- Lytic reactions of drugs with lipid membranes
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Propranolol is shown to undergo lipidation reactions in three types of lipid membrane: (1) synthetic single-component glycerophospholipid liposomes; (2) liposomes formed from complex lipid mixtures extracted from E. coli or liver cells; and (3) in cellulo in Hep G2 cells. Fourteen different lipidated propranolol homologues were identified in extracts from Hep G2 cells cultured in a medium supplemented with propranolol. This isolation of lipidated drug molecules from liver cells demonstrates a new drug reactivity in living systems. Acyl transfer from lipids to the alcoholic group of propranolol was favoured over transfer to the secondary amine. Migration of acyl groups from the alcohol to the amine was diminished. Other drugs that were examined did not form detectable levels of lipidation products, but many of these drugs did affect the lysolipid levels in model membranes. The propensity for a compound to induce lysolipid formation in a model system was found to be a predictor for phospholipidosis activity in cellulo.
- Britt, Hannah M.,García-Herrero, Clara A.,Denny, Paul W.,Mosely, Jackie A.,Sanderson, John M.
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p. 674 - 680
(2019/01/24)
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- Synthetic access to arsenic-containing phosphatidylcholines
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We wish to disclose the first synthesis of 1-O-hexadecanoyl-2-O-((15-(dimethylarsinoyl)pentadecanoyl)oxy)-sn-glycero-3-phosphocholine, which belongs to the group of arsenic-containing phosphatidylcholines (AsPCs), recently discovered in herring caviar. The synthesized product will serve as a model compound to study biological and toxicological properties of arsenolipids in food.
- Guttenberger, Nikolaus,Glabonjat, Ronald A.,Tassoti, Sebastian,Francesconi, Kevin A.
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supporting information
p. 2651 - 2653
(2017/06/14)
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- Syntheses and antiproliferative activities of novel phosphatidylcholines containing dehydroepiandrosterone moieties
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Dehydroepiandrosterone (DHEA) is a natural hormone with many beneficial properties including an anticancer activity. Unfortunately, DHEA is unstable in the body and exhibits cytotoxicity against healthy cells. In this study, a series of new phosphocholines containing DHEA at sn-1 and/or sn-2 positions were prepared. Succinic acid was used as a linker between the active drug and sn-glycero-3-phosphocholine. All the compounds were evaluated in vitro for their antiproliferative activities against four cell lines: Balb/3T3, HL-60, B16, and LNCaP. The results showed that phosphocholines with DHEA at sn-1 and/or sn-2 positions did not have cytotoxic effects on the normal cell line (Balb/3T3). Mixed-chain phospholipids with DHEA and fatty acid residues showed the highest activity against tumor cell lines. The most active compound, 11c, showed a moderate cytotoxic effect against the HL-60 and B16 cell lines.
- K?obucki, Marek,Grudniewska, Aleksandra,Smuga, Damian A.,Smuga, Ma?gorzata,Jarosz, Joanna,Wietrzyk, Joanna,Maciejewska, Gabriela,Wawrzeńczyk, Czes?aw
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p. 109 - 118
(2017/01/12)
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- Synthesis and biological evaluation of novel phosphatidylcholine analogues containing monoterpene acids as potent antiproliferative agents
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The synthesis of novel phosphatidylcholines with geranic and citronellic acids in sn-1 and sn-2 positions is described. The structured phospholipids were obtained in high yields (59-87%) and evaluated in vitro for their cytotoxic activity against several cancer cell lines of different origin: MV4-11, A-549, MCF-7, LOVO, LOVO/DX, HepG2 and also towards noncancer cell line BALB/3T3 (normal mice fibroblasts). The phosphatidylcholines modified with monoterpene acid showed a significantly higher antiproliferative activity than free monoterpene acids. The highest activity was observed for the terpene-phospholipids containing the isoprenoid acids in sn-1 position of phosphatidylcholine and palmitic acid in sn-2.
- Gliszczyńska, Anna,Niezgoda, Natalia,G?adkowski, Witold,Czarnecka, Marta,?witalska, Marta,Wietrzyk, Joanna
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- Peptidophospholipids: Synthesis, phospholipase A2 catalyzed hydrolysis, and application to development of phospholipid prodrugs
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New phospholipid analogues incorporating sn-2-peptide substituents have been prepared to probe the fundamental structural requirements for phospholipase A2 catalyzed hydrolysis of PLA2-directed synthetic substrates. Two structurally
- Rosseto, Renato,Hajdu, Joseph
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p. 110 - 116
(2014/07/08)
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- Synthesis of phosphatidylcholine with conjugated linoleic acid and studies on its cytotoxic activity
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Phospholipids with conjugated linoleic acid (CLA), which are potential lipid prodrugs, were synthesised. CLA was obtained by the alkali-isomerisation of linoleic acid and was subsequently used in the synthesis of 1,2-di(conjugated)linoleoyl-sn-glycero-3-phosphocholine in good (82%) yield. 1-Palmitoyl-2-(conjugated)linoleoyl-sn-glycero-3-phosphocholine was obtained by a two-step synthesis in 87% yield. All the compounds were tested in an in vitro cytotoxicity assay against two human cancer cell lines, HL-60 and MCF-7, and a mouse fibroblast cell line, Balb/3T3. The free form of CLA exhibited the highest activity against all cancer cell lines. Results obtained for the Balb/3T3 line proved that phosphatidylcholine derivatives decreased the cytotoxic effect of CLA against healthy cell lines.
- Niezgoda, Natalia,Mitula, Pawel,Kempinska, Katarzyna,Wietrzyk, Joanna,Wawrzenczyk, Czeslaw
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p. 354 - 361
(2013/05/22)
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- Acyl transfer from phosphocholine lipids to melittin
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Transfer of fatty acyl groups from membrane phospholipids to melittin, a commonly studied membrane-active peptide, has been observed to occur over extended time periods. Transfer can be detected after 1-2 days and selectively targets amino groups at the N-terminal end of the peptide.
- Pridmore, Catherine J.,Mosely, Jackie A.,Rodger, Alison,Sanderson, John M.
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supporting information; body text
p. 1422 - 1424
(2011/03/20)
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- Interfacial kinetic and binding properties of mammalian group IVB phospholipase A2 (cPLA2β) and comparison with the other cPLA2 isoforms
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The cytosolic (group IV) phospholipase A2 (cPLA2s) family contains six members. We have prepared recombinant proteins for human α, mouse β, human γ, human δ, human ε, and mouse ζ cPLA2s and have studied their interfacial kinetic and binding properties in vitro. Mouse cPLA2β action on phosphatidylcholine vesicles is activated by anionic phosphoinositides and cardiolipin but displays a requirement for Ca2+ only in the presence of cardiolipin. This activation pattern is explained by the effects of anionic phospholipids and Ca2+ on the interfacial binding of mouse cPLA2β and its C2 domain to vesicles. Ca2+-dependent binding of mouse cPLA 2β to cardiolipin-containing vesicles requires a patch of basic residues near the Ca2+-binding surface loops of the C2 domain, but binding to phosphoinositide-containing vesicles does not depend on any specific cluster of basic residues. Human cPLA2δ also displays Ca 2+- and cardiolipin-enhanced interfacial binding and activity. The lysophospholipase, phospholipase A1, and phospholipase A2 activities of the full set of mammalian cPLA2s were quantified. The relative level of these activities is very different among the isoforms, and human cPLA2δ stands out as having relatively high phospholipase A1 activity. We also tested the susceptibility of all cPLA 2 family members to a panel of previously reported inhibitors of human cPLA2α and analogs of these compounds. This led to the discovery of a potent and selective inhibitor of mouse cPLA2β. These in vitro studies help determine the regulation and function of the cPLA2 family members.
- Ghomashchi, Farideh,Naika, Gajendra S.,Bollinger, James G.,Aloulou, Ahmed,Lehr, Matthias,Leslie, Christina C.,Gelb, Michael H.
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experimental part
p. 36100 - 36111
(2011/12/16)
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- Lysophosphatidylethanolamine is - in contrast to - choline - generated under in vivo conditions exclusively by phospholipase A2 but not by hypochlorous acid
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Inflammatory liver diseases are associated with oxidative stress mediated particularly by neutrophilic granulocytes. At inflammatory loci, hypochlorous acid (HOCl) is generated by myeloperoxidase. HOCl reacts with a large variety of molecules and induces
- Schober, Celestina,Schiller, Juergen,Pinker, Franziska,Hengstler, Jan G.,Fuchs, Beate
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experimental part
p. 202 - 210
(2010/03/03)
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- Discrimination of chain positions in mixed short/long-chain glycerophosphocholines by NMR chemical shift variations
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The synthesis of a series of (1,2-) mixed short/long-chain glycerophosphocholines has been performed. Starting from glycerophosphorylcholine (GPC), and using regioselective acylation in the presence of dibutyltin oxide, a set of high-purity isomeric mixed-chain phospholipids was obtained. This has allowed the development of a simple NMR method for the structural determination of the isomeric 1(2)-short-2(1)-long- diacylglycerophosphocholines. The method is based on the observation that selected protons in the two series of isomeric phospholipids undergo systematic chemical shift variations Δδ that can be ascribed to the acyl substituents on the glycerol backbone. The observed patterns can be exploited as a simple method for the discrimination of regioisomeric unsymmetrical 1,2-diacylglycerophosphocholines.
- D'Arrigo, Paola,Mele, Andrea,Rossi, Cristina,Tessaro, Davide,Servi, Stefano
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experimental part
p. 1005 - 1011
(2009/12/03)
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- A practical selective synthesis of mixed short/long chains glycerophosphocholines
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Glycerophosphorylcholine (GPC) is transformed into the cyclic stannylene derivatives, which are selectively acylated to 1-acyl-2-lyso-glycerophosphocholines. The reaction is effective using C-2 to C-16 acid chlorides in 2-propanol. After solvent replacement the lyso-phospholipid (lyso-PL) is subjected to a second acylation using acid anhydrides in methylene chloride. A series of 1(2)-short-2(1)-long-diacyl-glycerophosphocholines are obtained in high yields and selectivity. No diacylation product was detected. In order to detect mixed-chain lipids with inverted disposition of acyl chains, the long chain was introduced first and the thus resulting isomeric compounds compared by NMR. An NMR method was developed in order to determine the positional purity of the isomeric compounds.
- D'Arrigo, Paola,Fasoli, Ezio,Pedrocchi-Fantoni, Giuseppe,Rossi, Cristina,Saraceno, Caterina,Tessaro, Davide,Servi, Stefano
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p. 113 - 118
(2008/02/04)
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- A new synthesis of lysophosphatidylcholines and related derivatives. Use of p-toluenesulfonate for hydroxyl group protection
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A new stereoselective synthesis of lysophosphatidylcholines is reported. The synthesis is based upon (1) the use of 3-p-toluenesulfonyl-sn-glycerol to provide the stereocenter for construction of the optically active lysophospholipid molecule, (2) tetrahydropyranylation of the secondary alcohol function to achieve orthogonal protection of the sn-2- and sn-3-glycerol positions, and (3) elaboration of the phosphodiester headgroup using a 2-chloro-1,3,2-dioxaphospholane/trimethylamine sequence. In the course of developing the synthesis it has been discovered that methoxyacetate displacement of the sn-3-p-toluenesulfonate yields a reactive methoxyacetyl ester, which in turn can be selectively cleaved with methanol/tertbutylamine, while the ester group at the sn-1-position remains unaffected. The sequence has been shown to be suitable for preparation of spectroscopically labeled lysophosphatidylcholines. One of these compounds was readily converted to a double-labeled mixed-chain phosphatidylcholine applicable for real-time fluorescence resonance energy transfer (FRET) assay of lipolytic enzymes. In addition, the work led to new synthetic strategies based on chemoselective manipulation of the tosyl group in the presence of other base-labile groups such as FMOC derivatives that are often used for the protection of amino and hydroxyl groups in syntheses.
- Rosseto, Renato,Bibak, Niloufar,DeOcampo, Rosemarie,Shah, Trishul,Gabrielian, Ara,Hajdu, Joseph
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p. 1691 - 1698
(2007/10/03)
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- Tin-mediated synthesis of lyso-phospholipids
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1-O-Acyl-sn-glycero-3-phosphocholine and 1-O-acyl-sn-glycero-3-phosphoric acid have been prepared selectively and with high yields from the corresponding diols, glycerophosphoryl choline and glycerol-3-phosphate. Starting from the diols, the activated tin ketals were prepared in 2-propanol by reaction with dialkyltin oxide. The intermediates were acylated in the same solvent with long-chain fatty acid chlorides, giving the corresponding 1-acyl-lyso- phospholipids in high yield and with complete regioselectivity. The catalytic nature of the tin-mediated acylation and the relevance of the solvent are discussed. The Royal Society of Chemistry 2006.
- Fasoli, Ezio,Arnone, Alberto,Caligiuri, Antonio,D'Arrigo, Paola,De Ferra, Lorenzo,Servi, Stefano
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p. 2974 - 2978
(2008/02/11)
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- Process for preparing lysophoshatidylcholine
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What is described is a process for preparing lysophosphatidylcholine by selective monoacylation of glycerophosphorylcholine (I), in the presence of an acylating agent and of dialkyltin derivatives, according to the following diagram: the process being particularly simple and having high overall yields.
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Page/Page column 7
(2010/11/08)
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- Process for preparing lysophosphatidylcholine
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What is described is a process for preparing lysophosphatidylcholine by selective monoacylation of glycerophosphoryleholine (1), in the presence of an acylating agent and of dialkyltin derivatives, according to the following diagram: the process being particularly simple and having high overall yields.
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Page/Page column 3
(2008/06/13)
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- Modulation of the in vitro activity of lysosomal phospholipase A1 by membrane lipids
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Lysosomal phospholipases play a critical role for degradation of cellular membranes after their lysosomal segregation. We investigated the regulation of lysosomal phospholipase A1 by cholesterol, phosphatidylethanolamine, and negatively-charged lipids in correlation with changes of biophysical properties of the membranes induced by these lipids. Lysosomal phospholipase A1 activity was determined towards phosphatidylcholine included in liposomes of variable composition using a whole-soluble lysosomal fraction of rat liver as enzymatic source. Phospholipase A1 activity was then related to membrane fluidity, lipid phase organization and membrane potential as determined by fluorescence depolarization of DPH, 31P NMR and capillary electrophoresis. Phospholipase A1 activity was markedly enhanced when the amount of negatively-charged lipids included in the vesicles was increased from 10 to around 30% of total phospholipids and the intensity of this effect depended on the nature of the acidic lipids used (ganglioside GM1 phosphatidylinositol ~ phosphatidylserine ~ phosphatidylglycerol ~ phosphatidylpropanol phosphatidic acid). For liposomes containing phosphatidylinositol, this increase of activity was not modified by the presence of phosphatidylethanolamine and enhanced by cholesterol only when the phosphatidylinositol content was lower than 18%. Our results, therefore show that both the surface-negative charge and the nature of the acidic lipid included in bilayers modulate the activity of phospholipase A1 towards phosphatidylcholine, while the change in lipid hydration or in fluidity of membrane are less critical. These observations may have physiological implications with respect to the rate of degradation of cellular membranes after their lysosomal segregation.
- Piret, Jocelyne,Schanck, André,Delfosse, Sylvie,Van Bambeke, Fran?oise,Kishore, Bellamkonda K.,Tulkens, Paul M.,Mingeot-Leclercq, Marie-Paule
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- A new approach to the synthesis of lysophospholipids: Preparation of lysophosphatidic acid and lysophosphatidylcholine from p-nitrophenyl glycerate
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A new stereospecific synthesis of lysophosphatidic acid and lysophosphatidylcholine is reported. The sequence relies on p-nitrophenyl-D- glycerate as a chiral synthon, including chemoselective reduction of the active ester function without affecting other carboxylic ester groups present in the molecule.
- Rosseto, Renato,Bibak, Niloufar,Hajdu, Joseph
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p. 7371 - 7373
(2007/10/03)
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- Efficient synthesis of phospholipids from glycidyl phosphates
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New efficient routes to enantiopure phospholipids, starting from (S)-glycidol, are described. Lysophosphatidic acids and phosphatidic acids were obtained in good overall yields from (S)-glycidol, in only three and four steps, respectively. Moreover, the strategy can also be used to produce phosphatidylcholines in three steps. Using dialkylphosphoramidites, (S)-glycidol was phosphorylated to give (R)-1-O-glycidyl dialkyl phosphates. Regiospecific epoxide opening, using hexadecanol or cesium palmitate, followed by phosphate deprotection, provided lysophosphatidic acids. 2-O-Esterification prior to phosphate deprotection provided 1,2-O-diacyl and 1-O-alkyl-2-O-acyl phosphatidic acids. Phosphorylation of (S)-glycidol using phosphorus oxychloride followed by in situ treatment with choline tosylate produced (R)-glycidyl phosphocholine. Subsequent nucleophilic opening of the epoxide using cesium palmitate produced 1-O palmitoyl-sn-glycero-3-phosphocholine, which has been used in syntheses of phosphatidylcholines.
- Lindberg, Jan,Ekeroth, Johan,Konradsson, Peter
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p. 194 - 199
(2007/10/03)
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- γ-Ray irradiation of liposomes of polymerizable phospholipids containing octadeca-2,4-dienoyl groups and characterization of the irradiated liposomes
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The synthesis of a variety of polymerizable phospholipids containing the octadeca-2,4-dienoyl moiety on 2-acyl chains and the characteristics of liposomes containing those phospholipids of the γ-irradiation are described. We synthesized three different polymerizable phosphocholines that have different 1-acyl chain lengths with the octadeca-2,4-dienoyl moiety on the 2- acyl chain: myristoyl (MODPC), palmitoyl (PODPC) and stearoyl (SODPC). The liposomes were prepared by extrusion through polycarbonate filters with a pore size of 0.2 μm, and were polymerized by γ-irradiation with various dose rates. The polymerization rate increased in the order SODPC>MODPC>PODPC. The mechanism of the polymerization of SODPC was the same as that of 1,2-bis- [(E,E)-octadeca-2,4-dienoyl]-sn-glycero-3-phosphocholine (DODPC), but differed from that of MODPC and PODPC. Freeze-thaw testing was used to evaluate the stability of the polymerizable liposomes. The MODPC liposome was more stable than other monofunctional liposomes. For similar irradiation, the polymerization behavior of the liposomes was significantly affected by the 1- acyl length.
- Akama, Kazuhiro,Yano, Yoshihiro,Tokuyama, Satoru,Hosoi, Fumio,Omichi, Hideki
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p. 1047 - 1059
(2007/10/03)
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- The stereospecific synthesis of mixed-acid phospholipids with polyunsaturated fatty acid from D-mannitol
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The polyunsaturated mixed-acid phosphatidylcholine, 1-palimoyl-2-linolenoyl-sn-glycerophosphocholine 1a and 1-stearoyl-2-linolenoyl-sn-glycerophosph 1b prepared from D-mannitol as an optically active starting material is described.
- Xia, Jie,Hui, Yong-Zheng
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p. 451 - 458
(2007/10/03)
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- Novel acyl donors for enzyme-catalyzed transacylation reactions
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Two novel acyl donors, cyclohexyl palmitate and 2,2'-biphenyl dipalmitate, for enzyme-catalyzed transacylation reactions are reported.
- Lin,Liu,Wu,Jen
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p. 2135 - 2138
(2007/10/02)
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- Nuclear Magnetic Resonance Evidence for Radiation Damage of Saturated Phosphatidylcholine in Bilayers
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Multilayer membranes of 1,2-dipalmitoyl-sn-glycero-3-phosphorylcholine were prepared in D2O and exposed to γ-radiation.Changes in the chemical structure due to irradiation were studied by (1)H, (13)C and (31)P NMR after lyophilization and dissolution in chloroform-methanol (1:2 v/v).One- and two-dimensional techniques were used. 1-Palmitoyl-sn-glycero-3-phosphorylcholine, 2-palmitoyl-sn-glycero-3-phosphorylcholine, glycero-3-phosphorylcholine and palmitic acid were identified as new components.Their development during irradiation was quantitatively determined.The results were discussed in terms of possible reaction steps responsible for the radiolytic decomposition. Key words: (1)H NMR, (13)C NMR, (31)P NMR, 1,2-dipalmitoyl-sn-glycero-3-phosphorylcholine, bilayer, radiation damage
- Casu, Mariano,Lai, Adolfo,Erriu, Gianni,Onnis, Salvatore,Zucca, Nazario
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p. 408 - 412
(2007/10/02)
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- Optically active oxiranes. Synthesis of PAF (Platelet Aggregating Factor)
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A number of epoxides bearing no function in the α-position have been converted into β-hydroxy sulfonium salts.Association with an otically active acid (dibenzoyltartaric) allowed the resolution.This method has been used to prepare the optically active glycidol octadecyl ether which was converted into (-) PAF. Key words: oxiranes / resolution / PAF synthesis
- Cimetiere, B,Jacob, L,Julia, M
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p. 926 - 938
(2007/10/02)
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- Polymerized Phosphatidylcholine Vesicles. Synthesis and Characterization
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The synthesis and characterization of photopolymerized vesicles derived from bis-L-α-phosphatidylcholine (3) 1--2-palmitoyl-L-α-phosphatidylcholine (4), and 1-palmitoyl-2--L-α-phosphatidylcholine (5) are described.Ultrasonic irradiation of 3, 4, 5, 20percent 3 + 80percent 4, and 20percent 3 + 80percent 5 in water at 50 deg C yields opalescent to optically clear dispersions.Electron microscopy, entrapment of sucrose, and permeability measurements provide strong evidence for closed multilamellar vesicles having diameters ranging between 350 and 1400 Angstroem.Fourier transform 1H NMR spectra of the aqueous dispersions as well as IR spectra of chloroform extracts establish that no significant lipid decomposition occurs during vesicle preparation.Direct UV irradiation (254 nm) produces polymerized analogues of similar size and shape which (1) entrap sucrose, (2) show reduced permeability, and (3) exhibit enchanced stability.
- Regen, Steven L.,Singh, Alok,Oehme, Guenter,Singh, Maninder
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p. 791 - 795
(2007/10/02)
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