- Activation of n-3 polyunsaturated fatty acids as oxime esters: A novel approach for their exclusive incorporation into the primary alcoholic positions of the glycerol moiety by lipase
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A novel approach has been developed for activating the highly bioactive long-chain n-3 polyunsaturated fatty acids EPA and DHA as oxime esters and incorporating them exclusively to the end-positions of glycerol and enantiopure 1-O-alkylglycerols. The Candida antarctica lipase B was observed to display a superb regioselectivity when using the acetoxime esters of EPA and DHA as acyldonors under mild condition to keep acyl-migration side-reaction under complete control. Regiopure 1,3-diacylglycerols, 1-O-alkyl-3-acyl-sn-glycerols and their antipodes possessing EPA and DHA were afforded in very high purity and yields.
- Magnusson, Carlos D.,Haraldsson, Gudmundur G.
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- Homologues and isomers of noladin ether, a putative novel endocannabinoid: Interaction with rat cannabinoid CB1 receptors
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Two regioisomers and 13 analogues of the putative endocannabinoid noladin ether (2-arachidonyl glyceryl ether, 2-AGE, 1) were synthesized and tested for their interaction with CB1 receptors in rat brain membranes. The results showed that a C-20 tetra-unsaturated moiety is necessary for high affinity, and that a series of alkyl glyceryl ethers of potential occurrence in brain tissues have less affinity than 2-AGE for CB1 receptors.
- Appendino, Giovanni,Ligresti, Alessia,Minassi, Alberto,Daddario, Nives,Bisogno, Tiziana,Di Marzo, Vincenzo
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- Stereospecific and regioselective opening of an oxirane system. A new efficient entry to 1- or 3-monoacyl- and 1- or 3-monoalkyl-sn-glycerols
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Acyl or alkyl glycidols in the presence of trifluoroacetic anhydride (TFAA) and trifluoroacetate anions, undergo a regioselective and stereospecific opening of the oxirane system to produce the bis(trifluoroacetylated) derivatives, from which the corresponding 1(3)-monoacyl-sn-glycerols or 1(3)-monoalkyl-sn-glycerols can be obtained directly in high purity (>99%) and in quantitative yields.
- Stamatov, Stephan D.,Stawinski, Jacek
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- ENANTIOMERE DER 2,2'-DINITROBIPHENYL-6,6'-DICARBONSAEURE ALS STEREOSELEKTIV WIRKSAME, REVERSIBLE SCHUTZGRUPPEN-II. STEREOSELEKTIVE SYNTHESEN VON LIPIDGRUNDKOERPERN ODER -BAUSTEINEN
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S-(-)-1,1'-diphenyl-2,2'-dinitro-6,6'-dicarboxylic acid (1) is used as an axial-chiral protecting group for the primary hydroxy group of glycerol and glycerol derivatives.Diesters of 1 were formed which have the largest distance between the nitro groups and the nucleophilic substituents on glycerol.After hydrogenolytical removal of the protecting group asymmetric glycerol derivatives were obtained with approximately 10percent enantiomeric excess.Hydroxybromination of 12 resulted mainly in he anti-Markovnikov 13a instead of the Markovnikov product 13b expected, which was present only in traces.This deviation is discussed.
- Mueller, H. K.,Burgold, J.
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- Method for preventing cancer metastasis
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The present invention relates to the use of a specific family of glycerolipid compounds of formula (I) described in the detailed description or the manufacture of a medicament for the prevention or for the treatment of cancer metastasis.
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(2015/11/10)
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- Autotaxin structure-activity relationships revealed through lysophosphatidylcholine analogs
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Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to form the bioactive lipid lysophosphatidic acid (LPA). LPA stimulates cell proliferation, cell survival, and cell migration and is involved in obesity, rheumatoid arthritis, neuropathic pain, atherosclerosis and various cancers, suggesting that ATX inhibitors have broad therapeutic potential. Product feedback inhibition of ATX by LPA has stimulated structure-activity studies focused on LPA analogs. However, LPA displays mixed mode inhibition, indicating that it can bind to both the enzyme and the enzyme-substrate complex. This suggests that LPA may not interact solely with the catalytic site. In this report we have prepared LPC analogs to help map out substrate structure-activity relationships. The structural variances include length and unsaturation of the fatty tail, choline and polar linker presence, acyl versus ether linkage of the hydrocarbon chain, and methylene and nitrogen replacement of the choline oxygen. All LPC analogs were assayed in competition with the synthetic substrate, FS-3, to show the preference ATX has for each alteration. Choline presence and methylene replacement of the choline oxygen were detrimental to ATX recognition. These findings provide insights into the structure of the enzyme in the vicinity of the catalytic site as well as suggesting that ATX produces rate enhancement, at least in part, by substrate destabilization.
- North, E. Jeffrey,Osborne, Daniel A.,Bridson, Peter K.,Baker, Daniel L.,Parrill, Abby L.
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experimental part
p. 3433 - 3442
(2009/09/30)
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- Sarcoglycosides A-C, new O-glycosylglycerol derivatives from the South China sea soft coral Sarcophyton infundibuliforme
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Chemical examination of the soft coral Sarcophyton infundibuliforme collected from the South China Sea resulted in the isolation of the three new O-glycosylglycerol derivatives sarcoglycosides A-C (1 - 3), together with two known compounds, chimyl alcohol
- Li, Liang,Wang, Chang-Yun,Shao, Chang-Lun,Guo, Yue-Wei,Li, Guo-Qiang,Sun, Xue-Ping,Han, Lei,Huang, Hui,Guan, Hua-Shi
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experimental part
p. 1495 - 1502
(2009/10/17)
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- Regioselective and stereospecific acylation across oxirane- and silyloxy systems as a novel strategy to the synthesis of enantiomerically pure mono-, di- and triglycerides
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A trifluoroacetate-catalyzed opening of the oxirane ring of glycidyl derivatives bearing allylic acyl or alkyl functionalities with trifluoroacetic anhydride (TFAA), provides an efficient entry to configurationally homogeneous 1(3)-acyl- or 1(3)-O-alkyl-sn-glycerols. Selective introduction of tert-butyldimethylsilyl- (TBDMS), or triisopropylsilyl- (TIPS) transient protections at the terminal sites within these key intermediates secures 1(3)-acyl- or 1(3)-O-alkyl-3(1)-O-TBDMS (or TIPS)-sn-glycerols as general bifunctional precursors to 1,2(2,3)-diacyl-, 1(3)-O-alkyl-2-acyl- and 1,3-diacyl-sn-glycerols and hence triester isosters. Incorporation of a requisite acyl residue at the central carbon of the silylated synthons with a subsequent Et3N·3HF-promoted, direct trichloroacetylation across the siloxy system by trichloroacetic anhydride (TCAA), followed by cleavage of the trichloroacetyl group, affords the respective 1,2(2,3)-diacyl- or 1(3)-O-alkyl-2-acyl-sn-glycerols. Alternatively, a reaction sequence involving: (i) attachment of a trichloroacetyl fragment at the stereogenic C2-centre of the monosilylated glycerides; (ii) replacement of the silyl moiety by a short- or long-chain carboxylic acid residue by means of the acylating agent: tetra-n-butylammonium bromide (TBABr)-carboxylic acid anhydride (CAA)-trimethylsilyl bromide (TMSBr); and (iii) removal of the trichloroacetyl replacement, provides pure 1,3-diacyl-sn-glycerols. The TBABr-CAA-TMSBr reagent system allows also a one-step conversion of 1,2-diacylglycerol silyl ethers into homochiral triglycerides with predefined asymmetry and degree of unsaturation. These compounds can also be accessed via a two-step one-pot approach where the trichloroacetyl derivatives of 1,2(2,3)- or 1,3-diacyl-sn-glycerols serve as triester building blocks for establishing the third ester bond at preselected C3(1)- or C2-positions within the glycerol skeleton at the very last synthetic stage. In all instances, the target compounds were produced under mild conditions, in high enantiomeric purity, and in practically quantitative yields. The Royal Society of Chemistry 2007.
- Stamatov, Stephan D.,Stawinski, Jacek
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p. 3787 - 3800
(2008/10/09)
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- Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis
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Novel synthetic forms of etherified oxidized phospholipids and methods of utilizing same for preventing and treating atherosclerosis and other related disorders, as well as inflammatory disorders, immune mediated diseases, autoimmune diseases and proliferative disorders, are provided. In addition, methods of synthesizing etherified and esterified oxidized phospholipids and of using same for preventing and treating atherosclerosis and other related disorders are also provided.
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- Self-organizing properties of natural and related synthetic glycolipids
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In this article we report on the syntheses, self-organizing properties, and structures of a variety of cerebrosides and related synthetic glycolipids. The thermotropic and lyotropic liquid crystalline properties of the materials were evaluated in detail. All of the families of materials studied exhibited columnar mesophases. In the dry state the aliphatic chains were found to be located on the exterior of the columns, whereas in the wet state the reverse was the case with the polar headgroups on the exterior. Thus, the aliphatic chains act almost like hydrocarbon solvents in the dry state.
- Dumoulin, Fabienne,Lafont, Dominique,Boullanger, Paul,Mackenzie, Grahame,Mehl, Georg H.,Goodby, John W.
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p. 13737 - 13748
(2007/10/03)
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- A Stereoselective and Highly Practical Synthesis of Cytosolic Phospholipase A2 Substrate, 2-S-Arachidonoyl-1-O-hexadecyl-sn-2-thioglycero-3-O-phosphocholine
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The substrate 1 of cytosolic phospholipase A2 (cPLA2) is an ether-type thiophospholipid with arachidonic acid at the C-2 position and is required for the chromogenic assay for reliable and convenient high throughput screening. The original method of synthesis of 1 has significant problems, resulting in extremely low overall yield and purity. We developed a novel and highly practical method of preparing sufficient quantities of pure 1 for assay. Our synthetic sequence is started with commercially available 1,2-O-isopropylidene-sn-grycerol (5) and is based on the following key steps: trityl migration reaction of 10 with boron trifluoride etherate to form 13, phosphocholine-forming reaction of 13 to yield 15, and efficient conversion of 15 into 1 by deprotection of a trityl group and condensation with arachidonic acid. Our method offers a practical means of large-scale production of 1 with excellent high chemical purity, because of the introduction of arachidonic acid at the last step of the synthetic sequence.
- Fuji, Masahiro,Watanabe, Fumihiko,Fujii, Yasuhiko,Hashizume, Hiroshi,Okuno, Takayuki,Shirahase, Kazuhiro,Teshirogi, Isao,Ohtani, Mitsuaki
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p. 6804 - 6809
(2007/10/03)
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- The chemical synthesis of a series of ether phospholipids from D-mannitol and their properties
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The synthesis of the novel ether phospholipids from D-mannitol as homochiral material using a new method for the removal of a tert-butyldimethylsilyl group for hydroxyl protection without acyl migration and their properties including bioactivity are described.
- Xia, Jie,Hui, Yong-Zheng
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p. 3131 - 3142
(2007/10/03)
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- Stereospecific and regiospecific ring opening of glycidol with primary and secondary alcohols mediated by diisobutylaluminium hydride
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Regiospecific ring opening of (R)-(+)- or (S)-(-)-glycidol 1a, b with primary and secondary alcohols in the presence of diisobutylaluminium hydride provides 1-O-alkyl-sn-glycerol 2 without formation of the undesired regioisomer, 2-O-alkylglycerol 3.The configuration of the glycidol is preserved in the product.
- Erukulla, Ravi Kumar,Byun, Hoe-Sup,Locke, David C.,Bittman, Robert
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p. 2199 - 2200
(2007/10/02)
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- Synthesis of a 'reverse ester' analogue of 1,2-sn-diglycerides from (S)-1,2-di-O-isoprophylideneglycerol; efficient, stereospecific nucleophilic displacement via a triflate at glycerol C-2
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An optically pure glyceride analogue in which the 2-O-ester grouping has been reversed was efficiently synthesised from (S)-di-O-isopropylideneglycerol by a sequence that featured an SN 2 displacement by the anion of diethyl malonate on a protected glycerol 2-O-triflate.
- Golding, Bernard T.,Griffin, Alice L.,Robinson, David H.
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p. 6459 - 6462
(2007/10/02)
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- Phosphocholine derivative inhibitors of phospholipase A2
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Phospocholine derivatives having the formula: STR1 in which W, Z, Q and R are described in the specification are disclosed as useful for inhibiting the enzyme phospholipase A2. Methods of making and using the compounds are also disclosed.
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- Regiospecific Opening of Glycidyl Derivatives Mediated by Boron Trifluoride. Asymmetric Synthesis of Ether-Linked Phospholipids
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A short, chiral synthesis of unnatural, cytotoxic ether-linked phospholipids is reported in which the key step is the very high regio- and stereospecific nucleophilic opening of the p-toluenesulfonate (1a, 1b) or tert-butyldiphenylsilyl ether (6a, 6b) derivatives of (R)- or (S)-glycidol with 1-hexadecanol using boron trifluoride etherate as catalyst.The enantiomeric excess of the ring-opened products was >94percent, as judged by 1H NMR and chiral HPLC analysis of the Mosher ester derivatives, indicating that ring opening of 1 and 6 proceeds without significant loss of optical purity.The synthetic strategy of using optically active glycidyl derivatives as the precursor of the glycerol backbone permits the desired enantiomers of 1(3)-O-2-O-methylphosphocholines (5a, 5b) to be generated in good yield and high optical purity from the ring-opened intermediates (2, 7) in three steps without the use of protecting groups.
- Guivisdalsky, Pedro N.,Bittman, Robert
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p. 4637 - 4642
(2007/10/02)
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- Synthesis of a Thiophospho Analogue of Platelet Activating Factor (RS)- and (S)-1-Hexadecyl-2-acetylglycero-3-thiophosphocoline
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A sequence for synthesis of the title compound from chloro(di-isopropylamino)methoxyphosphine is reported.
- Lamant, Valerie,Chap, Hugues,Klaebe, Alain,Perie, Jean J.,Willson, Michele
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p. 1608 - 1609
(2007/10/02)
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- STEREOSPECIFIC SYNTHESIS OF PAF ANALOGUES. PREPARATION OF 1-HEXADECYL 2-THIOACETYL-2-DEOXYGLYCEROPHOSPHOCHOLINE (2-THIOPAF)
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A new stereospecific synthesis of ether-phospholipids leading to 2-ThioPAF is reported.
- Bhatia, Suresh K.,Hajdu, Joseph
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p. 1729 - 1732
(2007/10/02)
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- Stereoselective Synthesis of Long-chain 1-O-(β-D-Maltosyl)-3-O-alkyl-sn-glycerols (Alkyl Glyceryl Ether Lysoglycolipids)
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The synthesis of long-chain 2-O-benzyl-3-O-alkyl-sn-glycerols 5 was improved, making these compounds easily accessible for glycosylation experiments.Glycosylation with α-acetobromomaltose following a modified Koenings-Knorr procedure after removal of the protective groups yielded the title compound 9 in good yields.These compounds represent examples of alkyl glyceryl ether lysoglycolipids.Some properties of these amphiphilic compounds with a nonionic carbohydrate head-group differ not much (critical micell concentration, hemolytic activity), other properties differ very much (antitumor efficiency) from the properties of the analogous compounds with a zwitterionic phosphorylcholine head-group.
- Prinz, Harald,Six, Lambert,Ruess, Klaus-Peter,Lieflaender, Manfred
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p. 217 - 225
(2007/10/02)
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