAAHA/A mice led to increased alcohol “binge” consumption. The specificity on alcohol vulnerability was suggested by the lack of any FAAH genotype difference on sucrose or saccharin intake. Using the “binge” DID model, we confirmed that selective CB1 receptor antagonist AM251 reduced alcohol intake in the wild-type mice. Conclusions These data suggest that there is direct and selective involvement of the human FAAH C385A SNP and CB1 receptors in alcohol “binge” drinking. PMID:26857901

  15. Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems

    PubMed Central

    Costa, Barbara; Conti, Silvia; Giagnoni, Gabriella; Colleoni, Mariapia

    2002-01-01

    The anti-inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo-oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan-induced acute paw inflammation and compared with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. Palmitoylethanolamide (1, 3, 5, 10 mg kg−1; p.o.) and indomethacin (5 mg kg−1; p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO2−/NO3−), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan-induced oedema in a dose- and time-dependent manner. This effect was not reversed by the selective CB2 receptor antagonist (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) (SR144528), 3 mg kg−1 p.o. On the fourth day after carrageenan injection, COX activity and the level of NO2−/NO3−, eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg−1) and indomethacin markedly reduced these increases. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity. PMID:12359622

  16. Pharmacological blockade of the fatty acid amide hydrolase (FAAH) alters neural proliferation, apoptosis and gliosis in the rat hippocampus, hypothalamus and striatum in a negative energy context.

    PubMed

    Rivera, Patricia; Bindila, Laura; Pastor, Antoni; Pérez-Martín, Margarita; Pavón, Francisco J; Serrano, Antonia; de la Torre, Rafael; Lutz, Beat; Rodríguez de Fonseca, Fernando; Suárez, Juan

    2015-01-01

    Endocannabinoids participate in the control of neurogenesis, neural cell death and gliosis. The pharmacological effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which limits the endocannabinoid degradation, was investigated in the present study. Cell proliferation (phospho-H3(+) or BrdU(+) cells) of the main adult neurogenic zones as well as apoptosis (cleaved caspase-3(+)), astroglia (GFAP(+)), and microglia (Iba1(+) cells) were analyzed in the hippocampus, hypothalamus and striatum of rats intraperitoneally treated with URB597 (0.3 mg/kg/day) at one dose/4-days resting or 5 doses (1 dose/day). Repeated URB597 treatment increased the plasma levels of the N-acylethanolamines oleoylethanolamide, palmitoylethanolamide and arachidonoylethanolamine, reduced the plasma levels of glucose, triglycerides and cholesterol, and induced a transitory body weight decrease. The hippocampi of repeated URB597-treated rats showed a reduced number of phospho-H3(+) and BrdU(+) subgranular cells as well as GFAP(+), Iba1(+) and cleaved caspase-3(+) cells, which was accompanied with decreased hippocampal expression of the cannabinoid CB1 receptor gene Cnr1 and Faah. In the hypothalami of these rats, the number of phospho-H3(+), GFAP(+) and 3-weeks-old BrdU(+) cells was specifically decreased. The reduced striatal expression of CB1 receptor in repeated URB597-treated rats was only associated with a reduced apoptosis. In contrast, the striatum of acute URB597-treated rats showed an increased number of subventricular proliferative, astroglial and apoptotic cells, which was accompanied with increased Faah expression. Main results indicated that FAAH inhibitor URB597 decreased neural proliferation, glia and apoptosis in a brain region-dependent manner, which were coupled to local changes in Faah and/or Cnr1 expression and a negative energy context. PMID:25870539

  17. Inhibition of carbohydrate-mediated glucagon-like peptide-1 (7-36)amide secretion by circulating non-esterified fatty acids.

    PubMed

    Ranganath, L; Norris, F; Morgan, L; Wright, J; Marks, V

    1999-04-01

    Two studies were performed to assess the entero-insular axis in simple obesity and the possible effect of variations in the level of circulating non-esterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7-36) amide]. In the first study, we compared the entero-pancreatic hormone response to oral carbohydrate in obese and lean women. Obese subjects demonstrated hyperinsulinaemia and impaired glucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 (GLP-1). These findings therefore provide no support for the hypothesis that overactivity of the entero-insular axis contributes to the hyperinsulinaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observations. In the second study, in which carbohydrate-stimulated GLP-1 responses were again evaluated in obese and lean women, circulating NEFA levels were modulated using either heparin (to increase serum NEFA) or acipimox (to reduce serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to carbohydrate alone or to carbohydrate plus heparin. We suggest that higher fasting and postprandial NEFA levels in obesity may tonically inhibit nutrient-mediated GLP-1 secretion, and that this results in attenuation of the GLP-1 response to carbohydrate. However, although serum NEFA levels post-acipimox were similarly suppressed in both lean and obese subjects, the GLP-1 response was again significantly lower in obese subjects, suggesting the possibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insulinotropic effect and to its postulated role as a satiety factor. PMID:10087239

  18. A new ellagic acid derivative from Polygonum runcinatum.

    PubMed

    Zhou, Zhi-Hong; Liu, Min-Zhuo; Wang, Meng-Hua; Qu, Wei; Sun, Jian-Bo; Liang, Jing-Yu; Wu, Fei-Hua

    2015-01-01

    A new ellagic acid derivative, 3,3'-dimethylellagic acid-4'-O-(6″-galloyl)-β-D-glucoside, named runcinatside (5), together with four known compounds 3,3'-dimethylellagic acid (1), 3,3',4'-trimethylellagic acid (2), 3,3'-dimethylellagic acid-4'-O-β-D-glucoside (3) and 3-methylellagic acid-4'-O-α-L-rhamno-pyranoside (4), was isolated from the roots of Polygonum runcinatum Buch.-Ham. ex D.Don Var. sinense Hemsl and the structures of these compounds were established by spectroscopic methods and comparison with previously reported data. All compounds showed antioxidant activities in vitro and compound 5 possessed the highest activity. PMID:25560313

  19. Production of Diethyl Terephthalate from Biomass-Derived Muconic Acid.

    PubMed

    Lu, Rui; Lu, Fang; Chen, Jiazhi; Yu, Weiqiang; Huang, Qianqian; Zhang, Junjie; Xu, Jie

    2016-01-01

    We report a cascade synthetic route to directly obtain diethyl terephthalate, a replacement for terephthalic acid, from biomass-derived muconic acid, ethanol, and ethylene. The process involves two steps: First, a substituted cyclohexene system is built through esterification and Diels-Alder reaction; then, a dehydrogenation reaction provides diethyl terephthalate. The key esterification reaction leads to improved solubility and modulates the electronic properties of muconic acid, thus promoting the Diels-Alder reaction with ethylene. With silicotungstic acid as the catalyst, nearly 100% conversion of muconic acid was achieved, and the cycloadducts were formed with more than 99.0% selectivity. The palladium-catalyzed dehydrogenation reaction preferentially occurs under neutral or mildly basic conditions. The total yield of diethyl terephthalate reached 80.6% based on the amount of muconic acid used in the two-step synthetic process. PMID:26592149

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

    DOEpatents

    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.

  1. Lipoproteini lipase-derived fatty acids: physiology and dysfunction.

    PubMed

    Lee, Jee; Goldberg, Ira J

    2007-12-01

    Under normal circumstances, most energy substrate used for heart contraction derives from fatty acids in the form of nonesterified fatty acids bound to albumin or fatty acids derived from lipolysis of lipoprotein-bound triglyceride by lipoprotein lipase (LpL). By creating LpL knockout mice (hLpL0), we learned that loss of cardiac LpL leads to myocardial dysfunction; therefore, neither nonesterified fatty acids nor increased glucose metabolism can replace LpL actions. hLpL0 mice do not survive abdominal aortic constriction and they develop more heart failure with hypertension. Conversely, we created a mouse overexpressing cardiomyocyte-anchored LpL. This transgene produced cardiac lipotoxicity and dilated cardiomyopathy. Methods to alter this phenotype and the causes of other models of lipotoxicity are currently being studied and will provide further insight into the physiology of lipid metabolism in the heart. PMID:18367009

  2. Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-Positive Pathogens: 2-(2-Phenylhydrazinylidene)alkanoic Acids and Related Derivatives.

    PubMed

    Maggio, Benedetta; Raffa, Demetrio; Raimondi, Maria Valeria; Cascioferro, Stella; Plescia, Fabiana; Schillaci, Domenico; Cusimano, Maria Grazia; Leonchiks, Ainars; Zhulenkovs, Dmitrijs; Basile, Livia; Daidone, Giuseppe

    2016-01-01

    A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compound resulted 2a, which showed inhibition of about 60% against S. aureus ATCC 29213, S. aureus ATCC 25923, S. aureus ATCC 6538 and S. epidermidis RP62A at a screening concentration of 100 µM. PMID:26907235

  3. Design, synthesis and biological evaluation of novel betulinic acid derivatives

    PubMed Central

    2012-01-01

    Background Tumor, is one of the major reason for human death, due to its widespread occurrence. Betulinic acid derivatives have attracted considerable attention as cancer chemopreventive agents and also as cancer therapeutics. Many of its derivatives inhibit the growth of human cancer cell lines by triggering apoptosis. With this background, we planned to synthesize a series of betulinic acid derivatives to assess their antiproliferation efficacy on human cancer cell lines. Results A series of novel betulinic acid derivatives were designed and synthesized as highlighted by the preliminary antitumor evaluation against MGC-803, PC3, A375, Bcap-37 and A431 human cancer cell lines in vitro. The pharmacological results showed that some of the compounds displayed moderate to high levels of antitumor activities with most of new exhibiting higher inhibitory activities compared to BA. The IC50 values of compound 3c on the five cancer cell lines were 2.3, 4.6, 3.3, 3.6, and 4.3 μM, respectively. Subsequent fluorescence staining and flow cytometry analysis (FCM) indicated that compound 3c could induce apoptosis in MGC-803 and PC3 cell lines, and the apoptosis ratios reached the peak (37.38% and 33.74%) after 36 h of treatment at 10 μM. Conclusions This study suggests that most of betulinic acid derivatives could inhibit the growth of human cancer cell lines. Furthermore, compound 3c could induce apoptosis of cancer cells. PMID:23174002

  4. Bioimaging for targeted delivery of hyaluronic Acid derivatives to the livers in cirrhotic mice using quantum dots.

    PubMed

    Kim, Ki Su; Hur, Wonhee; Park, Sang-Jun; Hong, Sung Woo; Choi, Jung Eun; Goh, Eun Ji; Yoon, Seung Kew; Hahn, Sei Kwang

    2010-06-22

    Liver fibrosis or cirrhosis is one of the representative liver diseases with a high morbidity and mortality worldwide. Over the past decades, many kinds of antifibrotic compounds have been investigated in vitro and in vivo for the treatment of liver cirrhosis. In this work, real-time bioimaging of hyaluronic acid (HA) derivatives was carried out using quantum dots (QDots) to assess the possibility of HA derivatives as target-specific drug delivery carriers for the treatment of liver diseases. HA-QDot conjugates with an HA modification degree of about 22 mol % was synthesized by amide bond formation between carboxyl groups of QDots and amine groups of adipic acid dihydrazide modified HA (HA-ADH). According to in vitro cell culture tests, HA-QDot conjugates were taken up more to the cells causing chronic liver diseases such as hepatic stellate cells (HSC-T6) and hepatoma cells (HepG2) than normal hepatocytes (FL83B). After tail-vein injection, HA-QDot conjugates were target-specific, being delivered to the cirrhotic liver with a slow clearance longer than 8 days. Furthermore, immunofluorescence and flow cytometric analyses of dissected liver tissues revealed the target-specific delivery of HA derivatives to liver sinusoidal endothelial cells (LSEC) and HSC. The results were thought to reflect the feasibility of HA derivatives as novel drug delivery carriers for the treatment of various chronic liver diseases including hepatitis, liver cirrhosis, and liver cancer. PMID:20518553

  5. Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline-7-Acetic Acid Derivatives With Amino Acid Moieties.

    PubMed

    Stavrakov, Georgi; Valcheva, Violeta; Voynikov, Yulian; Philipova, Irena; Atanasova, Mariyana; Konstantinov, Spiro; Peikov, Plamen; Doytchinova, Irini

    2016-03-01

    The theophylline-7-acetic acid (7-TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7-TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7-TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non-toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol. PMID:26502828

  6. Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 may protect against cognitive impairment in rats of chronic cerebral hypoperfusion via PI3K/AKT signaling.

    PubMed

    Su, Shao-Hua; Wang, Yue-Qing; Wu, Yi-Fang; Wang, Da-Peng; Lin, Qi; Hai, Jian

    2016-10-15

    The present study further investigated the protective effects of cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide hydrolase (FAAH) inhibitor URB597 (URB) on chronic cerebral hypoperfusion (CCH)-induced cognitive impairment in rats. Spatial learning and memory were assessed with the Morris water maze and by measuring Long-term potentiation. The expression of microtubule-associated protein-2 (MAP)-2, growth-associated protein-43 (GAP)-43, synaptophysin, cannabinoid receptor 1 (CB1), brain-derived neurotrophic factor (BDNF), FAAH, N-acylphosphatidylethanolamine phospholipase D(NAPE-PLD) and monoacyl glycerol lipase (MGL) as well as phosphoinositide 3-kinase (PI3K)/AKT signaling pathway molecules and downstream targets including AKT, phosphorylated (p-)AKT, cyclic AMP response element- binding protein (CREB), p-CREB, Bcl-2-associated death protein (BAD), p-BAD, glycogen synthase kinase (GSK)-3β, p-GSK-3β, forkhead box protein (FOXO) 3A and p-FOXO3A was determined by western blotting. WIN and URB treatment improved learning and memory performance, effects that were abolished by co-administration of the PI3K/AKT inhibitor LY294002. Moreover, WIN and URB reversed the decreases in MAP-2 and synaptophysin expression resulting from CCH, and stimulated BDNF and CB1 expression as well as CREB, FOXO3A, GSK-3β, and BAD phosphorylation, confirming that WIN and URB mediate neuroprotection by preventing neuronal apoptosis and improving cognition via PI3K/AKT signaling. These findings suggest that WIN and URB are promising agents for therapeutic management of CCH. PMID:27424778

  7. 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

    SciTech Connect

    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

    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.

  8. Incorporation of hydrogen atoms from deuterated water and stereospecifically deuterium-labeled nicotin amide nucleotides into fatty acids with the Escherichia coli fatty acid synthetase system.

    PubMed

    Saito, K; Kawaguchi, A; Okuda, S; Seyama, Y; Yamakawa, T

    1980-05-28

    The mechanism of hydrogen incorporation into fatty acids was investigated with intact Escherichia coli cells, a crude enzyme preparation and purified reductases of fatty acid synthetase system. The distributions of deuterium atoms incorporated into fatty acids from 2H2O and stereospecifically deuterium-labeled NADPH or NADH were determined by mass spectrometry. When E. coli was grown in 2H2O, almost every hydrogen atom of cellular fatty acids was incorporated from the medium. When fatty acids were synthesized from acetyl-CoA, malonyl-CoA and NADPH in the presence of a crude enzyme preparation of either E. coli or Bacillus subtilis, almost every hydrogen atom was also incorporated from the medium. In contrast to these results, purified beta-ketoacyl acyl carrier reductase directly transferred the HB hydrogen of NADPH to beta-ketoacyl acyl carrier protein, and purified enoyl acyl carrier protein reductase also transferred the HB hydrogen of NADPH and NADH directly to enoyl acyl carrier protein. In the crude enzyme preparation of E. coli, we found high activities which exchanged the HB hydrogen of NADPH with the deuterium of 2h2o. the conflicting results of the origin of hydrogen atoms of fatty acids mentioned above are explained by the presence of enzymes, which catalyzed the rapid exchange of NADPH with the deterium of 2H2O prior to the reaction of fatty acid synthetase. PMID:6990992

  9. Enantioselective Synthesis of α-Hydroxy Amides and β-Amino Alcohols from α-Keto Amides.

    PubMed

    Mamillapalli, N Chary; Sekar, Govindasamy

    2015-12-14

    Synthesis of enantiomerically enriched α-hydroxy amides and β-amino alcohols has been accomplished by enantioselective reduction of α-keto amides with hydrosilanes. A series of α-keto amides were reduced in the presence of chiral Cu(II)/(S)-DTBM-SEGPHOS catalyst to give the corresponding optically active α-hydroxy amides with excellent enantioselectivities by using (EtO)3SiH as a reducing agent. Furthermore, a one-pot complete reduction of both ketone and amide groups of α-keto amides has been achieved using the same chiral copper catalyst followed by tetra-n-butylammonium fluoride (TBAF) catalyst in presence of (EtO)3SiH to afford the corresponding chiral β-amino alcohol derivatives. PMID:26503887

  10. Extracting metal ions with diphosphonic acid, or derivative thereof

    DOEpatents

    Horwitz, Earl P.; Gatrone, Ralph C.; Nash, Kenneth L.

    1994-01-01

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulphur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described.

  11. Extracting metal ions with diphosphonic acid, or derivative thereof

    DOEpatents

    Horwitz, E.P.; Gatrone, R.C.; Nash, K.L.

    1994-07-26

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulfur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described. 1 fig.

  12. Membrane extraction with thermodynamically unstable diphosphonic acid derivatives

    DOEpatents

    Horwitz, E.P.; Gatrone, R.C.; Nash, K.L.

    1997-10-14

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulphur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described. 1 fig.

  13. Membrane extraction with thermodynamically unstable diphosphonic acid derivatives

    DOEpatents

    Horwitz, Earl Philip; Gatrone, Ralph Carl; Nash, Kenneth LaVerne

    1997-01-01

    Thermodynamically-unstable complexing agents which are diphosphonic acids and diphosphonic acid derivatives (or sulphur containing analogs), like carboxyhydroxymethanediphosphonic acid and vinylidene-1,1-diphosphonic acid, are capable of complexing with metal ions, and especially metal ions in the II, III, IV, V and VI oxidation states, to form stable, water-soluble metal ion complexes in moderately alkaline to highly-acidic media. However, the complexing agents can be decomposed, under mild conditions, into non-organic compounds which, for many purposes are environmentally-nondamaging compounds thereby degrading the complex and releasing the metal ion for disposal or recovery. Uses for such complexing agents as well as methods for their manufacture are also described.

  14. Structures of Plutonium(IV) and Uranium(VI) with N,N-Dialkyl Amides from Crystallography, X-ray Absorption Spectra, and Theoretical Calculations.

    PubMed

    Acher, Eléonor; Hacene Cherkaski, Yanis; Dumas, Thomas; Tamain, Christelle; Guillaumont, Dominique; Boubals, Nathalie; Javierre, Guilhem; Hennig, Christoph; Solari, Pier Lorenzo; Charbonnel, Marie-Christine

    2016-06-01

    The structures of plutonium(IV) and uranium(VI) ions with a series of N,N-dialkyl amides ligands with linear and branched alkyl chains were elucidated from single-crystal X-ray diffraction (XRD), extended X-ray absorption fine structure (EXAFS), and theoretical calculations. In the field of nuclear fuel reprocessing, N,N-dialkyl amides are alternative organic ligands to achieve the separation of uranium(VI) and plutonium(IV) from highly concentrated nitric acid solution. EXAFS analysis combined with XRD shows that the coordination structure of U(VI) is identical in the solution and in the solid state and is independent of the alkyl chain: two amide ligands and four bidentate nitrate ions coordinate the uranyl ion. With linear alkyl chain amides, Pu(IV) also adopt identical structures in the solid state and in solution with two amides and four bidentate nitrate ions. With branched alkyl chain amides, the coordination structure of Pu(IV) was more difficult to establish unambiguously from EXAFS. Density functional theory (DFT) calculations were consequently performed on a series of structures with different coordination modes. Structural parameters and Debye-Waller factors derived from the DFT calculations were used to compute EXAFS spectra without using fitting parameters. By using this methodology, it was possible to show that the branched alkyl chain amides form partly outer-sphere complexes with protonated ligands hydrogen bonded to nitrate ions. PMID:27171842

  15. Microwave-Assisted Syntheses of Amino Acid Ester Substituted Benzoic Acid Amides: Potential Inhibitors of Human CD81-Receptor HCV-E2 Interaction.

    PubMed

    Holzer, Marcel; Ziegler, Sigrid; Kronenberger, Bernd; Klein, Christian D; Hartmann, Rolf W

    2008-01-01

    Results from our group showed benzyl salicylate to be a moderate inhibitor of the CD81-LEL-HCV-E2 interaction. To increase the biological activity, heterocyclic substituted benzoic acids were coupled to amino acid esters via microwave assisted DCC-reaction. The prepared compounds were tested for their inhibitory potency by means of a fluorescence labeled antibody assay system using HUH7.5 cells. PMID:19662141

  16. Siro(haem)amide in Allochromatium vinosum and relevance of DsrL and DsrN, a homolog of cobyrinic acid a,c-diamide synthase, for sulphur oxidation.

    PubMed

    Lübbe, Yvonne J; Youn, Hyung-Sun; Timkovich, Russell; Dahl, Christiane

    2006-08-01

    In the purple sulphur bacterium Allochromatium vinosum, the prosthetic group of dissimilatory sulphite reductase (DsrAB) was identified as siroamide, an amidated form of the classical sirohaem. The genes dsrAB are the first two of a large cluster of genes necessary for the oxidation of sulphur globules stored intracellularly during growth on sulphide and thiosulphate. DsrN is homologous to cobyrinic acid a,c diamide synthase and may therefore catalyze glutamine-dependent amidation of sirohaem. Indeed, an A. vinosumDeltadsrN in frame deletion mutant showed a significantly reduced sulphur oxidation rate that was fully restored upon complementation with dsrN in trans. Sulphite reductase was still present in the DeltadsrN mutant. DsrL is a homolog of the small subunits of bacterial glutamate synthases and was proposed to deliver glutamine for sirohaem amidation. However, recombinant DsrL does not exhibit glutamate synthase activity nor does the gene complement a glutamate synthase-deficient Escherichia coli strain. Deletion of dsrL showed that the encoded protein is absolutely essential for sulphur oxidation in A. vinosum. PMID:16907720

  17. Synthesis and antihyperlipidemic activity of piperic acid derivatives.

    PubMed

    A, Rong; Bao, Narisu; Sun, Zhaorigetu; Borjihan, Gereltu; Qiao, Yanjiang; Jin, Zhuang

    2015-02-01

    A series of piperic acid derivatives were designed and synthesized from piperine/piperlonguminine, and their antihyperlipidemic activities evaluated in diet-induced hyperlipidemic rats with respect to simvastatin. Two promising analogues 3 and 10 were discovered and their antihyperlipidemic activities were comparable to or better than those of simvastatin. PMID:25920263

  18. Anticancer activity of branched-chain derivatives of oleic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A number of novel branched-chain derivatives (methyl, n-butyl, phenyl) of methyl oleate were produced by bromination in the allylic position and subsequent treatment with organocuprate reagents. These compounds and their free acid counterparts were tested in vitro for their antiproliferative activi...

  19. Palladium(III)-catalyzed fluorination of arylboronic acid derivatives.

    PubMed

    Mazzotti, Anthony R; Campbell, Michael G; Tang, Pingping; Murphy, Jennifer M; Ritter, Tobias

    2013-09-25

    A practical, palladium-catalyzed synthesis of aryl fluorides from arylboronic acid derivatives is presented. The reaction is operationally simple and amenable to multigram-scale synthesis. Evaluation of the reaction mechanism suggests a single-electron-transfer pathway, involving a Pd(III) intermediate that has been isolated and characterized. PMID:24040932

  20. Palladium-Catalyzed Carbonylation of β-Arylethylamide Directed by Oxalyl Amide in the Presence of Carbon Monoxide.

    PubMed

    Zhang, Li; Wang, Chao; Han, Jian; Huang, Zhi-Bin; Zhao, Yingsheng

    2016-06-17

    Pd-catalyzed regioselective coupling of β-C(sp(2))-H bonds in aromatic amines protected by oxalyl amide with carbon monoxide is reported. The reaction could tolerate various functional groups and could afford good to excellent yields of the corresponding 3,4-dihydroisoquinolinone derivatives. Remarkably, it could also tolerate β-arylethylamino acid and thiopheneethylamine derivatives, thus showing their potential for producing several important units for bioactive compound synthesis. PMID:27213988

  1. Synthesis and properties of coumaric acid derivative homo-polymers.

    PubMed

    Thi, Tran Hang; Matsusaki, Michiya; Shi, Dongjian; Kaneko, Tatsuo; Akashi, Mitsuru

    2008-01-01

    Poly(4-hydroxycinnamic acid) (P4HCA), poly(3-hydroxycinnamic acid) (P3HCA), poly(3-methoxy-4-hydroxycinnamic acid) (PMHCA) and poly(3,4-dihydroxycinnamic acid) (PDHCA) were synthesized by the thermal poly-condensation of the corresponding monomers, which are lignin precursors, coumaric acid derivatives consisting of cinnamoyl groups and different position and number of OH groups. The solubility of the homo-polymers in organic solvents decreased in the order of P3HCA > PDHCA > P4HCA > PMHCA. The wide angle X-ray diffraction (WAXD) results indicated that P4HCA or PMHCA with p-OH group had higher crystallinity, in contrast to P3HCA or PDHCA with m-OH group which had lower crystallinity. Crossed-polarizing microscopy suggested that P4HCA had the nematic liquid crystal properties at 220 degrees C and PDHCA showed birefringence properties at 200 degrees C. In cell-adhesion tests, PDHCA showed the highest cell adhesion (ca. 70%), whereas P3HCA, P4HCA and PMHCA had 50, 18 and 10% cell adhesion, respectively. The coumaric acid derivative homo-polymers can be useful as cell adhesion controllable thermotropic polymers for biomedical and environmental fields. PMID:18177555

  2. Salt forms of the pharmaceutical amide dihydrocarbamazepine.

    PubMed

    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. PMID:26846502

  3. Conformation-Specific IR and UV Spectroscopy of the Amino Acid Glutamine: Amide-Stacking and Hydrogen Bonding in AN Important Residue in Neurodegenerative Diseases

    NASA Astrophysics Data System (ADS)

    Walsh, Patrick S.; Dean, Jacob C.; Zwier, Timothy S.

    2014-06-01

    Glutamine plays an important role in several neurodegenerative diseases including Huntington's disease (HD) and Alzheimer's disease (AD). An intriguing aspect of the structure of glutamine is its incorporation of an amide group in its side chain, thereby opening up the possibility of forming amide-amide H-bonds between the peptide backbone and side chain. In this study the conformational preferences of two capped gluatamines Z(carboxybenzyl)-Glutamine-X (X=OH, NHMe) are studied under jet-cooled conditions in the gas phase in order to unlock the intrinsic structural motifs that are favored by this flexible sidechain. Conformational assignments are made by comparing the hydride stretch ( 3100-3700 cm-1) and amide I and II ( 1400-1800 cm-1) resonant ion-dip infrared spectra with predictions from harmonic frequency calculations. Assigned structures will be compared to previously published results on both natural and unnatural residues. Particular emphasis will be placed on the comparison between glutamine and unconstrained γ-peptides due to the similar three-carbon spacing between backbone and side chain in glutamine to the backbone spacing in γ-peptides. The ability of the glutamine side-chain to form amide stacked conformations will be a main focus, along with the prevalence of extended backbone type structures. W. H. James, III, C W. Müller, E. G. Buchanan, M. G. D. Nix, L. Guo, L. Roskop, M. S. Gordon, L. V. Slipchenko, S. H. Gellman, and T. S. Zwier, J. Am. Chem. Soc., 2009, 131(40), 14243-14245.

  4. Amino acid decarboxylations produced by lipid-derived reactive carbonyls in amino acid mixtures.

    PubMed

    Hidalgo, Francisco J; León, M Mercedes; Zamora, Rosario

    2016-10-15

    The formation of 2-phenylethylamine and phenylacetaldehyde in mixtures of phenylalanine, a lipid oxidation product, and a second amino acid was studied to determine the role of the second amino acid in the degradation of phenylalanine produced by lipid-derived reactive carbonyls. The presence of the second amino acid usually increased the formation of the amine and reduced the formation of the Strecker aldehyde. The reasons for this behaviour seem to be related to the α-amino group and the other functional groups (mainly amino or similar groups) present in the side-chain of the amino acid. These groups are suggested to modify the lipid-derived reactive carbonyl but not the reaction mechanism because the Ea of formation of both 2-phenylethylamine and phenylacetaldehyde remained unchanged in all studied systems. All these results suggest that the amine/aldehyde ratio obtained by amino acid degradation can be modified by adding free amino acids during food formulation. PMID:27173560

  5. The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats

    PubMed Central

    2011-01-01

    Background Neuropathic pain is a chronic disease resulting from dysfunction within the "pain matrix". The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. In this study, we have investigated the involvement of the transient receptor potential vanilloid type 1 (TRPV1) and the catabolic enzyme fatty acid amide hydrolase (FAAH) in the morphofunctional changes occurring in the pre-limbic/infra-limbic (PL/IL) cortex in neuropathic rats. Results The effect of N-arachidonoyl-serotonin (AA-5-HT), a hybrid FAAH inhibitor and TPRV1 channel antagonist, was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after repeated treatment with AA-5-HT. Consistently with the SNI-induced changes in PL/IL cortex neurons which underwent profound phenotypic reorganization, suggesting a profound imbalance between excitatory and inhibitory responses in the mPFC neurons, we found an increase in extracellular glutamate levels, as well as the up-regulation of FAAH and TRPV1 in the PL/IL cortex of SNI rats. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively. Conclusion These data suggest a possible involvement of endovanilloids in the cortical plastic changes

  6. Ultrasound-assisted direct oxidative amidation of benzyl alcohols catalyzed by graphite oxide.

    PubMed

    Mirza-Aghayan, Maryam; Ganjbakhsh, Nahid; Molaee Tavana, Mahdieh; Boukherroub, Rabah

    2016-09-01

    Ultrasound irradiation was successfully applied for the direct oxidative amidation of benzyl alcohols with amines into the corresponding amides using graphite oxide (GO) as an oxidative and reusable solid acid catalyst in acetonitrile as solvent at 50°C under air atmosphere. The direct oxidative amidation of benzyl alcohols takes place under mild conditions yielding the corresponding amides in good to high yields (69-95%) and short reaction times under metal-free conditions. PMID:27150743

  7. Highly versatile catalytic hydrogenation of carboxylic and carbonic acid derivatives using a Ru-triphos complex: molecular control over selectivity and substrate scope.

    PubMed

    vom Stein, Thorsten; Meuresch, Markus; Limper, Dominik; Schmitz, Marc; Hölscher, Markus; Coetzee, Jacorien; Cole-Hamilton, David J; Klankermayer, Jürgen; Leitner, Walter

    2014-09-24

    The complex [Ru(Triphos)(TMM)] (Triphos = 1,1,1-tris(diphenylphosphinomethyl)ethane, TMM = trimethylene methane) provides an efficient catalytic system for the hydrogenation of a broad range of challenging functionalities encompassing carboxylic esters, amides, carboxylic acids, carbonates, and urea derivatives. The key control factor for this unique substrate scope results from selective activation to generate either the neutral species [Ru(Triphos)(Solvent)H2] or the cationic intermediate [Ru(Triphos)(Solvent)(H)(H2)](+) in the presence of an acid additive. Multinuclear NMR spectroscopic studies demonstrated together with DFT investigations that the neutral species generally provides lower energy pathways for the multistep reduction cascades comprising hydrogen transfer to C═O groups and C-O bond cleavage. Carboxylic esters, lactones, anhydrides, secondary amides, and carboxylic acids were hydrogenated in good to excellent yields under these conditions. The formation of the catalytically inactive complexes [Ru(Triphos)(CO)H2] and [Ru(Triphos)(μ-H)]2 was identified as major deactivation pathways. The former complex results from substrate-dependent decarbonylation and constitutes a major limitation for the substrate scope under the neutral conditions. The deactivation via the carbonyl complex can be suppressed by addition of catalytic amounts of acids comprising non-coordinating anions such as HNTf2 (bis(trifluoromethane)sulfonimide). Although the corresponding cationic cycle shows higher overall barriers of activation, it provides a powerful hydrogenation pathway at elevated temperatures, enabling the selective reduction of primary amides, carbonates, and ureas in high yields. Thus, the complex [Ru(Triphos)(TMM)] provides a unique platform for the rational selection of reaction conditions for the selective hydrogenation of challenging functional groups and opens novel synthetic pathways for the utilization of renewable carbon sources. PMID:25208046

  8. Biological Activities of Oleanolic Acid Derivatives from Calendula officinalis Seeds.

    PubMed

    Zaki, Ahmed; Ashour, Ahmed; Mira, Amira; Kishikawa, Asuka; Nakagawa, Toshinori; Zhu, Qinchang; Shimizu, Kuniyoshi

    2016-05-01

    Phytochemical examination of butanol fraction of Calendula officinalis seeds led to the isolation of two compounds identified as 28-O-β-D-glucopyranosyl-oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS1) and oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS2). Biological evaluation was carried out for these two compounds such as melanin biosynthesis inhibitory, hyaluronic acid production activities, anti obesity using lipase inhibition and adipocyte differentiation as well as evaluation of the protective effect against hydrogen peroxide induced neurotoxicity in neuro-2A cells. The results showed that, compound CS2 has a melanin biosynthesis stimulatory activity; however, compound CS1 has a potent stimulatory effect for the production of hyaluronic acid on normal human dermal fibroblast from adult (NHDF-Ad). Both compounds did not show any inhibitory effect on both lipase and adipocyte differentiation. Compound CS2 could protect neuro-2A cells and increased cell viability against H2 O2 . These activities (melanin biosynthesis stimulatory and protective effect against H2 O2 of CS2 and hyaluronic acid productive activities of these triterpene derivatives) have been reported for the first time. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26887328

  9. Surface active molecules: preparation and properties of long chain n-acyl-l-alpha-amino-omega-guanidine alkyl acid derivatives.

    PubMed

    Infante, R; Dominguez, J G; Erra, P; Julia, R; Prats, M

    1984-12-01

    Synopsis A new route for the synthesis of long chain N(alpha)-acyl-l-alpha-amino-omega-guamdine alkyl acid derivatives, with cationic or amphoteric character has been established. The general formula of these compounds is shown below. A physico-chemical and antimicrobial study of these products as a function of the alkyl ester or sodium salt (R), the straight chain length of the fatty acid residue (x) and the number of carbons between the omega-guanidine and omega-carboxyl group (n) has been investigated. The water solubility, surface tension, critical micelle concentration (c.m.c.) and minimum inhibitory concentration (MIC) against Gram-positive and Gram-negative bacteria (including Pseudomonas) has been determined. Dicyclohexylcarbodiimide has been used to condense fatty acids and alpha-amino-omega-guanidine alkyl acids. In these conditions protection of the omega-guanidine group is not necessary. The main characteristic of this synthetic procedure is the use of very mild experimental conditions (temperature, pH) to form the amide linkage which leads to pure optical compounds in high yield in the absence of electrolytes. The results show that some structural modifications, particularly the protection of the carboxyl group, promote variations of the surfactant and antimicrobial properties. Only those molecules with the blocked carboxyl group (cationic molecules, where R = Me, Et or Pr) showed a good surfactant and antimicrobial activity. When the carboxyl group was unprotected (amphoteric molecules, where R = Na(+)) the resulting compounds were inactive. PMID:19467126

  10. Synthesis and properties of amides of 1-benzyl-3-methyl- and 1-butyl-3-phenyl-7-methyl-4-oxo-2-thioxo (2,4-dioxo)-1,2,3,4-tetrahydropyrido-[2,3-d]pyrimidine-6-carboxy lic acids.

    PubMed

    Sladowska, H; Zawisza, T

    1986-12-01

    Amides of 1-benzyl-3,7-dimethyl-4-oxo-2-thioxo-1,2,3,4- tetrahydropyrido[2,3]pyrimidine-6-carboxylic acid were obtained by the condensation of ammonia, primary and secondary cyclic amines with the corresponding acid chloride. As by - products amides of 1-benzyl-3,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyr imidine-6- carboxylic acid were isolated as a result of desulfuration. The same reaction performed with chloride of 1-butyl-7-methyl-3-phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyri do[2,3- d]pyrimidine-6-carboxylic acid gave mainly the corresponding 2,4-dioxo-amides. PMID:3556569

  11. [Cardioprotective properties of new glutamic acid derivative under stress conditions].

    PubMed

    Perfilova, V N; Sadikova, N V; Berestovitskaia, V M; Vasil'eva, O S

    2014-01-01

    The effect of new glutamic acid derivative on the cardiac ino- and chronotropic functions has been studied in experiments on rats exposed to 24-hour immobilization-and-pain stress. It is established that glutamic acid derivative RGPU-238 (glufimet) at a dose of 28.7 mg/kg increases the increment of myocardial contractility and relaxation rates and left ventricular pressure in stress-tested animals by 13 1,1, 72.4, and 118.6%, respectively, as compared to the control group during the test for adrenoreactivity. Compound RGPU-238 increases the increment of the maximum intensity of myocardium functioning by 196.5 % at 30 sec of isometric workload as compared to the control group. The cardioprotective effect of compound RGPU-238 is 1.5 - 2 times higher than that of the reference drug phenibut. PMID:25365864

  12. Gastroprotective effect and cytotoxicity of carnosic acid derivatives.

    PubMed

    Theoduloz, Cristina; Pertino, Mariano Walter; Rodríguez, Jaime A; Schmeda-Hirschmann, Guillermo

    2011-06-01

    Carnosic acid (CA) is the main phenolic diterpene of rosemary (Rosmarinus officinalis L., Lamiaceae) and presents gastroprotective effect in vitro and in vivo. To determine structure-activity relationships, seventeen esters and ethers of CA were prepared, comprising aliphatic, aromatic, and heterocyclic compounds. The naturally occurring 12-O-methylcarnosic acid (14) was also included in the study. The compounds were evaluated for their gastroprotective activity in the HCl/EtOH-induced gastric lesions model in mice, and for cytotoxicity in human adenocarcinoma AGS cells, Hep G2 hepatocellular carcinoma cells, and human lung fibroblasts. At 10 mg/kg, some of the CA derivatives (5, 8, 9, 12, 14, and 18) were more effective preventing gastric lesions than the reference compound lansoprazole at the same dose. The dibenzoate 9, diindoleacetate 12, and the derivative 18 showed the best gastroprotective effect combined with the lowest cytotoxicity. PMID:21246485

  13. Synthesis and antifungal activity of bile acid-derived oxazoles.

    PubMed

    Fernández, Lucía R; Svetaz, Laura; Butassi, Estefanía; Zacchino, Susana A; Palermo, Jorge A; Sánchez, Marianela

    2016-04-01

    Peracetylated bile acids (1a-g) were used as starting materials for the preparation of fourteen new derivatives bearing an oxazole moiety in their side chain (6a-g, 8a-g). The key step for the synthetic path was a Dakin-West reaction followed by a Robinson-Gabriel cyclodehydration. A simpler model oxazole (12) was also synthesized. The antifungal activity of the new compounds (6a-g) as well as their starting bile acids (1a-g) was tested against Candida albicans. Compounds 6e and 6g showed the highest percentages of inhibition (63.84% and 61.40% at 250 μg/mL respectively). Deacetylation of compounds 6a-g, led to compounds 8a-g which showed lower activities than the acetylated derivatives. PMID:26827629

  14. Microbial production of fatty acid-derived fuels and chemicals

    PubMed Central

    Lennen, Rebecca M; Pfleger, Brian F

    2013-01-01

    Fatty acid metabolism is an attractive route to produce liquid transportation fuels and commodity oleochemicals from renewable feedstocks. Recently, genes and enzymes, which comprise metabolic pathways for producing fatty acid-derived compounds (e.g. esters, alkanes, olefins, ketones, alcohols, polyesters) have been elucidated and used in engineered microbial hosts. The resulting strains often generate products at low percentages of maximum theoretical yields, leaving significant room for metabolic engineering. Economically viable processes will require strains to approach theoretical yields, particularly for replacement of petroleum-derived fuels. This review will describe recent progress toward this goal, highlighting the scientific discoveries of each pathway, ongoing biochemical studies to understand each enzyme, and metabolic engineering strategies that are being used to improve strain performance. PMID:23541503

  15. Branched-chain 2-keto acid decarboxylases derived from Psychrobacter.

    PubMed

    Wei, Jiashi; Timler, Jacobe G; Knutson, Carolann M; Barney, Brett M

    2013-09-01

    The conversion of branched-chain amino acids to branched-chain acids or alcohols is an important aspect of flavor in the food industry and is dependent on the Ehrlich pathway found in certain lactic acid bacteria. A key enzyme in the pathway, the 2-keto acid decarboxylase (KDC), is also of interest in biotechnology applications to produce small branched-chain alcohols that might serve as improved biofuels or other commodity feedstocks. This enzyme has been extensively studied in the model bacterium Lactococcus lactis, but is also found in other bacteria and higher organisms. In this report, distinct homologs of the L. lactis KDC originally annotated as pyruvate decarboxylases from Psychrobacter cryohalolentis K5 and P. arcticus 273-4 were cloned and characterized, confirming a related activity toward specific branched-chain 2-keto acids derived from branched-chain amino acids. Further, KDC activity was confirmed in intact cells and cell-free extracts of P. cryohalolentis K5 grown on both rich and defined media, indicating that the Ehrlich pathway may also be utilized in some psychrotrophs and psychrophiles. A comparison of the similarities and differences in the P. cryohalolentis K5 and P. arcticus 273-4 KDC activities to other bacterial KDCs is presented. PMID:23826991

  16. Interactions of salicylic acid derivatives with calcite crystals.

    PubMed

    Ukrainczyk, Marko; Gredičak, Matija; Jerić, Ivanka; Kralj, Damir

    2012-01-01

    Investigation of basic interactions between the active pharmaceutical compounds and calcium carbonates is of great importance because of the possibility to use the carbonates as a mineral carrier in drug delivery systems. In this study the mode and extent of interactions of salicylic acid and its amino acid derivates, chosen as pharmaceutically relevant model compounds, with calcite crystals are described. Therefore, the crystal growth kinetics of well defined rhombohedral calcite seed crystals in the systems containing salicylic acid (SA), 5-amino salicylic acid (5-ASA), N-salicyloil-l-aspartic acid (N-Sal-Asp) or N-salicyloil-l-glutamic acid (N-Sal-Glu), were investigated. The precipitation systems were of relatively low initial supersaturation and of apparently neutral pH. The data on the crystal growth rate reductions in the presence of the applied salicylate molecules were analyzed by means of Cabrera & Vermileya's, and Kubota & Mullin's models of interactions of the dissolved additives and crystal surfaces. The crystal growth kinetic experiments were additionally supported with the appropriate electrokinetic, spectroscopic and adsorption measurements. The Langmuir adsorption constants were determined and they were found to be in a good correlation with values obtained from crystal growth kinetic analyses. The results indicated that salicylate molecules preferentially adsorb along the steps on the growing calcite surfaces. The values of average spacing between the adjacent salicylate adsorption active sites and the average distance between the neighboring adsorbed salicylate molecules were also estimated. PMID:21963207

  17. 4-Hydroxybenzyl-substituted amino acid derivatives from Gastrodia elata

    PubMed Central

    Guo, Qinglan; Wang, Yanan; Lin, Sheng; Zhu, Chenggen; Chen, Minghua; Jiang, Zhibo; Xu, Chengbo; Zhang, Dan; Wei, Huailing; Shi, Jiangong

    2015-01-01

    Seven new 4-hydroxybenzyl-substituted amino acid derivatives (1−7), together with 11 known compounds, were isolated from an aqueous extract of the rhizomes of Gastrodia elata Blume. Their structures were determined by spectroscopic and chemical methods. Compounds 1−3 are pyroglutamate derivatives containing 4-hydroxybenzyl units at the N atom and 4−7 are the first examples of natural products with the 4-hydroxybenzyl unit linked via a thioether bond to 2-hydroxy-3-mercaptopropanoic acid (4−6) and 2-hydroxy-4-mercaptobutanoic acid (7), which would be biogenetically derived from cysteine and homocysteine, respectively. The structures of 1 and 2 were verified by synthesis, while the absolute configurations of 4, 5 and 7 were assigned using Mosher’s method based on the MPA determination rule of ΔδRS values. The known compound 4-(hydroxymethyl)-5-nitrobenzene-1,2-diol (8) exhibited activity against Fe2+-cysteine induced rat liver microsomal lipid peroxidation with IC50 values of 9.99×10−6 mol/L. PMID:26579466

  18. Synthesis and properties of synthetic fulvic acid derived from hematoxylin

    NASA Astrophysics Data System (ADS)

    Litvin, Valentina A.; Minaev, Boris F.; Baryshnikov, Gleb V.

    2015-04-01

    A model fulvic acid (FA) was synthesized from a natural dye, hematoxylin, in a slow oxidative polymerization/condensation reaction catalysed by OH- at pH ca. 12. The resulting dark-brown product, acidified to pH ca. 2, did not precipitate from the reaction solution. It was isolated and purified by cation-exchange resin. Its physicochemical and spectroscopic properties, as determined by means of elemental analysis, molecular weight analyses, Fourier transform infra red (FTIR) and ultraviolet-visible (UV-VIS) spectroscopy, X-ray diffraction and electron paramagnetic resonance (EPR) spectroscopy, showed a close resemblance to natural FA. The similarity and differences between synthetic fulvic acids derived from hematoxylin and the natural fulvic acids substances are discussed. Quantum-chemical calculations of the supposed primary oxidation products of hematoxylin are performed and compared with observations.

  19. Template directed reactions of 2-aminoadenylic acid derivatives

    NASA Technical Reports Server (NTRS)

    Webb, T. R.; Orgel, L. E.

    1982-01-01

    The template-directed oligomerization of activated derivatives of 2-aminoadenylic acid (paA) on polyuridylic acid (poly(U)) in aqueous buffers was studied. The reaction differs from that of adenylic acid (pA) under identical conditions, in that only di- and tri-nucleotides are observed as substantial products rather than a longer sequence of oligomers. The reaction of paA also differs from that of pA in that it does not require Mg (2+), and is less susceptible to increased temperature. The relevance of these observations to the chemical evolution of polynucleotide replication is discussed. Improved syntheses of paA and its diphosphate are reported.

  20. Selective anion sensing by a tris-amide CTV derivative: 1H NMR titration, self-assembled monolayers, and impedance spectroscopy.

    PubMed

    Zhang, Sheng; Echegoyen, Luis

    2005-02-16

    A hydrogen-bond forming tris(amide) receptor based on cyclotriveratrylene (CTV) was prepared. Self-assembled monolayers (SAMs) of the receptor were formed on gold surfaces. Desorption experiments show a surface coverage of 2.26 x 10(-10) mol/cm(2). (1)H NMR and UV measurements confirm that the receptor exhibits the highest affinity for acetate ions among the anions studied. Electrochemical impedance was used to investigate anion sensing by the SAMs and proved to be an efficient and convenient technique for detecting anions in aqueous solutions. Upon binding acetate anions, the monolayer-modified gold electrodes show a drastic increase of the R(ct) values when Fe(CN)(6)(3-/4-) is used as the redox probe. When the probe was changed to a positively charged one, Ru(NH3)(6)(3+/2+), the R(ct) values decreased monotonically as the acetate concentration was increased, thus confirming the accumulation of negative surface charge upon anion binding. H(2)PO(4-) shows some interference when sensing AcO-. Other monovalent anions such as Cl-, Br-, NO3(-) and HSO4(-) do not bind to the CTV receptor either in solution or on the surfaces. PMID:15701037

  1. Application of amino acid amides as chiral auxiliaries in difluoro dinitro benzene and cyanuric chloride moieties for high-performance liquid-chromatographic enantioseparation of selenomethionine and its mixture with methionine and cysteine.

    PubMed

    Bhushan, Ravi; Dubey, Rituraj

    2012-04-01

    L-Ala-NH(2), L-Val-NH(2), L-Leu-NH(2), and D-Phg-NH(2) were used as chiral auxiliaries to synthesize four chiral derivatizing reagents (CDRs) of each of the three categories, viz., difluoro dinitro benzene (DFDNB) based chiral variants, and cyanuric chloride (CC) based monochloro-s-triazine reagents (MCTs) and dichloro-s-triazine reagents (DCTs). DFDNB based chiral variants were synthesized by substituting one of the fluorine atoms of DFDNB with respective amino acid amides. The MCTs and DCTs were synthesized by substituting chlorine atom with aforesaid amino acid amide moieties in 6-methoxy dichloro-s-triazine and in CC, respectively. In total, 12 CDRs were characterized and used for microwave-assisted synthesis (45 s at 80% of 800 W using DFDNB-based chiral variants, 80 s at 90% of 800 W power using MCTs, and 50 s at 80% of 800 W power using DCTs) of diastereomers of (A) SeMet, and (B) mixture of (1) SeMet and Met, and (2) SeMet, Met, and Cys. The diastereomers were enantioseparated by reversed-phase high-performance liquid chromatography using gradient elution with mobile phases containing aq. TFA (0.1%)--MeCN in different compositions. The method was validated for accuracy, precision, and limit of detection. PMID:21293889

  2. Shoot-derived abscisic acid promotes root growth.

    PubMed

    McAdam, Scott A M; Brodribb, Timothy J; Ross, John J

    2016-03-01

    The phytohormone abscisic acid (ABA) plays a major role in regulating root growth. Most work to date has investigated the influence of root-sourced ABA on root growth during water stress. Here, we tested whether foliage-derived ABA could be transported to the roots, and whether this foliage-derived ABA had an influence on root growth under well-watered conditions. Using both application studies of deuterium-labelled ABA and reciprocal grafting between wild-type and ABA-biosynthetic mutant plants, we show that both ABA levels in the roots and root growth in representative angiosperms are controlled by ABA synthesized in the leaves rather than sourced from the roots. Foliage-derived ABA was found to promote root growth relative to shoot growth but to inhibit the development of lateral roots. Increased root auxin (IAA) levels in plants with ABA-deficient scions suggest that foliage-derived ABA inhibits root growth through the root growth-inhibitor IAA. These results highlight the physiological and morphological importance, beyond the control of stomata, of foliage-derived ABA. The use of foliar ABA as a signal for root growth has important implications for regulating root to shoot growth under normal conditions and suggests that leaf rather than root hydration is the main signal for regulating plant responses to moisture. PMID:26514625

  3. Biarylalkyl Carboxylic Acid Derivatives as Novel Antischistosomal Agents.

    PubMed

    Mäder, Patrick; Blohm, Ariane S; Quack, Thomas; Lange-Grünweller, Kerstin; Grünweller, Arnold; Hartmann, Roland K; Grevelding, Christoph G; Schlitzer, Martin

    2016-07-01

    Parasitic platyhelminths are responsible for serious infectious diseases, such as schistosomiasis, which affect humans as well as animals across vast regions of the world. The drug arsenal available for the treatment of these diseases is limited; for example, praziquantel is the only drug currently used to treat ≥240 million people each year infected with Schistosoma spp., and there is justified concern about the emergence of drug resistance. In this study, we screened biarylalkyl carboxylic acid derivatives for their antischistosomal activity against S. mansoni. These compounds showed significant influence on egg production, pairing stability, and vitality. Tegumental lesions or gut dilatation was also observed. Substitution of the terminal phenyl residue in the biaryl scaffold with a 3-hydroxy moiety and derivatization of the terminal carboxylic acid scaffold with carboxamides yielded compounds that displayed significant antischistosomal activity at concentrations as low as 10 μm with satisfying cytotoxicity values. The present study provides detailed insight into the structure-activity relationships of biarylalkyl carboxylic acid derivatives and thereby paves the way for a new drug-hit moiety for fighting schistosomiasis. PMID:27159334

  4. Synthesis and evaluation of colletoic acid core derivatives.

    PubMed

    Ling, Taotao; Gautam, Lekh Nath; Griffith, Elizabeth; Das, Sourav; Lang, Walter; Shadrick, William R; Shelat, Anang; Lee, Richard; Rivas, Fatima

    2016-03-01

    Cortisol homeostasis has been linked to the pathogenesis of metabolic syndrome (MetS), since it stimulates hepatic gluconeogenesis and adipogenesis. MetS is classified as a constellation of health conditions that increase the risk of type 2 diabetes and cardiovascular disease. Intracellular cortisol levels are regulated by 11β-hydroxysteroid dehydrogenase (type 1 and type 2) in a tissue dependent manner. The type 1 enzyme (11β-HSD1) is widely expressed in glucocorticoid targeted tissues and is responsible for the conversion of cortisone to the active cortisol. Local reduction of cortisol regeneration presents a potential strategy for MetS treatment. Recently we disclosed the total synthesis of (+)-colletoic acid as a potent 11β-HSD1 inhibitor. Herein, we describe our improved processing chemistry for the synthesis of the colletoic acid core to access a diverse number of derivatives for evaluation against 11β-HSD1. The Evan's chiral auxiliary was utilized to construct the acyclic precursor 12 to afford the acorane core 9 using a modified Heck reaction in excellent chemical yields. The colletoic acid core derivatives showed modest activity against 11β-HSD1 and will serve for further biological evaluation. PMID:26820555

  5. Novel sustainable polymers derived from renewable rosin and fatty acids

    NASA Astrophysics Data System (ADS)

    Wilbon, Perry

    In the work of this dissertation, polymers derived from renewable bio-based resources prepared by various polymerization techniques were investigated. The properties of these polymeric materials were characterized and discussed. Rosin was first converted into acrylate or methacrylate monomers for atom transfer radical polymerization (ATRP). Second, rosin was combined with vegetable oil to produce completely renewable novel polyesters by acyclic diene metathesis (ADMET) polymerization. Third, degradable block copolymers were synthesized composed of polycaprolactone and rosin grafted polycaprolactone with the aid of ring-opening polymerization (ROP). Finally, degradable polyesters were produced using vegetable oil derivatives as starting materials. These new rosin and fatty acid based renewable polymer materials will have potential applications as sustainable thermoplastics, thermoplastic elastomers, etc.

  6. Spectroscopic and structural elucidation of amino acid derivatives and small peptides: experimental and theoretical tools.

    PubMed

    Kolev, Tsonko; Spiteller, Michael; Koleva, Bojidarka

    2010-01-01

    structural information in the solid-state. It is obviously that only absolute crystallographic method can yield geometric parameters, bond lengths and angles, but the spectroscopic method presented can provide information about the dihedral angles for cis- and trans-configurated amide groups, mutual disposition of the aromatic fragments in peptides. Its validity is illustrated by comparing the theoretical and spectroscopic results obtained with available crystallographic data. The mini review can serve as a useful source of information not only for specialists in IR spectroscopy but, also, for other scientists, working in the field of structural analysis of amino acid derivatives and other small biologically active systems. PMID:19083080

  7. Esterification of fermentation-derived acids via pervaporation

    DOEpatents

    Datta, R.; Tsai, S.P.

    1998-03-03

    A low temperature method for esterifying ammonium- and amine-containing salts is provided whereby the salt is reacted with an alcohol in the presence of heat and a catalyst and then subjected to a dehydration and deamination process using pervaporation. The invention also provides for a method for producing esters of fermentation derived, organic acid salt comprising first cleaving the salt into its cationic part and anionic part, mixing the anionic part with an alcohol to create a mixture; heating the mixture in the presence of a catalyst to create an ester; dehydrating the now heated mixture; and separating the ester from the now-dehydrated mixture. 2 figs.

  8. Esterification of fermentation-derived acids via pervaporation

    DOEpatents

    Datta, Rathin; Tsai, Shih-Perng

    1998-01-01

    A low temperature method for esterifying ammonium- and amine-containing salts is provided whereby the salt is reacted with an alcohol in the presence of heat and a catalyst and then subjected to a dehydration and deamination process using pervaporation. The invention also provides for a method for producing esters of fermentation derived, organic acid salt comprising first cleaving the salt into its cationic part and anionic part, mixing the anionic part with an alcohol to create a mixture; heating the mixture in the presence of a catalyst to create an ester; dehydrating the now heated mixture; and separating the ester from the now-dehydrated mixture.

  9. Synthesis and biological activity of novel deoxycholic acid derivatives.

    PubMed

    Popadyuk, Irina I; Markov, Andrey V; Salomatina, Oksana V; Logashenko, Evgeniya B; Shernyukov, Andrey V; Zenkova, Marina A; Salakhutdinov, Nariman F

    2015-08-01

    We report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring deoxycholic acid (DCA) bearing 2-cyano-3-oxo-1-ene, 3-oxo-1(2)-ene or 3-oxo-4(5)-ene moieties in ring A and 12-oxo or 12-oxo-9(11)-ene moieties in ring C. Bioassays using murine macrophage-like cells and tumour cells show that the presence of the 9(11)-double bond associated with the increased polarity of ring A or with isoxazole ring joined to ring A, improves the ability of the compounds to inhibit cancer cell growth. PMID:26037611

  10. Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors.

    PubMed

    Ayers, Benjamin J; Glawar, Andreas F G; Martínez, R Fernando; Ngo, Nigel; Liu, Zilei; Fleet, George W J; Butters, Terry D; Nash, Robert J; Yu, Chu-Yi; Wormald, Mark R; Nakagawa, Shinpei; Adachi, Isao; Kato, Atsushi; Jenkinson, Sarah F

    2014-04-18

    All 16 stereoisomeric N-methyl 5-(hydroxymethyl)-3,4-dihydroxyproline amides have been synthesized from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers, including all eight with a (3R)-hydroxyl configuration, are low to submicromolar inhibitors of β-N-acetylhexosaminidases. A structural correlation between the proline amides is found with the ADMDP-acetamide analogues bearing an acetamidomethylpyrrolidine motif. The proline amides are generally more potent than their ADMDP-acetamide equivalents. β-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors. PMID:24641544

  11. Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.

    PubMed

    Wang, Xuekun; Zhao, Tianxiao; Yang, Baowei; Li, Zheng; Cui, Jian; Dai, Yuxuan; Qiu, Qianqian; Qiang, Hao; Huang, Wenlong; Qian, Hai

    2015-01-01

    Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50=62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus. PMID:25481394

  12. Synthesis and antimicrobial activities of new higher amino acid Schiff base derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid

    NASA Astrophysics Data System (ADS)

    Özdemir (nee Güngör), Özlem; Gürkan, Perihan; Özçelik, Berrin; Oyardı, Özlem

    2016-02-01

    Novel β-lactam derivatives (1c-3c) (1d-3d) were produced by using 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA) and the higher amino acid Schiff bases. The synthesized compounds were characterized by elemental analysis, IR, 1H/13C NMR and UV-vis spectra. Antibacterial activities of all the higher amino acid Schiff bases (1a-3a) (1b-3b) and β-lactam derivatives were screened against three gram negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii RSKK 02026), three gram positive bacteria (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 07005, Bacillus subtilis ATCC 6633) and their drug-resistant isolates by using broth microdilution method. Two fungi (Candida albicans and Candida krusei) were used for antifungal activity.

  13. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  14. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  15. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  16. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  17. 40 CFR 721.6110 - Alkyldi(alkyloxyhydroxypropyl) derivative, phosphoric acid esters, potassium salts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) derivative, phosphoric acid esters, potassium salts. 721.6110 Section 721.6110 Protection of Environment...) derivative, phosphoric acid esters, potassium salts. (a) Chemical substance and significant new uses subject...) derivative, phosphoric acid esters, potassium salts (PMN P-91-818) is subject to reporting under this...

  18. Combined dual effect of modulation of human neutrophils' oxidative burst and inhibition of colon cancer cells proliferation by hydroxycinnamic acid derivatives.

    PubMed

    Tavares-da-Silva, Elisiário J; Varela, Carla L; Pires, Ana S; Encarnação, João C; Abrantes, Ana M; Botelho, Maria F; Carvalho, Rui A; Proença, Carina; Freitas, Marisa; Fernandes, Eduarda; Roleira, Fernanda M F

    2016-08-15

    Colon cancer is one of the most incident cancers in the Western World. While both genetic and epigenetic factors may contribute to the development of colon cancer, it is known that chronic inflammation associated to excessive production of reactive oxygen and nitrogen species by phagocytes may ultimately initiate the multistep process of colon cancer development. Phenolic compounds, which reveal antioxidant and antiproliferative activities in colon cancer cells, can be a good approach to surpass this problem. In this work, hydroxycinnamic amides and the respective acid precursors were tested in vitro for their capacity to modulate human neutrophils' oxidative burst and simultaneously to inhibit growth of colon cancer cells. A phenolic amide derivative, caffeic acid hexylamide (CAHA) (4) was found to be the most active compound in both assays, inhibiting human neutrophils' oxidative burst, restraining the inflammatory process, inhibiting growth of colon cancer cells and triggering mitochondrial dysfunction that leads cancer cells to apoptosis. Altogether, these achievements can contribute to the understanding of the relationship between antioxidant and anticancer activities and based on the structure-activity relationships (SAR) established can be the starting point to find more effective phenolic compounds as anticancer agents. PMID:27290693

  19. Synthesis and anticancer activity of novel fluorinated asiatic acid derivatives.

    PubMed

    Gonçalves, Bruno M F; Salvador, Jorge A R; Marín, Silvia; Cascante, Marta

    2016-05-23

    A series of novel fluorinated Asiatic Acid (AA) derivatives were successfully synthesized, tested for their antiproliferative activity against HeLa and HT-29 cell lines, and their structure activity relationships were evaluated. The great majority of fluorinated derivatives showed stronger antiproliferative activity than AA in a concentration dependent manner. The most active compounds have a pentameric A-ring containing an α,β-unsaturated carbonyl group. The compounds with better cytotoxic activity were then evaluated against MCF-7, Jurkat, PC-3, A375, MIA PaCa-2 and BJ cell lines. Derivative 14 proved to be the most active compound among all tested derivatives and its mechanism of action was further investigated in HeLa cell line. The results showed that compound 14 induced cell cycle arrest in G0/G1 stage as a consequence of up-regulation of p21(cip1/waf1) and p27(kip1) and down-regulation of cyclin D3 and Cyclin E. Furthermore, compound 14 was found to induce caspase driven-apoptosis with activation of caspases-8 and caspase-3 and the cleavage of PARP. The cleavage of Bid into t-Bid, the up-regulation of Bax and the down-regulation of Bcl-2 were also observed after treatment of HeLa cells with compound 14. Taken together, these mechanistic studies revealed the involvement of extrinsic and intrinsic pathways in the apoptotic process induced by compound 14. Importantly, the antiproliferative activity of this compound on the non-tumor BJ human fibroblast cell line is weaker than in the tested cancer cell lines. The enhanced potency (between 45 and 90-fold more active than AA in a panel of cancer cell lines) and selectivity of this new AA derivative warrant further preclinical evaluation. PMID:26974379

  20. Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats

    PubMed Central

    Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

    2015-01-01

    Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography–tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID:26485038

  1. Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats.

    PubMed

    Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

    2015-01-01

    Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography-tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID:26485038

  2. Synthesis of a novel biologically active amide ester of 7,10-dihydroxy-8(E)-octadecanoic acid (DOD) using lipase

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hydroxy fatty acids (HFA) are known to have industrial potential because of their special properties such as high viscosity and reactivity. Among the hydroxy fatty acids, 7,10-dihydroxy-8(E)-octadecenoic acid (DOD) was successfully produced from oleic acid and lipid containing oleic acid by a bacter...

  3. Docosahexaenoic Acid-Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties.

    PubMed

    Kuda, Ondrej; Brezinova, Marie; Rombaldova, Martina; Slavikova, Barbora; Posta, Martin; Beier, Petr; Janovska, Petra; Veleba, Jiri; Kopecky, Jan; Kudova, Eva; Pelikanova, Terezie; Kopecky, Jan

    2016-09-01

    White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids-lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans. PMID:27313314

  4. Hydroxamic acid derivatives of mycophenolic acid inhibit histone deacetylase at the cellular level.

    PubMed

    Batovska, Daniela I; Kim, Dong Hoon; Mitsuhashi, Shinya; Cho, Yoon Sun; Kwon, Ho Jeong; Ubukata, Makoto

    2008-10-01

    Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively. PMID:18838793

  5. A potential plant-derived antifungal acetylenic acid mediates its activity by interfering with fatty acid homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses...

  6. Anti-inflammatory effects of hydroxycinnamic acid derivatives

    SciTech Connect

    Nagasaka, Reiko; Chotimarkorn, Chatchawan; Shafiqul, Islam Md.; Hori, Masatoshi; Ozaki, Hiroshi; Ushio, Hideki . E-mail: hushio@kaiyodai.ac.jp

    2007-06-29

    NF-{kappa}B family of transcription factors are involved in numerous cellular processes, including differentiation, proliferation, and inflammation. It was reported that hydroxycinnamic acid derivatives (HADs) are inhibitors of NF-{kappa}B activation. Rice bran oil contains a lot of phytosteryl ferulates, one of HADs. We have investigated effects of phytosteryl ferulates on NF-{kappa}B activation in macrophage. Cycloartenyl ferulate (CAF), one of phytosteryl ferulates, significantly reduced lipopolysaccharide (LPS)-induced NO production and mRNA expression of inducible NO synthase and cyclooxygenese-2 but upregulated SOD activity. Electrophoresis mobility shift assay revealed that CAF inhibited DNA-binding of NF-{kappa}B. CAF and phytosteryl ferulates probably have potentially anti-inflammatory properties.

  7. Four New Dicaffeoylquinic Acid Derivatives from Glasswort (Salicornia herbacea L.) and Their Antioxidative Activity.

    PubMed

    Cho, Jeong-Yong; Kim, Jin Young; Lee, Yu Geon; Lee, Hyoung Jae; Shim, Hyun Jeong; Lee, Ji Hye; Kim, Seon-Jae; Ham, Kyung-Sik; Moon, Jae-Hak

    2016-01-01

    Four new dicaffeoylquinic acid derivatives and two known 3-caffeoylquinic acid derivatives were isolated from methanol extracts using the aerial parts of Salicornia herbacea. The four new dicaffeoylquinic acid derivatives were established as 3-caffeoyl-5-dihydrocaffeoylquinic acid, 3-caffeoyl-5-dihydrocaffeoylquinic acid methyl ester, 3-caffeoyl-4-dihydrocaffeoylquinic acid methyl ester, and 3,5-di-dihydrocaffeoylquinic acid methyl ester. Their chemical structures were determined by nuclear magnetic resonance and electrospray ionization-mass spectroscopy (LC-ESI-MS). In addition, the presence of dicaffeoylquinic acid derivatives in this plant was reconfirmed by LC-ESI-MS/MS analysis. The isolated compounds strongly scavenged 1,1-diphenyl-2-picrylhydrazyl radicals and inhibited cholesteryl ester hydroperoxide formation during rat blood plasma oxidation induced by copper ions. These results indicate that the caffeoylquinic acid derivatives may partially contribute to the antioxidative effect of S. herbacea. PMID:27556430

  8. Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.

    PubMed

    Schwarz, Stefan; Lucas, Susana Dias; Sommerwerk, Sven; Csuk, René

    2014-07-01

    The development of remedies against the Alzheimer's disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE. PMID:24853320

  9. Studies of indium amides and nitrides

    SciTech Connect

    Purdy, A.P.; Berry, A.D.

    1993-12-31

    A reaction between InI{sub 3} and 3 eq. of KNH{sub 2} in liquid NH{sub 3} forms indium(III) amide (In(NH{sub 2}){sub 3}) a white, nearly insoluble compound. Indium(III) amide readily combines with KNH{sub 2} in liquid NH{sub 3} to form the mixed metal amide K{sub 2}In(NH{sub 2}){sub 5}. Other potassium and sodium derivatives MxIn(NH{sub 2}){sub 3+x} derivatives were prepared in a similar manner, but not all were obtained pure in the solid state. An impure tri-lithium derivative (Li{sub 3}In(NH{sub 2}){sub 6}) was obtained by adding a KNH{sub 2} solution (6 eq) to a solution of InI{sub 3} and 3 eq of LiI. Pyrolysis (in vacuo 25-300{degrees}C, under N{sub 2} 300-400{degrees}C) of In(NH{sub 2}){sub 3} or MxIn(NH{sub 2}){sub x+3} (M = Na, K) to 400{degrees}C results in the formation of InN, but indium metal is also formed from some of the mixed metal amides. The product from thermal decomposition of Li{sub 3}In(NH{sub 2}){sub 6} under vacuum was tentatively identified as the ternary nitride Li{sub 3}InN{sub 2}. Products were characterized by elemental analysis, IR spectroscopy, and powder x-ray diffraction experiments.

  10. Amide coordination effects in organolithiums

    SciTech Connect

    Bachrach, S.M.; Ritchie, J.P. )

    1989-04-26

    Organolithiums containing the amide group are examined by ab initio molecular orbital calculations with the 3-21G basis set. Amide coordination with the metal cation results in a large thermodynamic stabilization of the ion pair. Basis set superposition errors at 3-21G are estimated to favor the complex by 10-15 kcal mol{sup {minus}1}; nevertheless, qualitative trends at this level are believed to be reliable. The calculations stabilization energy due to the amide drops off depending upon whether lithiation occurs {alpha}, {beta}, or {gamma} to the amide - provided the cation is accessible to the amide oxygen. Without correction for basis set superposition error, stabilization energies at 3-21G (in kcal mol{sup {minus}1}) are 45 in acetamide, 40 in benzamide, and 38 in syn-bicyclo(1.1.1)-pentane-2-carboxamide. Amide coordination effects in lithiocubanes are also estimated and found to be large. Thus, thermodynamics plays an important role in amide-assisted metalations. In addition, formation of an acetamide-methyllithium complex is found to be 37.5 kcal mol{sup {minus}1} exothermic relative to separated molecules, suggesting that formation of this complex lies along the metalation reaction pathways. This complexation facilitates the reaction kinetically. Analysis of electron density distributions and electrostatic potentials shows that the carbanion-lithium and the amide-lithium interactions are primarily closed-shell ones, being essentially ionic bonds.

  11. Amides of non-steroidal anti-inflammatory drugs with thiomorpholine can yield hypolipidemic agents with improved anti-inflammatory activity.

    PubMed

    Theodosis-Nobelos, Panagiotis; Kourti, Malamati; Gavalas, Antonios; Rekka, Eleni A

    2016-02-01

    Novel amides of non steroidal anti-inflammatory drugs (NSAIDs), α-lipoic acid and indole-3-acetic acid with thiomorpholine were synthesised by a simple method and at high yields (60-92%). All the NSAID derivatives highly decreased lipidemic indices in the plasma of Triton treated hyperlipidemic rats. The most potent compound was the indomethacin derivative, which decreased total cholesterol, triglycerides and LDL cholesterol by 73%, 80% and 83%, respectively. They reduced acute inflammation equally or more than most parent acids. Hence, it could be concluded that amides of common NSAIDs with thiomorpholine acquire considerable hypolipidemic potency, while they preserve or augment their anti-inflammatory activity, thus addressing significant risk factors for atherogenesis. PMID:26750253

  12. Amino Acid-Derived Bifunctional Phosphines for Enantioselective Transformations.

    PubMed

    Wang, Tianli; Han, Xiaoyu; Zhong, Fangrui; Yao, Weijun; Lu, Yixin

    2016-07-19

    Even though seminal reports on phosphine catalysis appeared in the 1960s, in the last few decades of the past century trivalent phosphines were viewed primarily as useful ligands for transition-metal-mediated processes. The 1990s saw revived interest in using phosphines in organic catalysis, but the key advances in asymmetric phosphine catalysis have all come within the past decade. The uniqueness of phosphine catalysis can be attributed to the high nucleophilicity of the phosphorus atom. In typical phosphine-catalyzed reactions, nucleophilic attacks of the phosphorus atom on electron-deficient multiple bonds create different reactive ylide-type intermediates. When such structurally diverse zwitterionic species react with a variety of suitable substrates, new reaction patterns are often discovered and a diverse array of reactions can be developed. In recent years, substantial progress has been made in the field of asymmetric phosphine catalysis; many new reactions have been discovered, and numerous enantioselective processes have been reported. However, we felt that powerful and versatile phosphine catalysts that can work for a wide range of asymmetric reactions are still lacking. We therefore set our goal to develop a family of easily derived phosphine catalysts that are efficient in asymmetric induction for a broad range of phosphine-mediated transformations. This Account describes our efforts in the past few years on the development of amino acid-based bifunctional phosphines and their applications to enantioselective processes. Building upon our previous success in primary-amine-mediated enamine catalysis, we first established that bifunctional phosphines could be readily prepared from amino acids. In most of our studies, we chose threonine as the key backbone for catalyst development, and threonine-based monoamino acid or dipeptide bifunctional phosphines have displayed remarkable stereochemical control. We began our investigations by demonstrating the

  13. Anticholesterolemic effect of 3,4-di(OH)-phenylpropionic amides in high-cholesterol fed rats

    SciTech Connect

    Kim, Soon-Ja; Bok, Song-Hae; Lee, Sangku; Kim, Hye-Jin; Lee, Mi-Kyung; Park, Yong Bok; Choi, Myung-Sook . E-mail: mschoi@knu.ac.kr

    2005-10-01

    Two amide synthetic derivatives of 3,4-di(OH)-hydrocinnamate (HC), 3,4-dihydroxyphenylpropionic (L-serine methyl ester) amide (E030) and 3,4-dihydroxyphenylpropionic (L-aspartic acid) amide (E076), were investigated to compare their lipid-lowering efficacy with HC. Male rats were fed a 1 g/100 g high-cholesterol diet for 6 weeks with supplements of either clofibrate (0.02%, w/w), HC (0.025%, w/w), E030 (0.039%, w/w) or E076 (0.041%, w/w). The clofibrate supplement was used as a positive control for the lipid-lowering efficacy. The food intakes and body weight gains were not significantly different among the groups. The plasma and hepatic cholesterol and triglyceride levels were lower in clofibrate, HC, E030, and E076-supplemented groups compared to the control group. The supplementation of HC and its amide derivatives was as effective as clofibrate in increasing the ratio of HDL-cholesterol to total plasma cholesterol and reducing the atherogenic index (AI). The hepatic cholesterol level in the HC and E076 groups was significantly lower than that in the clofibrate group. The hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA reductase) and acyl-CoA:cholesterol acyltransferase (ACAT) activities were significantly lower in the all test groups than in the control group. The excretion of neutral sterol was significantly higher in the HC, E030, and E076-supplemented groups compared to the control group. The plasma AST and ALT activities, indirect indexes of hepatic toxicity, were significantly lower in the HC, E030, and E076-supplemented groups than in the control group. Accordingly, the current results suggest that E030 and E076, two amide synthetic derivatives of HC, are effective in lowering lipid activity.

  14. Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes.

    PubMed

    Ow, Yin-Yin; Stupans, Ieva

    2003-06-01

    Gallic acid and its structurally related compounds are found widely distributed in fruits and plants. Gallic acid, and its catechin derivatives are also present as one of the main phenolic components of both black and green tea. Esters of gallic acid have a diverse range of industrial uses, as antioxidants in food, in cosmetics and in the pharmaceutical industry. In addition, gallic acid is employed as a source material for inks, paints and colour developers. Studies utilising these compounds have found them to possess many potential therapeutic properties including anti-cancer and antimicrobial properties. In this review, studies of the effects of gallic acid, its esters, and gallic acid catechin derivatives on Phase I and Phase II enzymes are examined. Many published reports of the effects of the in vitro effects of gallic acid and its derivatives on drug metabolising enzymes concern effects directly on substrate (generally drug or mutagen) metabolism or indirectly through observed effects in Ames tests. In the case of the Ames test an antimutagenic effect may be observed through inhibition of CYP activation of indirectly acting mutagens and/or by scavenging of metabolically generated mutagenic electrophiles. There has been considerable interest in the in vivo effects of the gallate esters because of their incorporation into foodstuffs as antioxidants and in the catechin gallates with their potential role as chemoprotective agents. Principally an induction of Phase II enzymes has been observed however more recent studies using HepG2 cells and primary cultures of human hepatocytes provide evidence for the overall complexity of actions of individual components versus complex mixtures, such as those in food. Further systematic studies of mechanisms of induction and inhibition of drug metabolising enzymes by this group of compounds are warranted in the light of their distribution and consequent ingestion, current uses and suggested therapeutic potential. However, it

  15. Effects of Sodium Butyrate and Its Synthetic Amide Derivative on Liver Inflammation and Glucose Tolerance in an Animal Model of Steatosis Induced by High Fat Diet

    PubMed Central

    Mattace Raso, Giuseppina; Simeoli, Raffaele; Russo, Roberto; Iacono, Anna; Santoro, Anna; Paciello, Orlando; Ferrante, Maria Carmela; Canani, Roberto Berni; Calignano, Antonio; Meli, Rosaria

    2013-01-01

    Background & Aims Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Insulin resistance (IR) appears to be critical in its pathogenesis. We evaluated the effects of sodium butyrate (butyrate) and its synthetic derivative N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) in a rat model of insulin resistance and steatosis induced by high-fat diet (HFD). Methods After weaning, young male Sprague-Dawley rats were divided into 4 groups receiving different diets for 6 weeks: 1. control group (standard diet); 2. HFD; 3. HFD plus butyrate (20 mg/kg/die) and 4. HFD plus FBA (42.5 mg/Kg/die, the equimolecular dose of butyrate). Liver tissues of the rats were analyzed by Western blot and real-time PCR. Insulin resistance, liver inflammation and Toll-like pattern modifications were determined. Results Evaluation of these two preparations of butyrate showed a reduction of liver steatosis and inflammation in HFD fed animals. The compounds showed a similar potency in the normalisation of several variables, such as transaminases, homeostasis model assessment for insulin resistance index, and glucose tolerance. Both treatments significantly reduced hepatic TNF-α expression and restored GLUTs and PPARs, either in liver or adipose tissue. Finally, FBA showed a higher potency in reducing pro-inflammatory parameters in the liver, via suppression of Toll-like receptors and NF-κB activation. Conclusions Our results demonstrated a protective effect of butyrate in limiting molecular events underlying the onset of IR and NAFLD, suggesting a potential clinical relevance for this substance. In particular, its derivative, FBA, could represent an alternative therapeutic option to sodium butyrate, sharing a comparable efficacy, but a better palatability and compliance. PMID:23861927

  16. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  17. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  18. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  19. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... Substances § 721.10045 Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  20. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical... as oxo-substituted amino al-kan-oic acid derivative (PMN No. P-92-692) is subject to reporting...

  1. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical... as oxo-substituted amino al-kan-oic acid derivative (PMN No. P-92-692) is subject to reporting...

  2. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical... as oxo-substituted amino al-kan-oic acid derivative (PMN No. P-92-692) is subject to reporting...

  3. 40 CFR 721.10045 - Diazotized substituted heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (generic). 721.10045... derivative, nickel complex, alkaline salt (generic). (a) Chemical substance and significant new uses subject... heteromonocycle coupled with naphthalene sulfonic acid derivative, nickel complex, alkaline salt (PMN P-02-737)...

  4. Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid- and Multidrug-resistant Escherichia coli.

    PubMed

    Dwivedi, Gaurav Raj; Maurya, Anupam; Yadav, Dharmendra Kumar; Khan, Feroz; Darokar, Mahendra P; Srivastava, Santosh Kumar

    2015-09-01

    As a part of our drug discovery program, ursolic acid was chemically transformed into six semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid-sensitive and nalidixic acid-resistant strains of Escherichia coli. Although ursolic acid and its all semi-synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3-O-acetyl-urs-12-en-28-isopropyl ester (UA-4) and 3-O-acetyl-urs-12-en-28-n-butyl ester (UA-5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid-resistant and four and eightfold against nalidixic acid-sensitive, respectively. The UA-4 and UA-5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug-resistant clinical isolate of Escherichia coli-KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration-dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA-4 and UA-5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug-resistant Gram-negative infections. PMID:25476148

  5. Cannabimimetic fatty acid derivatives in cancer and inflammation.

    PubMed

    Di Marzo, V; Melck, D; De Petrocellis, L; Bisogno, T

    2000-04-01

    Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e. anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA), in the control of inflammation and of the proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2-AG can be induced by stimulation with either Ca(2+) ionophores, lipopolysaccharide, or platelet activating factor in macrophages, and by ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a widely used model for mast cells). These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate cytokine and/or arachidonate release from macrophages in vitro, regulate serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models of inflammatory pain. However, the involvement of endogenous CFADs and cannabinoid CB(1) and CB(2) receptors in these effects is still controversial. In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation. Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity. These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here. PMID:10785541

  6. Energy densification of biomass-derived organic acids

    DOEpatents

    Wheeler, M. Clayton; van Walsum, G. Peter; Schwartz, Thomas J.; van Heiningen, Adriaan

    2013-01-29

    A process for upgrading an organic acid includes neutralizing the organic acid to form a salt and thermally decomposing the resulting salt to form an energy densified product. In certain embodiments, the organic acid is levulinic acid. The process may further include upgrading the energy densified product by conversion to alcohol and subsequent dehydration.

  7. Copper-catalyzed direct amidation of heterocycles with N-fluorobenzenesulfonimide.

    PubMed

    Wang, Sichang; Ni, Zhangqin; Huang, Xin; Wang, Jichao; Pan, Yuanjiang

    2014-11-01

    A highly efficient amidation reaction of heterocycles with N-fluorobenzenesulfonimide (NFSI) has been developed, presumably proceeding via C-H bond activation. Cuprous iodide was employed as the catalyst, and various α-amidated heterocycle derivatives have been generated in good to excellent yields. This chemistry endowed an economic method of synthesis of valuable amidated heterocycles through a direct C-N bond-coupling processes. PMID:25310043

  8. Benzoic acid derivatives from Piper species and their antiparasitic activity.

    PubMed

    Flores, Ninoska; Jiménez, Ignacio A; Giménez, Alberto; Ruiz, Grace; Gutiérrez, David; Bourdy, Genevieve; Bazzocchi, Isabel L

    2008-09-01

    Piper glabratum and P. acutifolium were analyzed for their content of main secondary constituents, affording nine new benzoic acid derivatives (1, 2, 4, 5, 7, and 10-13), in addition to four known compounds (3, 6, 8, and 9). Their structures were elucidated on the basis of spectroscopic data. Riguera ester reactions and optical rotation measurements established the new compounds as racemates. In the search for antiparasitic agents, the compounds were evaluated in vitro against the promastigote forms of Leishmania spp., Trypanosoma cruzi, and Plasmodium falciparum. Among the evaluated compounds, methyl 3,4-dihydroxy-5-(3'-methyl-2'-butenyl)benzoate (7) exhibited leishmanicidal effect (IC50 13.8-18.5 microg/mL) against the three Leishmania strains used, and methyl 3,4-dihydroxy-5-(2-hydroxy-3-methylbutenyl)benzoate (1), methyl 4-hydroxy-3-(2-hydroxy-3-methyl-3-butenyl)benzoate (3), and methyl 3,4-dihydroxy-5-(3-methyl-2-butenyl) benzoate (7) showed significant trypanocidal activity, with IC50 values of 16.4, 15.6, and 18.5 microg/mL, respectively. PMID:18712933

  9. Discotic liquid crystal derived from zinc tetraaminophthalocyanine and perfluorooctanoic acid

    NASA Astrophysics Data System (ADS)

    Meng, Fanbao; Zhou, Naiyu; Diao, Na; Du, Chang

    2013-12-01

    A novel kind of metallo-phthalocyanine derivative, zinc 2,9,16,23-tetraaminophthalocyanine perfluorooctanoate (Zn-APc-pFOA), was synthesized from zinc tetraaminophthalocyanine and perfluorooctanoic acid. The chemical structure, liquid crystalline behavior, and electrorheological properties were characterized by the use of various experimental techniques, methods, and instruments, including FT-IR and UV-vis spectroscopy, 1H-NMR, x-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, polarized optical microscopy, the four-point method, a relative permittivity test instrument, and a rotating viscometer. Zn-APc-pFOA shows a discotic hexagonal columnar mesophase over a wide temperature range. The dielectric constant and conductivity of Zn-APc-pFOA are 11.4 and 6.34 × 10-3 S cm-1, respectively. The 20 V% silicone oil-Zn-APc-pFOA fluid shows an electrorheological (ER) effect. Zn-APc-pFOA is a semiconductor with a high dielectric constant, causing a mismatch of conductivity and dielectric constant between the Zn-APc-pFOA and silicone oil. Furthermore, some synergistic effect could occur between the semiconducting property and the molecular orientation of the discotic liquid crystals in Zn-APc-pFOA suspensions, resulting in a high ER effect.

  10. GLP-1(32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight Gain in Obese Mice.

    PubMed

    Tomas, Eva; Stanojevic, Violeta; McManus, Karen; Khatri, Ashok; Everill, Paul; Bachovchin, William W; Habener, Joel F

    2015-07-01

    The prevalence of obesity-related diabetes is increasing worldwide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure and curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in diet-induced obese mice. The pentapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetyl-CoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes, GLP-1(32-36)amide activated AMPK and inhibited acetyl-CoA carboxylase, suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy, the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure, GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders. PMID:25858562

  11. GLP-1(32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight Gain in Obese Mice

    PubMed Central

    Tomas, Eva; Stanojevic, Violeta; McManus, Karen; Khatri, Ashok; Everill, Paul; Bachovchin, William W.

    2015-01-01

    The prevalence of obesity-related diabetes is increasing worldwide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure and curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in diet-induced obese mice. The pentapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetyl-CoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes, GLP-1(32-36)amide activated AMPK and inhibited acetyl-CoA carboxylase, suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy, the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure, GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders. PMID:25858562

  12. Possible evidence of amide bond formation between sinapinic acid and lysine-containing bacterial proteins by matrix-assisted laser desorption/ionization (MALDI) at 355 nm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We previously reported the apparent formation of matrix adducts of 3,5-dimethoxy-4-hydroxy-cinnamic acid (sinapinic acid or SA) via covalent attachment to disulfide bond-containing proteins (HdeA, HdeB and YbgS) from bacterial cell lysates ionized by matrix-assisted laser desorption/ionization (MALD...

  13. Tandem dissolution of UO3 in amide-based acidic ionic liquid and in situ electrodeposition of UO2 with regeneration of the ionic liquid: a closed cycle.

    PubMed

    Wanigasekara, Eranda; Freiderich, John W; Sun, Xiao-Guang; Meisner, Roberta A; Luo, Huimin; Delmau, Lætitia H; Dai, Sheng; Moyer, Bruce A

    2016-06-21

    A closed cycle is demonstrated for the tandem dissolution and electroreduction of UO3 to UO2 with regeneration of the acidic ionic liquid. The dissolution is achieved by use of the acidic ionic liquid [DMAH][NTf2] in [EMIM][NTf2] serving as the diluent. A sequential dissolution, electroreduction, and regeneration cycle is presented. PMID:27255672

  14. Electrophilic Activation of α,β-Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ-Butyrolactones.

    PubMed

    Zhang, Ming; Kumagai, Naoya; Shibasaki, Masakatsu

    2016-04-11

    Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β-unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β-unsaturated 7-azaindoline amides act as reactive electrophiles to participate in catalytic diastereo- and enantioselective vinylogous conjugate addition of γ-butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner. PMID:26970428

  15. Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A.

    PubMed

    Vaidya, S; Bostedor, R; Kurtz, M M; Bergstrom, J D; Bansal, V S

    1998-07-01

    The zaragozic acids are potent inhibitors of squalene synthase. In vivo studies in mice confirmed our earlier observations that inhibition of squalene synthase by zaragozic acid A was accompanied by an increase in the incorporation of label from [3H]mevalonate into farnesyl-diphosphate (FPP)-derived isoprenoic acids (J. D. Bergstrom et al., 1993, Proc. Natl. Acad. Sci. USA 90, 80-84). Farnesyl-diphosphate-derived metabolites appear transiently in the liver. We were unable to detect any farnesol formation in the zaragozic acid-treated animals which indicates that FPP is readily converted to farnesoic acid and dicarboxylic acids in the liver. These metabolites were found to be produced only in the liver and not in the kidney. trans-3,7-Dimethyl-2-octaen-1,8-dioic acid and 3, 7-dimethyloctan-1,8-dioic acid were identified as the major end products of farnesyl-diphosphate metabolism in the urine of mice treated with zaragozic acid A. Quantitative analysis of these FPP-derived dicarboxylic acids by gas-liquid chromatography revealed that approximately 11 mg of total dicarboxylic acids is excreted per day into the urine of a mouse after 3 days of treatment with zaragozic acid A. PMID:9647670

  16. Vacuolar deposition of ascorbate-derived oxalic acid in barley

    SciTech Connect

    Wagner, G.J.

    1981-03-01

    L-(1-/sup 14/C)Ascorbic acid was supplied to detached barley seedlings to determine the subcellular location of oxalic acid, one of its metabolic products. Intact vacuoles isolated from protoplasts of labeled leaves contained (/sup 14/C)oxalic acid which accounted for about 70% of the intraprotoplast soluble oxalic acid. Tracer-labeled oxalate accounted for 36 and 72% of the /sup 14/C associated with leaf vacuoles of seedlings labeled for 22 and 96 hours, respectively.

  17. Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142.

    PubMed

    Shin, Hee Jae; Pil, Gam Bang; Heo, Soo-Jin; Lee, Hyi-Seung; Lee, Jong Seok; Lee, Yeon-Ju; Lee, Jihoon; Won, Ho Shik

    2016-01-01

    Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1-5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production and the new tanzawaic acid Q (1) inhibited the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA expressions in RAW 264.7 macrophages. Additionally, compound 1 reduced the mRNA levels of inflammatory cytokines. Taken together, the results of this study demonstrated that the new tanzawaic acid derivative inhibits LPS-induced inflammation. This is the first report on the anti-inflammatory activity of tanzawaic acid Q (1). PMID:26761016

  18. Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142

    PubMed Central

    Shin, Hee Jae; Pil, Gam Bang; Heo, Soo-Jin; Lee, Hyi-Seung; Lee, Jong Seok; Lee, Yeon-Ju; Lee, Jihoon; Won, Ho Shik

    2016-01-01

    Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1–5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production and the new tanzawaic acid Q (1) inhibited the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA expressions in RAW 264.7 macrophages. Additionally, compound 1 reduced the mRNA levels of inflammatory cytokines. Taken together, the results of this study demonstrated that the new tanzawaic acid derivative inhibits LPS-induced inflammation. This is the first report on the anti-inflammatory activity of tanzawaic acid Q (1). PMID:26761016

  19. Tandem dissolution of UO 3 in amide-based acidic ionic liquid and in situ electrodeposition of UO 2 with regeneration of the ionic liquid: a closed cycle

    DOE PAGESBeta

    Wanigasekara, Eranda; Freiderich, John W.; Sun, Xiao-Guang; Meisner, Roberta A.; Luo, Huimin; Delmau, Lætitia H.; Dai, Sheng; Moyer, Bruce A.

    2016-05-19

    A closed cycle is demonstrated for the tandem dissolution and electroreduction of UO3 to UO2 with regeneration of the acidic ionic liquid. The dissolution is achieved by use of the acidic ionic liquid N,N-dimethylacetimidium bis(trifluoromethanesulfonimide) in 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonimide) serving as the diluent. Bulk electrolysis performed at 1.0 V vs. Ag reference yields a dark brown-black uranium deposit (UO2) on the cathode. Anodic oxidation of water in the presence of dimethylacetamide regenerates the acidic ionic liquid. We have demonstrated the individual steps in the cycle together with a sequential dissolution, electroreduction, and regeneration cycle.

  20. Metabolic engineering of yeast to produce fatty acid-derived biofuels: bottlenecks and solutions.

    PubMed

    Sheng, Jiayuan; Feng, Xueyang

    2015-01-01

    Fatty acid-derived biofuels can be a better solution than bioethanol to replace petroleum fuel, since they have similar energy content and combustion properties as current transportation fuels. The environmentally friendly microbial fermentation process has been used to synthesize advanced biofuels from renewable feedstock. Due to their robustness as well as the high tolerance to fermentation inhibitors and phage contamination, yeast strains such as Saccharomyces cerevisiae and Yarrowia lipolytica have attracted tremendous attention in recent studies regarding the production of fatty acid-derived biofuels, including fatty acids, fatty acid ethyl esters, fatty alcohols, and fatty alkanes. However, the native yeast strains cannot produce fatty acids and fatty acid-derived biofuels in large quantities. To this end, we have summarized recent publications in this review on metabolic engineering of yeast strains to improve the production of fatty acid-derived biofuels, identified the bottlenecks that limit the productivity of biofuels, and categorized the appropriate approaches to overcome these obstacles. PMID:26106371

  1. Metabolic engineering of yeast to produce fatty acid-derived biofuels: bottlenecks and solutions

    PubMed Central

    Sheng, Jiayuan; Feng, Xueyang

    2015-01-01

    Fatty acid-derived biofuels can be a better solution than bioethanol to replace petroleum fuel, since they have similar energy content and combustion properties as current transportation fuels. The environmentally friendly microbial fermentation process has been used to synthesize advanced biofuels from renewable feedstock. Due to their robustness as well as the high tolerance to fermentation inhibitors and phage contamination, yeast strains such as Saccharomyces cerevisiae and Yarrowia lipolytica have attracted tremendous attention in recent studies regarding the production of fatty acid-derived biofuels, including fatty acids, fatty acid ethyl esters, fatty alcohols, and fatty alkanes. However, the native yeast strains cannot produce fatty acids and fatty acid-derived biofuels in large quantities. To this end, we have summarized recent publications in this review on metabolic engineering of yeast strains to improve the production of fatty acid-derived biofuels, identified the bottlenecks that limit the productivity of biofuels, and categorized the appropriate approaches to overcome these obstacles. PMID:26106371

  2. Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

    PubMed

    Khom, S; Hintersteiner, J; Luger, D; Haider, M; Pototschnig, G; Mihovilovic, M D; Schwarzer, C; Hering, S

    2016-06-01

    Valerenic acid (VA)-a β2/3-selective GABA type A (GABAA) receptor modulator-displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA's methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas

  3. Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives

    PubMed Central

    Hintersteiner, J.; Luger, D.; Haider, M.; Pototschnig, G.; Mihovilovic, M. D.; Schwarzer, C.; Hering, S.

    2016-01-01

    Valerenic acid (VA)—a β2/3-selective GABA type A (GABAA) receptor modulator—displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA’s methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg

  4. Formation of Amides from Imines via Cyanide-Mediated Metal-Free Aerobic Oxidation.

    PubMed

    Seo, Hong-Ahn; Cho, Yeon-Ho; Lee, Ye-Sol; Cheon, Cheol-Hong

    2015-12-18

    A new protocol for the direct formation of amides from imines derived from aromatic aldehydes via metal-free aerobic oxidation in the presence of cyanide is described. This protocol was applicable to various aldimines, and the desired amides were obtained in moderate to good yields. Mechanistic studies suggested that this aerobic oxidative amidation might proceed via the addition of cyanide to imines followed by proton transfer from carbon to nitrogen in the original imines, leading to carbanions of α-amino nitriles, which undergo subsequent oxidation with molecular oxygen in air to provide the desired amide compounds. PMID:26580330

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

    PubMed

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

    1999-02-22

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

  6. Biosynthesis of peptide neurotransmitters: studies on the formation of peptide amides.

    PubMed

    Bradbury, A F; Smyth, D G

    1988-01-01

    A high proportion of peptide transmitters and peptide hormones terminate their peptide chain in a C-terminal amide group which is essential for their biological activity. The specificity of an enzyme that catalyses the formation of the amide was investigated with the aid of synthetic peptide substrates. With peptides containing l-amino acids the enzyme exhibited an essential requirement for glycine in the C-terminal position; amidation did not take place with peptides that had leucine, alanine, glutamic acid, lysine or N-methylglycine at the C-terminus and a peptide extended by the attachment of lysine to the C-terminal glycine did not act as a substrate. Amidation did occur with a peptide containing C-terminal D-alanine but no reaction was detected with peptides having C-terminal, D-serine or D-leucine. In tripeptides with a neutral amino acid in the penultimate position, amidation, took place readily but the reaction was slower when this position was occupied by an acidic or a basic residue. A series of overlapping peptides with C-terminal glycine, based on partial sequences of calcitonin, underwent amidation at similar rates, indicating that the amidating enzyme recognizes only a limited sequence at the C-terminus of its substrates. The results provide evidence that the amidating enzyme has a highly compact substrate binding site. PMID:2906151

  7. Detection of boronic acid derivatives in cells using a fluorescent sensor.

    PubMed

    Hattori, Yoshihide; Ishimura, Miki; Ohta, Youichirou; Takenaka, Hiroshi; Watanabe, Tsubasa; Tanaka, Hiroki; Ono, Koji; Kirihata, Mitsunori

    2015-07-01

    The detection of boron-containing compounds requires very expensive facilities and/or tedious sample pretreatments. In an effort to develop a convenient detection method for boronic acid derivatives, boron chelating-ligands were synthesized for use as fluorescent sensors. In this paper, the synthesis and properties of fluorescent sensors for boronic acid derivatives are reported. PMID:26022725

  8. Contact allergy to dehydroabietic acid derivatives isolated from Portuguese colophony.

    PubMed

    Karlberg, A T; Boman, A; Hacksell, U; Jacobsson, S; Nilsson, J L

    1988-09-01

    7-oxodehydroabietic acid and 15-hydroxydehydroabietic acid were isolated as their methyl esters from Portuguese colophony of the gum rosin type and identified as contact allergens. Another oxidation product of dehydroabietic acid, 15-hydroxy-7-oxodehydroabietic acid, was synthesized and identified as a component of Portuguese gum rosin. 7-oxodehydroabietic acid was found to a be a grade III allergen according to the GPMT method. Guinea pigs induced with gum rosin showed only a low response to the isolated compounds, while patients with a known allergy to gum rosin reacted to a greater extent. The results imply that the content of oxidized dehydroabietic acids in gum rosin is too low to give a marked sensitization in the animals. However, the patients might have come in contact with the allergens in technically modified rosins. The compounds showed a pattern of cross-reactivity in the animal experiments as well as among the patch tested patients. PMID:3191677

  9. Hydroxyoctadecadienoic acids: Oxidised derivatives of linoleic acid and their role in inflammation associated with metabolic syndrome and cancer.

    PubMed

    Vangaveti, Venkat N; Jansen, Holger; Kennedy, Richard Lee; Malabu, Usman H

    2016-08-15

    Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo-​octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner. Chemical Compounds: Linoleic acid (PubChem CID: 5280450), 9- hydroxyoctadecadienoic acid (PubChem CID: 5312830), 13- hydroxyoctadecadienoic acid (PubChem CID: 6443013), 9-oxo

  10. Salicylic acid and some of its derivatives as antibacterial agents for viscose fabric.

    PubMed

    Kantouch, A; El-Sayed, A Atef; Salama, M; El-Kheir, A Abou; Mowafi, S

    2013-11-01

    Salicylic acid and three of its derivatives were used to provide antibacterial properties to viscose fabrics. The four bactericides used were bonded to the viscose fabrics using epichlorohydrin or polymer binders. Optimization of the salicylic acid and its derivatives as well as the concentration of polymers was reported. The ability of the polymer binders to attract and bind the four bactericides was observed. The overall results show that the antibacterial reactivity of salicylic acid and its derivatives are in the following order 5-bromosalicylic acid>salicylic acid>5-chlorosalicylic acid>4-chlorosalicylic acid. Using epichlorohydrin as a binding agent, unfortunately, inhibits the bactericidal activity of the four bactericides. The FTIR study concludes that the reaction between salicylic acid as well as its derivatives with epichlorohydrin takes place through the phenolic group of the acids. The unexpected deterioration in the bactericidal properties of salicylic acid and its derivatives as a result of the treatment with epichlorohydrin could be due to the nature of interaction between the epichlorohydrin molecule and the acids molecules. PVP and PU show superior ability to sustain the four bactericides used even after 10 washing cycles. PMID:24076193

  11. cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline

    PubMed Central

    2016-01-01

    Summary Proline (Pro) is an outstanding amino acid in various biochemical and physicochemical perspectives, especially when considering the cis–trans isomerism of the peptidyl-Pro amide bond. Elucidation of the roles of Pro in chemical or biological systems and engineering of its features can be addressed with various Pro analogues. Here we report an experimental work investigating the basic physicochemical properties of two Pro analogues which possess a 3,4-double bond: 3,4-dehydroproline and 4-trifluoromethyl-3,4-dehydroproline. Both indicate a flat pyrroline ring in their crystal structures, in agreement with previous theoretical calculations. In solution, the peptide mimics exhibit an almost unchanged equilibrium of the trans/cis ratios compared to that of Pro and 4-trifluoromethylproline derivatives. Finally we demonstrate that the 3,4-double bond in the investigated structures leads to an increase of the amide rotational barriers, presumably due to an interplay with the transition state. PMID:27340450

  12. Distillation of natural fatty acids and their chemical derivatives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Well over 1,000 different fatty acids are known which are natural components of fats, oils (triacylglycerols), and other related compounds. These fatty acids can have different alkyl chain lengths, 0-6 carbon-carbon double bonds possessing cis- or trans-geometry, and can contain a variety of functio...

  13. Production and applications of carbohydrate-derived sugar acids as generic biobased chemicals.

    PubMed

    Mehtiö, Tuomas; Toivari, Mervi; Wiebe, Marilyn G; Harlin, Ali; Penttilä, Merja; Koivula, Anu

    2016-10-01

    This review considers the chemical and biotechnological synthesis of acids that are obtained by direct oxidation of mono- or oligosaccharide, referred to as sugar acids. It focuses on sugar acids which can be readily derived from plant biomass sources and their current and future applications. The three main classes of sugar acids are aldonic, aldaric and uronic acids. Interest in organic acids derived from sugars has recently increased, as part of the interest to develop biorefineries which produce not only biofuels, but also chemicals to replace those currently derived from petroleum. More than half of the most desirable biologically produced platform chemicals are organic acids. Currently, the only sugar acid with high commercial production is d-gluconic acid. However, other sugar acids such as d-glucaric and meso-galactaric acids are being produced at a lower scale. The sugar acids have application as sequestering agents and binders, corrosion inhibitors, biodegradable chelators for pharmaceuticals and pH regulators. There is also considerable interest in the use of these molecules in the production of synthetic polymers, including polyamides, polyesters and hydrogels. Further development of these sugar acids will lead to higher volume production of the appropriate sugar acids and will help support the next generation of biorefineries. PMID:26177333

  14. The nomenclature of 1-aminoalkylphosphonic acids and derivatives: evolution of the code system.

    PubMed

    Drabowicz, Józef; Jakubowski, Hieronim; Kudzin, Marcin H; Kudzin, Zbigniew H

    2015-01-01

    The approach for the unification of published proposals for the nomenclature and abbreviations of aminoalkylphosphonic acids and their derivatives is presented. Their modification was made on the basis of the IUPAC-IUB rules concerning the nomenclature and code system of proteinogenic amino acids. Our present proposal formulates the supplementary code and nomenclature system allowing unambiguous description of phosphonic analogs of proteinogenic amino acids, their analogs, homologs, metabolites, and derivatives including phosphonopeptides. PMID:25730210

  15. Sophorolipid-derived unsaturated and epoxy fatty acid estolides as plasticizers for poly(3-hydroxybutyrate)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Unsaturated and epoxy fatty acid estolides were synthesized from the omega and omega-1 hydroxy fatty acids derived from sophorolipids (SLs) prepared by fermentation from glucose:soybean oil and glucose:oleic acid, respectively. These estolides were utilized as additives in solution-cast poly(3-hydro...

  16. Cinnamic Acid and Its Derivatives Inhibit Fructose-Mediated Protein Glycation

    PubMed Central

    Adisakwattana, Sirichai; Sompong, Weerachat; Meeprom, Aramsri; Ngamukote, Sathaporn; Yibchok-anun, Sirintorn

    2012-01-01

    Cinnamic acid and its derivatives have shown a variety of pharmacologic properties. However, little is known about the antiglycation properties of cinnamic acid and its derivatives. The present study sought to characterize the protein glycation inhibitory activity of cinnamic acid and its derivatives in a bovine serum albumin (BSA)/fructose system. The results demonstrated that cinnamic acid and its derivatives significantly inhibited the formation of advanced glycation end products (AGEs) by approximately 11.96–63.36% at a concentration of 1 mM. The strongest inhibitory activity against the formation of AGEs was shown by cinnamic acid. Furthermore, cinnamic acid and its derivatives reduced the level of fructosamine, the formation of Nɛ-(carboxymethyl) lysine (CML), and the level of amyloid cross β-structure. Cinnamic acid and its derivatives also prevented oxidative protein damages, including effects on protein carbonyl formation and thiol oxidation of BSA. Our findings may lead to the possibility of using cinnamic acid and its derivatives for preventing AGE-mediated diabetic complications. PMID:22408423

  17. Antiparasitic activity of prenylated benzoic acid derivatives from Piper species.

    PubMed

    Flores, Ninoska; Jiménez, Ignacio A; Giménez, Alberto; Ruiz, Grace; Gutiérrez, David; Bourdy, Genevieve; Bazzocchi, Isabel L

    2009-03-01

    Fractionation of dichloromethane extracts from the leaves of Piper heterophyllum and P. aduncum afforded three prenylated hydroxybenzoic acids, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid, 3-[(2E,6E,10E)-11-carboxy-13-hydroxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl]-4,5-dihydroxybenzoic acid and 3-[(2E,6E,10E)-11-carboxy-14-hydroxy-3,7,15-trimethyl-2,6,10,15-hexadecatetraenyl]-4,5-dihydroxybenzoic acid, along with the known compounds, 4,5-dihydroxy-3-(E,E,E-11-formyl-3,7,15-trimethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid (arieianal), 3,4-dihydroxy-5-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 4-hydroxy-3-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid, 4-hydroxy-3-(3,7-dimethyl-2,6-octadienyl)benzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid. Their structures were elucidated on the basis of spectroscopic data, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC) and comparison with data reported in the literature. Riguera ester reactions and optical rotation measurements established the compounds as racemates. The antiparasitic activity of the compounds were tested against three strains of Leishmania spp., Trypanosoma cruzi and Plasmodium falciparum. The results showed that 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid exhibited potent and selective activity against L. braziliensis (IC(50) 6.5 microg/ml), higher that pentamidine used as control. Moreover, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl- 2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid showed moderate antiplasmodial (IC(50) 3.2 microg/ml) and trypanocidal (16.5 microg/ml) activities, respectively. PMID:19361822

  18. Succinic acid monoethyl ester, a novel insulinotropic agent: effect on lipid composition and lipid peroxidation in streptozotocin-nicotin-amide induced type 2 diabetic rats.

    PubMed

    Saravanan, Ramalingam; Pari, Leelavinothan

    2007-02-01

    Succinic acid monoethyl ester (EMS) is recently proposed as an insulinotropic agent for the treatment of non-insulin dependent diabetes mellitus. Oxidative stress has been suggested to be a contributory factor in the development and complications of diabetes. In the present study the effect of EMS and Metformin on plasma glucose, insulin, serum and tissue lipid profile, lipoproteins and lipid peroxidation in streptozotocin-nicotinamide induced type 2 diabetic model was investigated. The carboxylic nutrient EMS was administered intraperitonially (8 micromol/g body weight) to streptozotocin diabetic rats for 30 days. The levels of thiobarbituric acid reactive substances (TBARS) and hydroperoxides in liver and kidney and serum and tissue lipids [cholesterol, triglycerides, phospholipids and free fatty acids] and very low density lipoprotein-cholesterol (VLDL-C) and low density lipoprotein-cholesterol (LDL-C), were significantly increased in diabetic rats, whereas the levels of high-density lipoprotein-cholesterol (HDL-C) and antiatherogenic index (AAI) (ratio of HDL to total cholesterol) were significantly decreased. The effect of EMS was compared with metformin, a reference drug. Treatment with EMS and metformin resulted in a significant reduction of plasma glucose with increase plasma insulin in diabetic rats. EMS also resulted in a significant decrease in serum and tissue lipids and lipid peroxidation products. These biochemical observations were supplemented by histopathological examination of liver and kidney section. Our results suggest the possible antihyperlipidemic and antiperoxidative effect of EMS apart from its antidiabetic effect. PMID:17006620

  19. Chemical Synthesis of Uncommon Natural Bile Acids: The 9α-Hydroxy Derivatives of Chenodeoxycholic and Lithocholic Acids.

    PubMed

    Iida, Takashi; Namegawa, Kazunari; Nakane, Naoya; Iida, Kyoko; Hofmann, Alan Frederick; Omura, Kaoru

    2016-09-01

    The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ(9(11))-derivatives using in situ generated monochloroalane (AlH2Cl) prepared from LiAlH4 and AlCl3, (2) epoxidation of the deoxygenated Δ(9(11))-enes using m-chloroperbenzoic acid catalyzed by 4,4'-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9α-hydroxylation of the Δ(9(11))-enes with AlH2Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO2) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The (1)H- and (13)C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids. PMID:27319285

  20. Gastroprotective effect and cytotoxicity of labdeneamides with amino acids.

    PubMed

    Schmeda-Hirschmann, Guillermo; Rodríguez, Jaime A; Theoduloz, Cristina; Valderrama, Jaime A

    2011-03-01

    Semisynthetic aromatic amides from ARAUCARIA ARAUCANA diterpene acids have been shown to display a relevant gastroprotective effect with low cytotoxicity. The aim of this work was to assess the gastroprotective effect of amino acid amides from imbricatolic acid and its 8(9)-en isomer in the ethanol/HCl-induced gastric lesions model in mice as well as to determine the cytotoxicity of the obtained compounds on the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma (AGS), and liver hepatocellular carcinoma (Hep G2). The diterpenes 15-acetoxyimbricatolic acid, its 8(9)-en isomer, 15-hydroxyimbricatolic acid, and the 8(9)-en derivative, bearing a COOH function at C-19, were used as starting compounds. New amides with C-protected amino acids were prepared. The study reports the effect of a single oral administration of either compound 50 min before the induction of gastric lesions by ethanol/HCl. Some 20 amino acid monoamides were obtained. Dose-response experiments on the glycyl derivatives showed that at a single oral dose of 100 mg/kg, the compounds presented an effect comparable to the reference drug lansoprazole at 20 mg/kg and at 50 mg/kg reduced gastric lesions by about 50%. All derivatives obtained in amounts > 30 mg were compared at a single oral dose of 50 mg/kg. The best gastroprotective effect was observed for the exomethylene derivatives bearing a valine residue at C-19 either with an acetoxy or free hydroxy group at C-15. The tryptophanyl derivative from the acetate belonging to the 8,9-en series presented selective cytotoxicity against hepatocytes. The glycyl amide of 15-acetoxyimbricatolic acid was the most cytotoxic and less selective compound with IC₅₀ values between 47 and 103 µM for the studied cell lines. This is the first report on the obtention of semisynthetic amino acid amides from labdane diterpenes. PMID:20862639

  1. Amidation of esters with amino alcohols using organobase catalysis.

    PubMed

    Caldwell, Nicola; Campbell, Peter S; Jamieson, Craig; Potjewyd, Frances; Simpson, Iain; Watson, Allan J B

    2014-10-01

    A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate. PMID:25226088

  2. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis

    PubMed Central

    Pisithkul, Tippapha; Jacobson, Tyler B.; O'Brien, Thomas J.; Stevenson, David M.

    2015-01-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using 13C-labeled sugars and [15N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. PMID:26070680

  3. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis.

    PubMed

    Pisithkul, Tippapha; Jacobson, Tyler B; O'Brien, Thomas J; Stevenson, David M; Amador-Noguez, Daniel

    2015-09-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using (13)C-labeled sugars and [(15)N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. PMID:26070680

  4. Amidation reaction of eugenyl oxyacetate ethyl ester with 1,3 diaminopropane

    NASA Astrophysics Data System (ADS)

    Suryanti, V.; Wibowo, F. R.; Kusumaningsih, T.; Wibowo, A. H.; Khumaidah, S. A.; Wijayanti, L. A.

    2016-04-01

    Eugenol having various substituents on the aromatic ring (hydroxy, methoxy and allyl) are useful for starting material in synthesizing of its derivatives. Eugenol derivatives have shown wide future potential applications in many areas, especially as future drugs against many diseases. The aim of this work was to synthesize an amide of eugenol derivative. The starting material used was eugenol from clove oil and the reaction was conducted in 3 step reactions to give the final product. Firstly, eugenol was converted into eugenyl oxyacetate [2-(4-allyl-2-methoxyphenoxy) acetic acid] as a white crystal with 70.5% yield, which was then esterified with ethanol to have eugenyl oxyacetate ethyl ester [ethyl 2-(4-allyl-2-methoxyphenoxy) acetate] as brown liquid in 75.7%. The last step was the reaction between eugenyl oxyacetate ethyl ester and 1,3 diaminopropane to give 2-(4-allyl-2-methoxyphenoxy)-N-(3-aminopropyl) acetamide as a brown powder with 71.6% yield, where the amidation reaction was occurred.

  5. Synthesis, spectroscopic and structural perspective of new ferrocenyl amides

    NASA Astrophysics Data System (ADS)

    Etter, Martin; Nigar, Asifa; Ali, Naveed Zafar; Akhter, Zareen; Dinnebier, Robert E.

    2016-05-01

    Two new ferrocene derivatives with amide linkages were synthesized by the condensation of 4-ferrocenylaniline with n-alkyl acid chloride derivatives as pristine orange solids in good yields. FTIR and 1H/13C NMR studies have confirmed the basic structure of the molecules with the involvement of intermolecular H-bonding, which together with the ferrocene-like packing ensures the stability of the crystal structure. Crystal structures for both compounds were solved by Rietveld refinements of high resolution X-ray powder diffraction data. The XRD results show that both compounds crystallize in the monoclinic space group P21/c. The primary feature of the crystal structure is a double layer of ferrocenyl groups stretched out in the b-c -plane perpendicular to the a-axis, with packing of the ferrocenyl groups occurring in a manner similar to that of pure ferrocene. Despite the close structural similarity, both compounds differ in the optimized geometry of respective Ferrocene conformers. The Cp rings are eclipsed for one Ferrocene conformer and close to staggered for the other, owing to the low energy barrier for the rotation of a cyclopentadienyl ring relative to the rest of the molecule.

  6. Endocannabinoid and Cannabinoid-Like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study

    PubMed Central

    Fichna, Jakub; Wood, JodiAnne T.; Papanastasiou, Malvina; Vadivel, Subramanian K.; Oprocha, Piotr; Sałaga, Maciej; Sobczak, Marta; Mokrowiecka, Anna; Cygankiewicz, Adam I.; Zakrzewski, Piotr K.; Małecka-Panas, Ewa; Krajewska, Wanda M.; Kościelniak, Piotr; Makriyannis, Alexandros; Storr, Martin A.

    2013-01-01

    Aims Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. Methods AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. Results Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. Conclusion IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms. PMID:24386448

  7. Stability decrease of RNA double helices by phenylalanine-, tyrosine- and tryptophane-amides. Analysis in terms of site binding and relation to melting proteins.

    PubMed Central

    Pörschke, D; Jung, M

    1982-01-01

    The amides of L-phenylalanine, L-tyrosine and L-tryptophane decrease the melting temperatures tm of poly(A)*poly(U) and poly(I)*poly(C) double helices at low concentrations (1 mM), whereas high concentrations finally lead to an increase of tm. This dependence of the tm-values upon the ligand concentration can be represented quantitatively by a simple site binding model, providing binding parameters for the interaction between the amides and the nucleic acids both in the double- and the single-stranded conformation. According to these data the affinity to the single strands is higher than that to the double strands and increases in the series Phe less than Tyr less than Trp. The binding constants decrease with increasing salt concentration as expected for an interaction driven by electrostatic attraction. However, part of the interaction is also due to stacking between the aromatic amides and the nucleic acid bases. The present results indicate a direct correlation between the presence of aromatic amino acids at the binding site of helix destabilising proteins and the properties of simple derivatives of these amino acids. Furthermore the results suggest that very simple peptides containing aromatic amino acids served as a starting point for the evolution of helix destabilising proteins. PMID:7145717

  8. Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol.

    PubMed

    Bostedor, R G; Karkas, J D; Arison, B H; Bansal, V S; Vaidya, S; Germershausen, J I; Kurtz, M M; Bergstrom, J D

    1997-04-01

    Farnesyl diphosphate, the substrate for squalene synthase, accumulates in the presence of zaragozic acid A, a squalene synthase inhibitor. A possible metabolic fate for farnesyl diphosphate is its conversion to farnesol, then to farnesoic acid, and finally to farnesol-derived dicarboxylic acids (FDDCAs) which would then be excreted in the urine. Seven dicarboxylic acids were isolated by high performance liquid chromatography (HPLC) from urine of either rats or dogs treated with zaragozic acid A or rats fed farnesol. Their structures were determined by nuclear magnetic resonance analysis. Two 12-carbon, four 10-carbon, and one 7-carbon FDDCA were identified. The profile of urinary dicarboxylic acids from rats fed farnesol was virtually identical to that produced by treating with zaragozic acid A, establishing that these dicarboxylic acids are farnesol-derived. By feeding [1-14C]farnesol and comparing the mass of the dicarboxylic acids produced with the ultraviolet absorption of the HPLC peaks, a method to quantitate the ultraviolet-absorbing FDDCAs was devised. When rats were treated with zaragozic acid A, large amounts of FDDCAs were excreted in the urine. The high level of FDDCAs that were found suggests that their synthesis is the major metabolic fate for carbon diverted from cholesterol synthesis by a squalene synthase inhibitor. A metabolic pathway is proposed to explain the production of each of these FDDCAs. PMID:9083051

  9. Novel biomarkers of the metabolism of caffeic acid derivatives in vivo.

    PubMed

    Rechner, A R; Spencer, J P; Kuhnle, G; Hahn, U; Rice-Evans, C A

    2001-06-01

    The purpose of this study was to investigate biomarkers of the bioavailability and metabolism of hydroxycinnamate derivatives through the determination of the pharmacokinetics of their urinary elimination and identification of the metabolites excreted. Coffee was used as a rich source of caffeic acid derivatives and human supplementation was undertaken. The results show a highly significant increase in the excretion of ferulic, isoferulic, dihydroferulic acid (3-(4-hydroxy-3-methoxyphenyl)-propionic acid), and vanillic acid postsupplementation relative to the levels presupplementation. Thus, ferulic, isoferulic, and dihydroferulic acids are specific biomarkers for the bioavailability and metabolism of dietary caffeic acid esters. Isoferulic acid is a unique biomarker as it is not a dietary component, however, dihydroferulic acid may well derive from other flavonoids with a structurally related B-ring. 3-Hydroxyhippuric acid has also been identified as an indicator for bioavailability and metabolism of phenolic compounds, and shows a highly significant excretion increase postsupplementation. The results reveal isoferulic acid (and possibly dihydroferulic acid) as novel markers of caffeoyl quinic acid metabolism. PMID:11368919

  10. [Phenolic acid derivatives from Bauhinia glauca subsp. pernervosa].

    PubMed

    Zhao, Qiao-Li; Wu, Zeng-Bao; Zheng, Zhi-Hui; Lu, Xin-Hua; Liang, Hong; Cheng, Wei; Zhang, Qing-Ying; Zhao, Yu-Ying

    2011-08-01

    To study the chemical constituents of Bauhinia glauca subsp. pernervosa, eleven phenolic acids were isolated from a 95% ethanol extract by using a combination of various chromatographic techniques including column chromatography over silica gel, ODS, MCI, Sephadex LH-20, and semi-preparative HPLC. By spectroscopic techniques including 1H NMR, 13C NMR, 2D NMR, and HR-ESI-MS, these compounds were identified as isopropyl O-beta-(6'-O-galloyl)-glucopyranoside (1), ethyl O-beta-(6'-O-galloyl)-glucopyranoside (2), 3, 4, 5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside (3), 3, 4, 5-trimethoxyphenyl-beta-D-glucopyranoside (4), gallic acid (5), methyl gallate (6), ethyl gallate (7), protocatechuic acid (8), 3, 5-dimethoxy-4-hydroxybenzoic acid (9), erigeside C (10) and glucosyringic acid (11). Among them, compound 1 is a new polyhydroxyl compound; compounds 2, 10, and 11 were isolated from the genus Bauhinia for the first time, and the other compounds were isolated from the plant for the first time. Compounds 6 and 8 showed significant protein tyrosine phosphatase1B (PTP1B) inhibitory activity in vitro with the IC50 values of 72.3 and 54.1 micromol x L(-1), respectively. PMID:22007520

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

    SciTech Connect

    Budzik, Jonathan M.; Poor, Catherine B.; Faull, Kym F.; Whitelegge, Julian P.; He, Chuan; Schneewind, Olaf

    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.

  12. First synthesis of etidronate partial amides starting from PCl3.

    PubMed

    Turhanen, Petri A; Niemi, Riku; Peräkylä, Mikael; Järvinen, Tomi; Vepsäläinen, Jouko J

    2003-09-21

    Methods for the preparation of mixed tetra-amide esters 1 and 2, the partial amide ester 3, and tri- and P,P-diamides 4 and 5 from monophosphorus spieces 12, 8 and 9, respectively, were developed. Compounds 8 and 9 were obtained from phosphorus trichloride via MeOPCl2, which was treated with 2 eq. and 4 eq. of piperidine, followed by water or acetyl chloride, respectively. Tetrasubstituted amide bisphosphonates 1 and 2 were selectively dealkylated with lithium or silyl halide to achieve target compounds 3-5. Piperidine was found to be a good desilylation reagent. Quantum mechanical calculations illustrate why derivative 2 was produced in low yield. The usefulness of compounds 1, 3 and 4 as prodrugs of etidronate was determined in aqueous buffer and human serum. PMID:14527155

  13. Amidation of Bioactive Peptides: The Structure of the Lyase Domain of the Amidating Enzyme

    SciTech Connect

    Chufan, E.; De, M; Eipper, B; Mains, R; Amzel, L

    2009-01-01

    Many neuropeptides and peptide hormones require amidation of their carboxy terminal for full biological activity. The enzyme peptidyl-{alpha}-hydroxyglycine {alpha}-amidating lyase (PAL; EC 4.3.2.5) catalyzes the second and last step of this reaction, N-dealkylation of the peptidyl-{alpha}-hydroxyglycine to generate the {alpha}-amidated peptide and glyoxylate. Here we report the X-ray crystal structure of the PAL catalytic core (PALcc) alone and in complex with the nonpeptidic substrate {alpha}-hydroxyhippuric acid. The structures show that PAL folds as a six-bladed {Beta}-propeller. The active site is formed by a Zn(II) ion coordinated by three histidine residues; the substrate binds to this site with its {alpha}-hydroxyl group coordinated to the Zn(II) ion. The structures also reveal a tyrosine residue (Tyr{sup 654}) at the active site as the catalytic base for hydroxyl deprotonation, an unusual role for tyrosine. A reaction mechanism is proposed based on this structural data and validated by biochemical analysis of site-directed PALcc mutants.

  14. Synthesis and antimycobacterial evaluation of new trans-cinnamic acid hydrazide derivatives.

    PubMed

    Carvalho, Samir A; da Silva, Edson F; de Souza, Marcus V N; Lourenço, Maria C S; Vicente, Felipe R

    2008-01-15

    In this work, we report the synthesis and the antimycobacterial evaluation of new trans-cinnamic acid derivatives of isonicotinic acid series (5) and benzoic acid series (6), designed by exploring the molecular hybridization approach between isoniazid (1) and trans-cinnamic acid derivative (3). The minimum inhibitory concentration (MIC) of the compounds 5a-d and 6c exhibited activity between 3.12 and 12.5 microg/mL and could be a good start point to find new lead compounds against multi-drug resistant tuberculosis. PMID:18068364

  15. Lactic acid as an invaluable green solvent for ultrasound-assisted scalable synthesis of pyrrole derivatives.

    PubMed

    Wang, Shi-Fan; Guo, Chao-Lun; Cui, Ke-ke; Zhu, Yan-Ting; Ding, Jun-Xiong; Zou, Xin-Yue; Li, Yi-Hang

    2015-09-01

    Lactic acid has been used as a bio-based green solvent to study the ultrasound-assisted scale-up synthesis. We report here, for the first time, on the novel and scalable process for synthesis of pyrrole derivatives in lactic acid solvent under ultrasonic radiation. Eighteen pyrrole derivatives have been synthesized in lactic acid solvent under ultrasonic radiation and characterized by (1)H NMR, IR, ESI MS. The results show, under ultrasonic radiation, lactic acid solvent can overcome the scale-up challenges and exhibited many advantages, such as bio-based origin, shorter reaction time, lower volatility, higher yields, and ease of isolating the products. PMID:25605585

  16. Technetium radiodiagnostic fatty acids derived from bisamide bisthiol ligands

    DOEpatents

    Jones, Alun G.; Lister-James, John; Davison, Alan

    1988-05-24

    A bisamide-bisthiol ligand containing fatty acid substituted thiol useful for producing Tc-labelled radiodiagnostic imaging agents is described. The ligand forms a complex with the radionuclide .sup.99m Tc suitable for administration as a radiopharmaceutical to obtain images of the heart for diagnosis of myocardial disfunction.

  17. Nitrogen Derivatives of Soybean Oil and Fatty Acid Methyl Esters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vegetable oil based products are eco-friendly and non-toxic in nature, which is increasing their utilization in lot of applications. The presence of double bonds in some of the fatty acids, are attractive sites for functionalization. In this study we have used these sites for functionalization usi...

  18. An Alkyne Diboration/6π-Electrocyclization Strategy for the Synthesis of Pyridine Boronic Acid Derivatives.

    PubMed

    Mora-Radó, Helena; Bialy, Laurent; Czechtizky, Werngard; Méndez, María; Harrity, Joseph P A

    2016-05-01

    A new and efficient synthesis of pyridine-based heteroaromatic boronic acid derivatives is reported through a novel diboration/6π-electrocyclization strategy. This method delivers a range of functionalized heterocycles from readily available starting materials. PMID:27059895

  19. Fragmentation patterns of {alpha}-phenylcinnamic acid derivatives upon electron impact ionization; a computational approach

    SciTech Connect

    Palinko, I.; Tasi, G.; Toeroek, B.

    1995-04-01

    Secondary transformations such as fragmentation and rearrangement reacting are computed for {proportional_to}-phenylcinnamic acid derivations upon electron impact ionization. (AIP) {copyright}{ital 1995 American Institute of Physics}

  20. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide: A promising positron emission tomography ligand for fatty acid amide hydrolase.

    PubMed

    Shimoda, Yoko; Fujinaga, Masayuki; Hatori, Akiko; Yui, Joji; Zhang, Yiding; Nengaki, Nobuki; Kurihara, Yusuke; Yamasaki, Tomoteru; Xie, Lin; Kumata, Katsushi; Ishii, Hideki; Zhang, Ming-Rong

    2016-02-15

    To visualize fatty acid amide hydrolase (FAAH) in brain in vivo, we developed a novel positron emission tomography (PET) ligand N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide ([(11)C]DFMC, [(11)C]1). DFMC (1) was shown to have high binding affinity (IC50: 6.1nM) for FAAH. [(11)C]1 was synthesized by C-(11)C coupling reaction of arylboronic ester 2 with [(11)C]methyl iodide in the presence of Pd catalyst. At the end of synthesis, [(11)C]1 was obtained with a radiochemical yield of 20±10% (based on [(11)C]CO2, decay-corrected, n=5) and specific activity of 48-166GBq/μmol. After the injection of [(11)C]1 in mice, high uptake of radioactivity (>2% ID/g) was distributed in the lung, liver, kidney, and brain, organs with high FAAH expression. PET images of rat brains for [(11)C]1 revealed high uptakes in the cerebellar nucleus (SUV=2.4) and frontal cortex (SUV=2.0), two known brain regions with high FAAH expression. Pretreatment with the FAAH-selective inhibitor URB597 reduced the brain uptake. Higher than 90% of the total radioactivity in the rat brain was irreversible at 30min after the radioligand injection. The present results indicate that [(11)C]1 is a promising PET ligand for imaging of FAAH in living brain. PMID:26740152

  1. Demonstration of proof of mechanism and pharmacokinetics and pharmacodynamic relationship with 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), an inhibitor of 11 -hydroxysteroid dehydrogenase type 1, in cynomolgus monkeys.

    PubMed

    Bhat, B Ganesh; Hosea, Natilie; Fanjul, Andrea; Herrera, Jocelyn; Chapman, Justin; Thalacker, Fred; Stewart, Paul M; Rejto, Paul A

    2008-01-01

    Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) play a key role in ligand-induced activation of the GR through the production of cortisol. Evidence from genetically modified mice suggests that inhibition of 11betaHSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11betaHSD1 inhibitor, 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), that is selective for the primate and human enzymes. The objective of this study was to demonstrate target inhibition with PF-915275 and to quantify the relationship between target inhibition and drug exposure in monkeys. We characterized the ability of PF-915275 to inhibit the conversion of prednisone, a synthetic cortisone analog that can be distinguished from the endogenous substrate cortisone, enabling a direct measure of substrate to product conversion without the complication of feedback. Adult cynomolgus monkeys were administered either vehicle or various doses of PF-915275 followed by a 10-mg/kg dose of prednisone. Prednisone conversion to prednisolone and the concentrations of PF-915275 were measured by liquid chromatography/tandem mass spectrometry. PF-915275 dose-dependently inhibited 11betaHSD1-mediated conversion of prednisone to prednisolone, with a maximum of 87% inhibition at a 3-mg/kg dose. An exposure-response relationship was demonstrated, with an estimated EC(50) of 391 nM (total) and 17 nM (free). Insulin levels were also reduced in a dose-related manner. These results should enable the development of a biomarker for evaluating target modulation in humans that will aid in identifying 11betaHSD1 inhibitors to treat diabetes and other related metabolic diseases. PMID:17921190

  2. Fluoride-Mediated Capture of a Noncovalent Bound State of a Reversible Covalent Enzyme Inhibitor: X-ray Crystallographic Analysis of an Exceptionally Potent α-Ketoheterocycle Inhibitor of Fatty Acid Amide Hydrolase

    PubMed Central

    Mileni, Mauro; Garfunkle, Joie; Ezzili, Cyrine; Cravatt, Benjamin F.; Stevens, Raymond C.; Boger, Dale L.

    2011-01-01

    Two cocrystal X-ray structures of the exceptionally potent α-ketoheterocycle inhibitor 1 (Ki = 290 pM) bound to a humanized variant of rat fatty acid amide hydrolase (FAAH) are disclosed, representing noncovalently and covalently bound states of the same inhibitor with the enzyme. Key to securing the structure of the noncovalently bound state of the inhibitor was the inclusion of fluoride ion in the crystallization conditions that is proposed to bind the oxyanion hole precluding inhibitor covalent adduct formation with stabilization of the tetrahedral hemiketal. This permitted the opportunity to detect important noncovalent interactions stabilizing the binding of the inhibitor within the FAAH active site independent of the covalent reaction. Remarkably, noncovalently bound 1 in the presence of fluoride appears to capture the active site in the same “in action” state with the three catalytic residues Ser241–Ser217–Lys142 occupying essentially identical positions observed in the covalently bound structure of 1, suggesting that this technique of introducing fluoride may have important applications in structural studies beyond inhibiting substrate or inhibitor oxyanion hole binding. Key insights to emerge from the studies include the observations that noncovalently bound 1 binds in its ketone (not gem diol) form, that the terminal phenyl group in the acyl side chain of the inhibitor serves as the key anchoring interaction overriding the intricate polar interactions in the cytosolic port, and that the role of the central activating heterocycle is dominated by its intrinsic electron-withdrawing properties. These two structures are also briefly compared with five X-ray structures of α-ketoheterocycle-based inhibitors bound to FAAH recently disclosed. PMID:21355555

  3. Fluoride-Mediated Capture of a Noncovalent Bound State of a Reversible Covalent Enzyme Inhibitor: X-ray Crystallographic Analysis of an Exceptionally Potent [alpha]-Ketoheterocycle Inhibitor of Fatty Acid Amide Hydrolase

    SciTech Connect

    Mileni, Mauro; Garfunkle, Joie; Ezzili, Cyrine; Cravatt, Benjamin F.; Stevens, Raymond C.; Boger, Dale L.

    2011-11-02

    Two cocrystal X-ray structures of the exceptionally potent {alpha}-ketoheterocycle inhibitor 1 (K{sub i} = 290 pM) bound to a humanized variant of rat fatty acid amide hydrolase (FAAH) are disclosed, representing noncovalently and covalently bound states of the same inhibitor with the enzyme. Key to securing the structure of the noncovalently bound state of the inhibitor was the inclusion of fluoride ion in the crystallization conditions that is proposed to bind the oxyanion hole precluding inhibitor covalent adduct formation with stabilization of the tetrahedral hemiketal. This permitted the opportunity to detect important noncovalent interactions stabilizing the binding of the inhibitor within the FAAH active site independent of the covalent reaction. Remarkably, noncovalently bound 1 in the presence of fluoride appears to capture the active site in the same 'in action' state with the three catalytic residues Ser241-Ser217-Lys142 occupying essentially identical positions observed in the covalently bound structure of 1, suggesting that this technique of introducing fluoride may have important applications in structural studies beyond inhibiting substrate or inhibitor oxyanion hole binding. Key insights to emerge from the studies include the observations that noncovalently bound 1 binds in its ketone (not gem diol) form, that the terminal phenyl group in the acyl side chain of the inhibitor serves as the key anchoring interaction overriding the intricate polar interactions in the cytosolic port, and that the role of the central activating heterocycle is dominated by its intrinsic electron-withdrawing properties. These two structures are also briefly compared with five X-ray structures of {alpha}-ketoheterocycle-based inhibitors bound to FAAH recently disclosed.

  4. Silica with immobilized phosphinic acid-derivative for uranium extraction.

    PubMed

    Budnyak, Tetyana M; Strizhak, Alexander V; Gładysz-Płaska, Agnieszka; Sternik, Dariusz; Komarov, Igor V; Kołodyńska, Dorota; Majdan, Marek; Tertykh, Valentin А

    2016-08-15

    A novel adsorbent benzoimidazol-2-yl-phenylphosphinic acid/aminosilica adsorbent (BImPhP(O)(OH)/SiO2NH2) was prepared by carbonyldiimidazole-mediated coupling of aminosilica with 1-carboxymethylbenzoimidazol-2-yl-phenylphosphinic acid. It was obtained through direct phosphorylation of 1-cyanomethylbenzoimidazole by phenylphosphonic dichloride followed by basic hydrolysis of the nitrile. The obtained sorbent was well characterized by physicochemical methods, such as differential scanning calorimetry-mass spectrometry (DSC-MS), surface area and pore distribution analysis (ASAP), scanning electron microscopy (SEM), X-ray photoelectron (XPS) and Fourier transform infrared (FTIR) spectroscopies. The adsorption behavior of the sorbent and initial silica gel as well as aminosilica gel with respect to uranium(VI) from the aqueous media has been studied under varying operating conditions of pH, concentration of uranium(VI), contact time, and desorption in different media. The synthesized material was found to show an increase in adsorption activity with respect to uranyl ions in comparison with the initial compounds. In particular, the highest adsorption capacity for the obtained modified silica was found at the neutral pH, where one gram of the adsorbent can extract 176mg of uranium. Under the same conditions the aminosilica extracts 166mg/g, and the silica - 144mg/g of uranium. In the acidic medium, which is common for uranium nuclear wastes, the synthesized adsorbent extracts 27mg/g, the aminosilica - 16mg/g, and the silica - 14mg/g of uranium. It was found that 15% of uranium ions leached from the prepared material in acidic solutions, while 4% of uranium can be removed in a phosphate solution. PMID:27177215

  5. Conversion of covalently mercurated nucleic acids to tritiated and halogenated derivatives.

    PubMed Central

    Dale, R M; Ward, D C; Livingston, D C; Martin, E

    1975-01-01

    Mercurated nucleic acids are converted to the corresponding tritiated, brominated, and iodinated derivatives by treatment with sodium borotritiide, N-bromosuccinimide, and elemental iodine, respectively. All three reactions occur under mild conditions in neutral aqueous solutions. Mercury-halogen conversions are essentially quantitative at both the mono- and polynucleotide levels. Tritiation reactions also proceed efficiently with mononucleotides, although polymers undergo incomplete demercuration. In spite of the latter limitation , these reactions provide novel and efficient synthetic routes to radiolabeled nucleic acid derivatives. PMID:1144066

  6. Solid-State Characterization and Biological Activity of Betulonic Acid Derivatives.

    PubMed

    Ledeţi, Ionuţ; Avram, Ştefana; Bercean, Vasile; Vlase, Gabriela; Vlase, Titus; Ledeţi, Adriana; Zupko, Istvan; Mioc, Marius; Şuta, Lenuţa-Maria; Şoica, Codruţa; Dehelean, Cristina

    2015-01-01

    Betulonic acid belongs to the pentacyclic triterpenic derivative class and can be obtained through the selective oxidation of betulin. In this study we set obtaining several functionalized derivatives of this compound by its condensation with several amino compounds such as aminoguanidine, hydroxylamine, n-butylamine and thiosemicarbazide as our goal. The functionalization of the parent compound led to several molecules with antiproliferative potential, the most promising being 3-2-carbamothioylhydrazonolup-20(29)-en-28-oic acid. PMID:26694347

  7. Polymer Amide as an Early Topology

    PubMed Central

    McGeoch, Julie E. M.; McGeoch, Malcolm W.

    2014-01-01

    Hydrophobic polymer amide (HPA) could have been one of the first normal density materials to accrete in space. We present ab initio calculations of the energetics of amino acid polymerization via gas phase collisions. The initial hydrogen-bonded di-peptide is sufficiently stable to proceed in many cases via a transition state into a di-peptide with an associated bound water molecule of condensation. The energetics of polymerization are only favorable when the water remains bound. Further polymerization leads to a hydrophobic surface that is phase-separated from, but hydrogen bonded to, a small bulk water complex. The kinetics of the collision and subsequent polymerization are discussed for the low-density conditions of a molecular cloud. This polymer in the gas phase has the properties to make a topology, viz. hydrophobicity allowing phase separation from bulk water, capability to withstand large temperature ranges, versatility of form and charge separation. Its flexible tetrahedral carbon atoms that alternate with more rigid amide groups allow it to deform and reform in hazardous conditions and its density of hydrogen bonds provides adhesion that would support accretion to it of silicon and metal elements to form a stellar dust material. PMID:25048204

  8. Two Major Bile Acids in the Hornbills, (24R,25S)-3α,7α,24-Trihydroxy-5β-cholestan-27-oyl Taurine and Its 12α-Hydroxy Derivative.

    PubMed

    Satoh, Rika; Ogata, Hiroaki; Saito, Tetsuya; Zhou, Biao; Omura, Kaoru; Kurabuchi, Satoshi; Mitamura, Kuniko; Ikegawa, Shigeo; Hagey, Lee R; Hofmann, Alan F; Iida, Takashi

    2016-06-01

    Two major bile acids were isolated from the gallbladder bile of two hornbill species from the Bucerotidae family of the avian order Bucerotiformes Buceros bicornis (great hornbill) and Penelopides panini (Visayan tarictic hornbill). Their structures were determined to be 3α,7α,24-dihydroxy-5β-cholestan-27-oic acid and its 12α-hydroxy derivative, 3α,7α,12α,24-tetrahydroxy-5β-cholestan-27-oic acid (varanic acid, VA), both present in bile as their corresponding taurine amidates. The four diastereomers of varanic acid were synthesized and their assigned structures were confirmed by X-ray crystallographic analysis. VA and its 12-deoxy derivative were found to have a (24R,25S)-configuration. 13 additional hornbill species were also analyzed by HPLC and showed similar bile acid patterns to B. bicornis and P. panini. The previous stereochemical assignment for (24R,25S)-VA isolated from the bile of varanid lizards and the Gila monster should now be revised to the (24S,25S)-configuration. PMID:27108034

  9. Pd(II)-catalysed meta-C–H functionalizations of benzoic acid derivatives

    PubMed Central

    Li, Shangda; Cai, Lei; Ji, Huafang; Yang, Long; Li, Gang

    2016-01-01

    Benzoic acids are highly important structural motifs in drug molecules and natural products. Selective C–H bond functionalization of benzoic acids will provide synthetically useful tools for step-economical organic synthesis. Although direct ortho-C–H functionalizations of benzoic acids or their derivatives have been intensely studied, the ability to activate meta-C–H bond of benzoic acids or their derivatives in a general manner via transition-metal catalysis has been largely unsuccessful. Although chelation-assisted meta-C–H functionalization of electron-rich arenes was reported, chelation-assisted meta-C–H activation of electron-poor arenes such as benzoic acid derivatives remains a formidable challenge. Herein, we report a general protocol for meta-C–H olefination of benzoic acid derivatives using a nitrile-based sulfonamide template. A broad range of benzoic acid derivatives are meta-selectively olefinated using molecular oxygen as the terminal oxidant. The meta-C–H acetoxylation, product of which is further transformed at the meta-position, is also reported. PMID:26813919

  10. Synthesis of amide-functionalized cellulose esters by olefin cross-metathesis.

    PubMed

    Meng, Xiangtao; Edgar, Kevin J

    2015-11-01

    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. PMID:26256383

  11. Chemical synthesis of the 3-sulfooxy-7-N-acetylglucosaminyl-24-amidated conjugates of 3beta,7beta-dihydroxy-5-cholen-24-oic acid, and related compounds: unusual, major metabolites of bile acid in a patient with Niemann-Pick disease type C1.

    PubMed

    Iida, Takashi; Kakiyama, Genta; Hibiya, Yohei; Miyata, Shohei; Inoue, Takehiko; Ohno, Kohsaku; Goto, Takaaki; Mano, Nariyasu; Goto, Junichi; Nambara, Toshio; Hofmann, Alan F

    2006-01-01

    The chemical synthesis of 3beta,7beta-dihydroxy-5-cholen-24-oic acid, triply conjugated by sulfuric acid at C-3, by N-acetylglucosamine (GlcNAc) at C-7, and by glycine or taurine at C-24, is described. These are unusual, major metabolites of bile acid found to be excreted in the urine of a patient with Niemann-Pick disease type C1. Analogous double-conjugates of 3beta-hydroxy-7-oxo-5-cholen-24-oic acid were also prepared. The principal reactions involved were: (1) beta-d-N-acetylglucosaminidation at C-7 of methyl 3beta-tert-butyldimethylsilyloxy (TBDMSi)-7beta-hydroxy-5-cholen-24-oate with 2-acetamido-1alpha-chloro-1,2-dideoxy-3,4,6-tri-O-acetyl-d-glucopyranose in the presence of CdCO(3) in boiling toluene; (2) sulfation at C-3 of the resulting 3beta-TBDMSi-7beta-GlcNAc with sulfur trioxide-trimethylamine complex in pyridine; and (3) direct amidation at C-24 of the 3beta-sulfooxy-7beta-GlcNAc conjugate with glycine methyl ester hydrochloride (or taurine) using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as a coupling agent in DMF. The structures of the multi-conjugated bile acids were characterized by liquid chromatography-mass spectrometry with an electrospray ionization probe under the positive and negative ionization modes. PMID:16197972

  12. Conversion of methyl oleate to branched-chain hydroxy fatty acid derivatives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As part of a project to develop new and expanded uses of oilseed products and by-products (such as biodiesel, fuel additives, and lubricants), studies were conducted on the synthetic conversion of oleic acid (in ester form) to branched-chain fatty acid ester derivatives. In these studies, methyl ol...

  13. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified...

  14. 40 CFR 721.430 - Oxo-substituted amino-al-kanoic acid derivative.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Oxo-substituted amino-al-kanoic acid... Specific Chemical Substances § 721.430 Oxo-substituted amino-al-kanoic acid derivative. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified...

  15. Mass spectral analysis of C3 and C4 aliphatic amino acid derivatives.

    NASA Technical Reports Server (NTRS)

    Lawless, J. G.; Chadha, M. S.

    1971-01-01

    Diagnostic criteria are obtained for the distinction of alpha, beta, gamma, and N-methyl isomers of the C3 and C4 aliphatic amino acids, using mass spectral analysis of the derivatives of these acids. The use of deuterium labeling has helped in the understanding of certain fragmentation pathways.

  16. Biodiesel Derived from a Source Enriched in Palmitoleic Acid, Macadamia Nut Oil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Biodiesel is an alternative diesel fuel commonly produced from commodity vegetable oils such as palm, rapeseeed (canola) and soybean. These oils generally have fatty acid profiles that vary within the range of C16 and C18 fatty acids. Thus, the biodiesel fuels derived from these oils possess the c...

  17. Fatty acid profile and Unigene-derived simple sequence repeat markers in tung tree (Vernicia fordii)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tung tree (Vernicia fordii) provides the sole source of tung oil widely used in industry. Lack of fatty acid composition and molecular markers hinders biochemical, genetic and breeding research. The objectives of this study were to determine fatty acid profiles and develop unigene-derived simple se...

  18. Synthesis of novel naphthoquinone aliphatic amides and esters and their anticancer evaluation.

    PubMed

    Kongkathip, Boonsong; Akkarasamiyo, Sunisa; Hasitapan, Komkrit; Sittikul, Pichamon; Boonyalai, Nonlawat; Kongkathip, Ngampong

    2013-02-01

    Fourteen new naphthoquinone aliphatic amides and seventeen naphthoquinone aliphatic esters were synthesized in nine to ten steps from 1-hydroxy-2-naphthoic acid with 9-25% overall yield for the amides, and 16-21% overall yield for the esters. The key step of the amide synthesis is a coupling reaction between amine and various aliphatic acids using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as a coupling agent while for the ester synthesis, DCC/DMAP or CDI was used as the coupling reagent between aliphatic acids and naphthoquinone alcohol. Both naphthoquinone amides and esters were evaluated for their anticancer activity against KB cells. It was found that naphthoquinone aliphatic amides showed stronger anticancer activity than those of the esters when the chains are longer than 7-carbon atoms. The optimum chain of amides is expected to be 16-carbon atoms. In addition, naphthoquinone aliphatic esters with α-methyl on the ester moiety possessed much stronger anticancer activity than the straight chains. Decatenation assay revealed that naphthoquinone amide with 16-carbon atoms chain at 15 μM and 20 μM can completely inhibit hTopoIIα activity while at 10 μM the enzyme activity was moderately inhibited. Molecular docking result also showed the same trend as the cytotoxicity and decatenation assay. PMID:23313636

  19. Amino Acid-Derived Metabolites from the Ascidian Aplidium sp.

    PubMed

    Won, Tae Hyung; Kim, Chang-Kwon; Lee, So-Hyoung; Rho, Boon Jo; Lee, Sang Kook; Oh, Dong-Chan; Oh, Ki-Bong; Shin, Jongheon

    2015-06-01

    Four new iodobenzene-containing dipeptides (1-4), a related bromotryptophan-containing dipeptide (5), and an iodophenethylamine (6) were isolated from the ascidian Aplidium sp. collected off the coast of Chuja-do, Korea. The structures of these novel compounds, designated as apliamides A-E (1-5) and apliamine A (6) were determined via combined spectroscopic analyses. The absolute configuration of the amino acid residue in 1 was determined by advanced Marfey's analysis. Several of these compounds exhibited moderate cytotoxicity and significant inhibition against Na+/K+-ATPase (4). PMID:26087023

  20. Amide enolate additions to acylsilanes: in situ generation of unusual and stereoselective homoenolate equivalents.

    PubMed

    Lettan, Robert B; Galliford, Chris V; Woodward, Chase C; Scheidt, Karl A

    2009-07-01

    The synthesis of beta-hydroxy carbonyl compounds is an important goal due to their prevalence in bioactive molecules. A novel approach to construct these structural motifs involves the multicomponent reaction of acylsilanes, amides, and electrophiles. The addition of amide enolates to acylsilanes generates beta-silyloxy homoenolate reactivity by undergoing a 1,2-Brook rearrangement. These unique nucleophiles formed in situ can then undergo addition to alkyl halides, aldehydes, ketones, and imines. The gamma-amino-beta-hydroxy amide products derived from the addition of these homoenolates to N-diphenylphosphinyl imines are generated with excellent diastereoselectivity (> or = 20:1) and can be efficiently converted to highly valuable gamma-lactams. Finally, the use of optically active amide enolates delivers beta-hydroxy amide products with high levels of diastereoselectivity (> or = 10:1). PMID:19505076

  1. Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense.

    PubMed

    Suganuma, Keisuke; Sarwono, Albertus Eka Yudistira; Mitsuhashi, Shinya; Jąkalski, Marcin; Okada, Tadashi; Nthatisi, Molefe; Yamagishi, Junya; Ubukata, Makoto; Inoue, Noboru

    2016-07-01

    This study aimed to evaluate the trypanocidal activity of mycophenolic acid (MPA) and its derivatives for Trypanosoma congolense The proliferation of T. congolense was completely inhibited by adding <1 μM MPA and its derivatives. In addition, the IMP dehydrogenase in T. congolense was molecularly characterized as the target of these compounds. The results suggest that MPA and its derivatives have the potential to be new candidates as novel trypanocidal drugs. PMID:27139487

  2. Langmuir films of an amide extracted from Piperaceae and its interaction with phospholipids

    NASA Astrophysics Data System (ADS)

    Antunes, P. A.; Oliveira, O. N.; Aroca, R. F.; Chierice, G. O.; Constantino, C. J. L.

    2005-06-01

    In this work, we investigate Langmuir monolayers from an amide extracted from dried roots of Ottonia propinqua, a native Brazilian plant believed to exhibit anesthetic and hallucinogen activities. In addition to producing monolayers from the amide itself, we probe the molecular-level action of the amide on phospholipids employed as simple membrane models. The surface pressure-molecular area ( π- A) isotherms for the amide were little affected by a number of subphase conditions. Almost no changes were observed upon varying the compression speed, spreading volume onto the surface, ions in the subphase, ionic strength and the solution solvent. However, stronger effects occurred when the subphase temperature and pH were altered, as the isotherms were shifted to larger areas with increasing temperatures and decreasing pHs. These results are discussed in terms of the molecular packing adopted by the amide at the air-water interface. In the mixed films with arachidic acid, the area per molecule varied linearly with the concentration of amide, probably due to phase separation. On the other hand, in the mixed films with dipalmitoyl phosphatidyl choline (DPPC), small amounts of the amide were sufficient to change the π- A isotherms significantly. This points to a strong molecular-level interaction, probably between the phosphate group in the zwitterion of DPPC and the nitrogen from the amidic group.

  3. Anti-AIDS Agents 78 †. Design, Synthesis, Metabolic Stability Assessment, and Antiviral Evaluation of Novel Betulinic Acid Derivatives as Potent Anti-Human Immunodeficiency Virus (HIV) Agents

    PubMed Central

    Qian, Keduo; Yu, Donglei; Chen, Chin-Ho; Huang, Li; Morris-Natschke, Susan L.; Nitz, Theodore J.; Salzwedel, Karl; Reddick, Mary; Allaway, Graham P.; Lee, Kuo-Hsiung

    2009-01-01

    In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives, as well as seven novel 3,28-disubstituted BA analogs were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50: 0.09 μM), when compared to HIV entry inhibitors 3b (IC9564) and 4 (A43-D). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 μM and 0.006 μM, respectively. These results are slightly better than that of bevirimat (2), which is currently in Phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates. PMID:19388685

  4. Percutaneous absorption of nicotinic acid derivatives in vitro.

    PubMed

    Dal Pozzo, A; Donzelli, G; Liggeri, E; Rodriguez, L

    1991-01-01

    The permeation rates through isolated epidermis of a homologous series of glycol, polyglycol, and alkyl esters of nicotinic acid were measured in vitro in a two-compartment diffusion cell assembly, using an isotonic buffered solution as the receiving phase. The esters were applied from aqueous solutions and also as the pure liquids. The results were consistent with those reported by other using compounds of equal or different structures either in vitro or in vivo. The experiments are compared in terms of partition equilibrium between vehicle and tissue and distribution from tissue to the receiving phase. It was demonstrated that the plateau observed in skin permeabilities of the compounds beyond a certain degree of lipophilicity is the result of the effect of water when used as the vehicle in the laboratory models. PMID:2013851

  5. Hydroxycinnamic Acid Derivatives Obtained from a Commercial Crataegus Extract and from Authentic Crataegus spp.

    PubMed

    Kuczkowiak, Ulrich; Petereit, Frank; Nahrstedt, Adolf

    2014-12-01

    Eleven hydroxycinnamic acid derivatives were isolated from a 70% methanolic Crataegus extract (Crataegi folium cum flore) and partly verified and quantified for individual Crataegus species (C. laevigata, C. monogyna, C. nigra, C. pentagyna) by HPLC: 3-O-(E)-p-coumaroylquinic acid (1), 5-O-(E)-p-coumaroyl-quinic acid (2), 4-O-(E)-p-coumaroylquinic acid (3), 3-O-(E)-caffeoylquinic acid (4), 4-O-(E)-caffeoylquinic acid (5), 5-O-(E)-caffeoylquinic acid (6), 3,5-di-O-(E)-caffeoylquinic acid (7), 4,5-di-O-(E)-caffeoylquinic acid (8), (-)-2-O-(E)-caffeoyl-L-threonic acid (9), (-)-4-O-(E)-caffeoyl-L-threonic acid (10), and (-)-4-O-(E)-p-coumaroyl-L-threonic acid (11). Further, (-)-2-O-(E)-caffeoyl-D-malic acid (12) was isolated from C. submollis and also identified for C. pentagyna and C. nigra by co-chromatography. The isolates 10 and 11 were not found in the authentic fresh specimen, indicating that they may be formed during extraction by acyl migration from the 2-O-acylderivatives. Also, 9 and 11 are described here for the first time. All structures were assigned on the basis of their spectroscopic data ((1)H-, (13)C-NMR, MS, optical rotation). PMID:26171328

  6. Hydroxycinnamic Acid Derivatives Obtained from a Commercial Crataegus Extract and from Authentic Crataegus spp.§

    PubMed Central

    Kuczkowiak, Ulrich; Petereit, Frank; Nahrstedt, Adolf

    2014-01-01

    Abstract Eleven hydroxycinnamic acid derivatives were isolated from a 70% methanolic Crataegus extract (Crataegi folium cum flore) and partly verified and quantified for individual Crataegus species (C. laevigata, C. monogyna, C. nigra, C. pentagyna) by HPLC: 3-O-(E)-p-coumaroylquinic acid (1), 5-O-(E)-p-coumaroyl-quinic acid (2), 4-O-(E)-p-coumaroylquinic acid (3), 3-O-(E)-caffeoylquinic acid (4), 4-O-(E)-caffeoylquinic acid (5), 5-O-(E)-caffeoylquinic acid (6), 3,5-di-O-(E)-caffeoylquinic acid (7), 4,5-di-O-(E)-caffeoylquinic acid (8), (-)-2-O-(E)-caffeoyl-L-threonic acid (9), (-)-4-O-(E)-caffeoyl-L-threonic acid (10), and (-)-4-O-(E)-p-coumaroyl-L-threonic acid (11). Further, (-)-2-O-(E)-caffeoyl-D-malic acid (12) was isolated from C. submollis and also identified for C. pentagyna and C. nigra by co-chromatography. The isolates 10 and 11 were not found in the authentic fresh specimen, indicating that they may be formed during extraction by acyl migration from the 2-O-acylderivatives. Also, 9 and 11 are described here for the first time. All structures were assigned on the basis of their spectroscopic data (1H-, 13C-NMR, MS, optical rotation). PMID:26171328

  7. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents.

    PubMed

    Grover, Gaurav; Kini, Suvarna G

    2006-02-01

    In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H(2)SO(4) and fuming HNO(3). Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, (1)H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative

  8. Irbic acid, a dicaffeoylquinic acid derivative from Centella asiatica cell cultures.

    PubMed

    Antognoni, Fabiana; Perellino, Nicoletta Crespi; Crippa, Sergio; Dal Toso, Roberto; Danieli, Bruno; Minghetti, Anacleto; Poli, Ferruccio; Pressi, Giovanna

    2011-10-01

    3,5-O-dicaffeoyl-4-O-malonilquinic acid (1) (irbic acid) has been isolated for the first time from cell cultures of Centella asiatica and till now it has never been reported to be present in the intact plant. Evidence of its structure was obtained by spectroscopic analyses (MS/NMR). Besides 1, cell cultures produce also the known 3,5-O-dicaffeoylquinic acid, chlorogenic acid, and the triferulic acid 2 (4-O-8'/4'-O-8″-didehydrotriferulic acid). Biological activities were evaluated for compound 1, which showed to have a strong radical scavenging capacity, together with a high inhibitory activity on collagenase. This suggests a possible utilization of this substance as a topical agent to reduce the skin ageing process. PMID:21635941

  9. Identification and quantitation of new glutamic acid derivatives in soy sauce by UPLC/MS/MS.

    PubMed

    Frerot, Eric; Chen, Ting

    2013-10-01

    Glutamic acid is an abundant amino acid that lends a characteristic umami taste to foods. In fermented foods, glutamic acid can be found as a free amino acid formed by proteolysis or as a non-proteolytic derivative formed by microorganisms. The aim of the present study was to identify different structures of glutamic acid derivatives in a typical fermented protein-based food product, soy sauce. An acidic fraction was prepared with anion-exchange solid-phase extraction (SPE) and analyzed by UPLC/MS/MS and UPLC/TOF-MS. α-Glutamyl, γ-glutamyl, and pyroglutamyl dipeptides, as well as lactoyl amino acids, were identified in the acidic fraction of soy sauce. They were chemically synthesized for confirmation of their occurrence and quantified in the selected reaction monitoring (SRM) mode. Pyroglutamyl dipeptides accounted for 770 mg/kg of soy sauce, followed by lactoyl amino acids (135 mg/kg) and γ-glutamyl dipeptides (70 mg/kg). In addition, N-succinoylglutamic acid was identified for the first time in food as a minor compound in soy sauce (5 mg/kg). PMID:24130027

  10. A biosynthetic pathway for a prominent class of microbiota-derived bile acids

    PubMed Central

    Devlin, A. Sloan; Fischbach, Michael A.

    2015-01-01

    The gut bile acid pool is millimolar in concentration, varies widely in composition among individuals, and is linked to metabolic disease and cancer. Although these molecules derive almost exclusively from the microbiota, remarkably little is known about which bacterial species and genes are responsible for their biosynthesis. Here, we report a biosynthetic pathway for the second most abundant class in the gut, iso (3β-hydroxy) bile acids, whose levels exceed 300 µM in some humans and are absent in others. We show, for the first time, that iso bile acids are produced by Ruminococcus gnavus, a far more abundant commensal than previously known producers; and that the iso bile acid pathway detoxifies deoxycholic acid, favoring the growth of the keystone genus Bacteroides. By revealing the biosynthetic genes for an abundant class of bile acids, our work sets the stage for predicting and rationally altering the composition of the bile acid pool. PMID:26192599

  11. Microbial production of amino acids and derived chemicals: synthetic biology approaches to strain development.

    PubMed

    Wendisch, Volker F

    2014-12-01

    Amino acids are produced at the multi-million-ton-scale with fermentative production of l-glutamate and l-lysine alone being estimated to amount to more than five million tons in the year 2013. Metabolic engineering constantly improves productivities of amino acid producing strains, mainly Corynebacterium glutamicum and Escherichia coli strains. Classical mutagenesis and screening have been accelerated by combination with intracellular metabolite sensing. Synthetic biology approaches have allowed access to new carbon sources to realize a flexible feedstock concept. Moreover, new pathways for amino acid production as well as fermentative production of non-native compounds derived from amino acids or their metabolic precursors were developed. These include dipeptides, α,ω-diamines, α,ω-diacids, keto acids, acetylated amino acids and ω-amino acids. PMID:24922334

  12. Astrocyte-derived phosphatidic acid promotes dendritic branching

    PubMed Central

    Zhu, Yan-Bing; Gao, Weizhen; Zhang, Yongbo; Jia, Feng; Zhang, Hai-Long; Liu, Ying-Zi; Sun, Xue-Fang; Yin, Yuhua; Yin, Dong-Min

    2016-01-01

    Astrocytes play critical roles in neural circuit formation and function. Recent studies have revealed several secreted and contact-mediated signals from astrocytes which are essential for neurite outgrowth and synapse formation. However, the mechanisms underlying the regulation of dendritic branching by astrocytes remain elusive. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine (PC) to generate phosphatidic acid (PA) and choline, has been implicated in the regulation of neurite outgrowth. Here we showed that knockdown of PLD1 selectively in astrocytes reduced dendritic branching of neurons in neuron-glia mixed culture. Further studies from sandwich-like cocultures and astrocyte conditioned medium suggested that astrocyte PLD1 regulated dendritic branching through secreted signals. We later demonstrated that PA was the key mediator for astrocyte PLD1 to regulate dendritic branching. Moreover, PA itself was sufficient to promote dendritic branching of neurons. Lastly, we showed that PA could activate protein kinase A (PKA) in neurons and promote dendritic branching through PKA signaling. Taken together, our results demonstrate that astrocyte PLD1 and its lipid product PA are essential regulators of dendritic branching in neurons. These results may provide new insight into mechanisms underlying how astrocytes regulate dendrite growth of neurons. PMID:26883475

  13. Effect of the structure of gallic acid and its derivatives on their interaction with plant ferritin.

    PubMed

    Wang, Qunqun; Zhou, Kai; Ning, Yong; Zhao, Guanghua

    2016-12-15

    Gallic acid and its derivatives co-exist with protein components in foodstuffs, but there is few report on their interaction with proteins. On the other hand, plant ferritin represents not only a novel class of iron supplement, but also a new nanocarrier for encapsulation of bioactive nutrients. However, plant ferritin is easy to be degraded by pepsin in the stomach, thereby limiting its application. Herein, we investigated the interaction of gallic acid and its derivatives with recombinant soybean seed H-2 ferritin (rH-2). We found that these phenolic acids interacted with rH-2 in a structure-dependent manner; namely, gallic acid (GA), methyl gallate (MEGA) and propyl gallate (PG) having three HO groups can bind to rH-2, while their analogues with two HO groups cannot. Consequently, such binding largely inhibited ferritin degradation by pepsin. These findings advance our understanding of the relationship between the structure and function of phenolic acids. PMID:27451180

  14. Bioconversion of volatile fatty acids derived from waste activated sludge into lipids by Cryptococcus curvatus.

    PubMed

    Liu, Jia; Liu, Jia-Nan; Yuan, Ming; Shen, Zi-Heng; Peng, Kai-Ming; Lu, Li-Jun; Huang, Xiang-Feng

    2016-07-01

    Pure volatile fatty acid (VFA) solution derived from waste activated sludge (WAS) was used to produce microbial lipids as culture medium in this study, which aimed to realize the resource recovery of WAS and provide low-cost feedstock for biodiesel production simultaneously. Cryptococcus curvatus was selected among three oleaginous yeast to produce lipids with VFAs derived from WAS. In batch cultivation, lipid contents increased from 10.2% to 16.8% when carbon to nitrogen ratio increased from about 3.5 to 165 after removal of ammonia nitrogen by struvite precipitation. The lipid content further increased to 39.6% and the biomass increased from 1.56g/L to 4.53g/L after cultivation for five cycles using sequencing batch culture (SBC) strategy. The lipids produced from WAS-derived VFA solution contained nearly 50% of monounsaturated fatty acids, including palmitic acid, heptadecanoic acid, ginkgolic acid, stearic acid, oleic acid, and linoleic acid, which showed the adequacy of biodiesel production. PMID:27038264

  15. Photochemical synthesis and anticancer activity of barbituric acid, thiobarbituric acid, thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives.

    PubMed

    Laxmi, S Vijaya; Rajitha, G; Rajitha, B; Rao, Asha Jyothi

    2016-04-01

    2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines. PMID:27118996

  16. Sterically-controlled intermolecular Friedel-Crafts acylation with twisted amides via selective N-C cleavage under mild conditions.

    PubMed

    Liu, Yongmei; Meng, Guangrong; Liu, Ruzhang; Szostak, Michal

    2016-05-21

    Highly chemoselective Friedel-Crafts acylation with twisted amides under mild conditions is reported for the first time. The reaction shows high functional group tolerance, obviating the need for preformed sensitive organometallic reagents and expensive transition metal catalysts. The high reactivity of amides is switched on by ground-state steric distortion to disrupt the amide bond nN→πCO* resonance as a critical design feature. Conceptually, this new acid-promoted mechanism of twisted amides provides direct access to bench-stable acylating reagents under mild, metal-free conditions. PMID:27139813

  17. Condensation Reactions and Formation of Amides, Esters, and Nitriles Under Hydrothermal Conditions

    NASA Astrophysics Data System (ADS)

    Rushdi, Ahmed I.; Simoneit, Bernd R. T.

    2004-06-01

    Hydrothermal pyrolysis experiments were performed to assess condensation (dehydration) reactions to amide, ester, and nitrile functionalities from lipid precursors. Beside product formation, organic compound alteration and stability were also evaluated. Mixtures of nonadecanoic acid, hexadecanedioic acid, or hexadecanamide with water, ammonium bicarbonate, and oxalic acid were heated at 300°C for 72 h. In addition, mixtures of ammonium bicarbonate and oxalic acid solutions were used to test the abiotic formation of organic nitrogen compounds at the same temperature. The resulting products were condensation compounds such as amides, nitriles, and minor quantities of N-methylalkyl amides, alkanols, and esters. Mixtures of alkyl amide in water or oxalic acid yielded mainly hydrolysis and dehydration products, and with ammonium bicarbonate and oxalic acid the yield of condensation products was enhanced. The synthesis experiments with oxalic acid and ammonium bicarbonate solutions yielded homologous series of alkyl amides, alkyl amines, alkanes, and alkanoic acids, all with no carbon number predominances. These organic nitrogen compounds are stable and survive under the elevated temperatures of hydrothermal fluids.

  18. Thiourea derivatives incorporating a hippuric acid moiety: synthesis and evaluation of antibacterial and antifungal activities.

    PubMed

    Abbas, Samir Y; El-Sharief, Marwa A M Sh; Basyouni, Wahid M; Fakhr, Issa M I; El-Gammal, Eman W

    2013-06-01

    New series of thiourea derivatives incorporating a hippuric acid moiety have been synthesized through the reaction of 4-hippuric acid isothiocyanate with various nitrogen nucleophiles such as aliphatic amines, aromatic amines, sulfa drugs, aminopyrazoles, phenylhydrazine and hydrazides. The synthesized compounds were tested against bacterial and fungal strains. Most of compounds, such as 2-(4-(3-(3-bromophenyl)thioureido)benzamido)acetic acid and 2-(4-(3-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)thioureido)benzamido)acetic acid, showed significant antibacterial and antifungal activities. These compounds comprise a new class of promising broad-spectrum antibacterial and antifungal agents. PMID:23644194

  19. Bile acids are toxic for isolated cardiac mitochondria: a possible cause for hepatic-derived cardiomyopathies?

    PubMed

    Ferreira, Manuela; Coxito, Pedro M; Sardão, Vilma A; Palmeira, Carlos M; Oliveira, Paulo J

    2005-01-01

    Cholestasis and other liver diseases may affect the heart through the toxic effects of the retained bile acids on cardiac mitochondria, which could explain the origin of hepatic-derived cardiomyopathies. The objective of this work was to test the hypothesis that bile acids are toxic to heart mitochondria for concentrations that are relevant for cholestasis. Heart mitochondria were isolated from rat and subjected to incubation with selected bile acids (litocholic acid [LCA], deoxycholic acid [DCA], chenodeoxycholic acid [CDCA], glycochenodeoxycholic acid [GCDC], taurodeoxycholic acid [TDCA], and glycoursodeoxycholic acid [GUDC]). We observed that the most toxic bile acids were also the most lipophilic ones (LCA, DCA, and CDCA), inducing a decrease on state 3 respiration, respiratory control ratio, and membrane potential and causing the induction of the mitochondrial permeability transition. GUDC was the bile acid with lower indexes of toxicity on isolated heart mitochondria. The results of this research indicate that at toxicologically relevant concentrations, most bile acids (mainly the most lipophilic) alter mitochondrial bioenergetics. The impairment of cardiac mitochondrial function may be an important cause for the observed cardiac alterations during cholestasis. PMID:15738586

  20. Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell.

    PubMed

    Weylandt, Karsten-H

    2016-08-15

    Recent years have seen the description and elucidation of a new class of anti-inflammatory and pro-resolving lipid mediators. The arachidonic acid (AA)-derived compounds in this class are called lipoxins and have been described in great detail since their discovery thirty years ago. The new players are mediators derived from fish oil omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), called resolvins, protectins and maresins. Taken together, these mediators are also called specialized pro-resolution mediators (SPMs). As compared to the AA/EPA/DHA-derived compounds, research regarding mediators formed from the n-3 and n-6 docosapentaenoic acids (DPAn-3 and DPAn-6) is sparse. However, mono- di- and trihydroxy derivates of the DPAs have anti-inflammatory properties as well, even though mechanisms of their anti-inflammatory action have not been fully elucidated. This review aims to summarize current knowledge regarding the DPA-derived SPMs and their actions. PMID:26546723