- H-Phosphonate Synthesis and Biological Evaluation of an Immunomodulatory Phosphoglycolipid from Thermophilic Bacteria
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The synthesis of a library of bacterial phosphoglycolipid, PGL-1, is described. Key features of the synthesis include regioselective esterification of the primary alcohol of the diacylglycerol moiety and an H-phosphonate method to install the phosphate in PGL-1 in comparison with earlier reported procedures. A representative set of PGL-1 analogues was prepared and evaluated for their biological activities. Results showed that the immunological activity of PGL-1 is dependent on the chain lengths of the fatty acids.
- Gan, Chin Heng,Hua, Kuo-Feng,Lam, Yulin,Li, Lan-Hui,Peng, Yi-Jen,Wei, Chih-Feng,Wijaya, Hadhi,Wu, Shih-Hsiung
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- Synthesis and enantiospecific analysis of enantiostructured triacylglycerols containing n-3 polyunsaturated fatty acids
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The stereospecific structure of triacylglycerols (TAGs) affects the bioavailability of fatty acids. Lack of enantiopure reference compounds and effective enantiospecific methods have hindered the stereospecific analysis of individual TAGs. Twelve novel enantiostructured AAB-type TAGs were synthesized containing one of the three n-3 polyunsaturated fatty acid: α-linolenic acid (ALA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) in sn-1 or sn-3 position. These compounds formed six enantiomer pairs, which were separated with recycling high-performance liquid chromatography using chiral columns and UV detection. The chromatographic retention behavior of the enantiomers and the stereospecific elution order were studied. The enantiomer with an n-3 PUFA in the sn-1 position eluted faster than the enantiomer with the n-3 PUFA in the sn-3 position, regardless of the carbon chain length and number of double bonds of the PUFA. TAG enantiomers containing DHA exhibited highly different retention on the chiral column and were separated after the first column, whereas recycling was needed to separate the enantiomer pairs containing ALA or EPA. The system using two identical columns and one mobile phase, without sample derivatization, proved to be very effective also for peak purity assessment, confirming the enantiopurity of the synthesized structured TAGs being higher than 98 percent (96 percent ee).
- Gudmundsson, Haraldur G.,Haraldsson, Gudmundur G.,Kallio, Heikki,Kalpio, Marika,Linderborg, Kaisa M.,Magnússon, Jóhann D.,Yang, Baoru
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- Total Synthesis of the Lipid-Anchor-Attached Core Trisaccharides of Lipoteichoic Acids of Streptococcus pneumoniae and Streptococcus oralis Uo5
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Herein we report an efficient total synthesis of lipid-anchor-appended core trisaccharides of lipoteichoic acids of Streptococcus pneumoniae and Streptococcus oralis Uo5. The key features include the expedient synthesis of the rare sugar 2,4,6-trideoxy-2-acetamido-4-amino-d-Galp building block via one-pot sequential SN2 reactions and the α-selective coupling of d-thioglucoside with the diacyl glycerol acceptor to construct a common disaccharide acceptor, which was utilized in the total synthesis of target molecules 1 and 2.
- Ghotekar, Balasaheb K.,Kulkarni, Suvarn S.,Podilapu, Ananda Rao
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supporting information
(2020/02/04)
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- Remarkable functions of sn-3 hydroxy and phosphocholine groups in 1,2-diacyl-sn-glycerolipids to induce clockwise (+)-helicity around the 1,2-diacyl moiety: Evidence from conformation analysis by 1H NMR spectroscopy
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Cell-membrane glycerolipids exhibit a common structural backbone of asymmetric 1,2-diacyl-sn-glycerol bearing polar head groups in the sn-3 position. In this study, the possible effects of sn-3 head groups on the helical conformational property around the 1,2-diacyl moiety in the solution state were examined. 1H NMR Karplus relation studies were carried out using a series of 1,2-dipalmitoyl-sn-glycerols bearing different sn-3 substituents (namely palmitoyl, benzyl, hydrogen, and phosphates). The 1H NMR analysis indicated that the helical property around the 1,2-diacyl moiety is considerably affected by these sn-3 substituents. The sn-3 hydroxy group induced a unique helical property, which was considerably dependent on the solvents used. In CDCl3 solution, three staggered conformers, namely gt(+), gg(?) and tg, were randomized, while in more polar solvents, the gt(+) conformer with (+)-helicity was amplified at the expense of gg(?) and tg conformers. The sn-3 phosphocholine in phosphatidylcholine exhibited a greater effect on the gt(+) conformer, which was independent of the solvents used. From the 1H NMR analysis, the helical conformational properties around the 1,2-diacyl moiety conformed to a simple empirical rule, which permitted the proposal of a conformational diagram for 1,2-dipalmitoyl-sn-glycerols in the solution states.
- Nishida, Yoshihiro,Yuan, Mengfei,Fukuda, Kazuo,Fujisawa, Kaito,Dohi, Hirofumi,Uzawa, Hirotaka
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p. 1999 - 2009
(2017/10/16)
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- Verification study for an empirical rule in diverse helical conformational behaviors of asymmetric 1,2-diacyl-sn-glycerols in the solution state
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Cell-membrane glycerophospholipids and glycolipids have a common asymmetric skeleton of 1,2-diacyl-sn-glycerols. The 1,2-diacyl moiety in solutions permits a rapid equilibrium among three helical conformers, namely gt(+), gg(?), and tg, to display diverse conformational properties. The conformational property changes variably not only by head groups at the sn-3 position, but also by the solvent conditions applied. Recently, we came across an empirical rule in the conformational diversity in the solution state when we assumed the term of ‘helical disparity’ for the equilibrium between gt(+) and gg(?) conformers with reversed helical signs for each other. The sign and magnitude of the helical disparity (%) governs the (+)- or (?)-chirality around the lipid tail and corresponds to the magnitude of the exciton couplet CD (circular dichroism) bands. The empirical rule expresses that the disparity (%) changes linearly by the function of gt(+) population (%). Herein, the rule was verified by 1H NMR spectroscopy using different types of 1,2-diacyl-sn-glycerols as model compounds. The present paper describes that the rule is formulated with a general equation (Eq-1): ‘helical disparity (%)’ = [gt(+)?gg(?)] (%) = A[gt(+)?B], in which A and B are constants taking values around 1.3 and 38, respectively. This rule is maintained regardless of the 1,2-diacyl and sn-3 substituent groups as far as examined here, while affording several exceptions. With Eq-1 (A = 1.3, B = 38), a conformational diagram can be obtained. This allows us to overview the diverse helical conformational properties of the asymmetric 1,2-diacyl-sn-glycerols in the solutions state.
- Nishida, Yoshihiro,Mengfei, Yuan,Fujisawa, Kaito,Kitagawa, Sakura,Dohi, Hirofumi,Uzawa, Hirotaka
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p. 1435 - 1443
(2017/10/30)
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- SYNTHETIC ANALOGUES OF PHOSPHATIDYL-MYO-INOSITOL MANNOSIDES WITH AN INHIBITORY ACTIVITY OF THE INFLAMMATORY RESPONSE
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The present invention relates to novel synthetic analogues of phosphatidyl-myo-inositol mannosides (hereinafter referred to as PIMs) of general formula (I): or a pharmaceutically acceptable salt thereof, to the method for preparing same and to the use thereof in the prevention or treatment of a disease associated with the overexpression of cytokines or of chemokines, in particular of TNF and/or of IL-12. The invention also relates to a pharmaceutical composition comprising at least one synthetic derivative of PIM.
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Page/Page column 9-10
(2011/10/04)
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- Efficient chemoenzymatic enantioselective synthesis of diacylglycerols (DAG)
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A new efficient chemoenzymatic methodology for the production of 3-O-benzyl-sn-glycerol and 1,2-O-dipalmitoyl-sn-glycerol has been developed. It starts from racemic 1-O-benzylglycerol and is based on the sequential enzymatic acylation-Mitsunobu inversion-enzymatic hydrolysis, which has been performed without isolation of the intermediates. In this way a 70-75% yield of 3-O-benzyl-sn-glycerol with 94-96% ee has been obtained.
- Guanti, Giuseppe,Banfi, Luca,Basso, Andrea,Bevilacqua, Elisabetta,Bondanza, Laura,Riva, Renata
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p. 2889 - 2892
(2007/10/03)
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- Synthesis of a small library of mixed-acid phospholipids from D-mannitol as a homochiral starting material
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Synthesis of a series of mixed-acid phospholipids containing a polyunsaturated fatty acid using a newly protecting strategy are described. Thus, benzyl and methyl α-(2,4-dinitrophenyl)acetic acid which were respectively removed by BCl3 and 354 nm light are used as protecting groups.
- Xia, Jie,Hui, Yong-Zheng
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p. 1659 - 1663
(2007/10/03)
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- ω-Mercapto analogs of naturally occurring lipids
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Analogs of natural lipids, where one of the alkyl chains carries a terminal thiol functionality, were prepared by N- or O-acylation of sphingosine or monoacylglycerol derivatives, respectively, thus creating lipid mimics suitable for anchoring to e.g. gold surfaces.
- Ohlsson, Joergen,Magnusson, Goeran
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p. 2011 - 2014
(2007/10/03)
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- General Method for the Synthesis of Phospholipid Derivatives of 1,2-O-Diacyl-sn-glycerols
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An efficient phosphite coupling protocol is described for the syntheses of the major classes of phospholipids that are derived from 1,2-O-diacyl-sn-glycerols and analogues thereof.The symmetrical diacyl glycerols 10c,d were prepared by straightforward acylation of 3-O-benzyl-sn-glycerol (7) with the appropriate carboxylic acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP).A simple method for preparing saturated and unstaturated mixed 1,2-O-diacyl-sn-glycerols was then devised that involved stepwise acylation of 7 with different alkyl carboxylic acids and debenzylation; this procedure is exemplified by the preparation of 10a,b.The 1,2-O-diacyl-sn-glycerols 10a-d were then coupled with suitably protected lipid head groups employing reactive alkyl or aryl dichlorophosphites to give intermediate phosphite triesters in high overall yields.Oxidation or sulfurization of these phosphites proceeded smoothly to give the corresponding phosphate or phosphorothioate triesters, deprotection of which then provided the phosphatidylcholines 16 and 17, the phosphatidylethanolamine 20, the phosphatidylserine 28, and the phosphatidylinositols 37 and 38.Preparation of 37 and 38 required the invention of an improved method for resolving the isopropylidene-protected D-myo-inositol derivative 33.This phosphite coupling procedure was modified to assemble phospholipids bearing polyunsaturated acyl side chains at the sn-2-position as exemplified by the preparation of the phosphatidylethanolamine 26.The one-pot phosphite coupling procedure is also applicable to the syntheses of a variety of other biologically interesting phospholipid analogues.For example, the phosphatidylinositol analogues 49-51, in which the hydroxyl group at C(2) of the inositol ring has been modified, were prepared in excellent overall yields by conjoining the 1,2-O-diacyl-sn-glycerol 10c with the protected inositol derivatives 44, 45, and 48.Phospholipid analogues that contain other replacements of the phosphate group including phosphoramidates and thiophosphates may be prepared as evidenced by the syntheses of 56 and 61 in which the sn-3 oxygen atom of the 1,2-O-diacyl-sn-glycerol moiety is replaced with an N-benzyl group or a sulfur atom, respectively.
- Martin, Stephen F.,Josey, John A.,Wong, Yue-Ling,Dean, Daniel W.
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p. 4805 - 4820
(2007/10/02)
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- Nucleoside conjugates. 10. Synthesis and antitumor activity of 1-β-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitins
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Three 1-β-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitins from L-, D- and DL-α-dipalmitoylphosphatidic acids have been synthesized and their antitumor activity against two ara-C2 resistant L1210 lymphoid leukemia sublines in mice were evaluated. These new prodrugs of ara-C include ara-CDP-L-dipalmitin (1), ara-CDP-D-dipalmitin (2), and ara-CDP-DL-dipalmitin (3). The L and DL isomers produced significant increase in life span (>400%) and four to five long-term survivors (>45 days) out of six animals bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C (I)], while the D isomer displayed a marginal activity (ILS 100-121%). In contrast, the L isomer was completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C (II)]. However, the results demonstrate that the L and DL isomers of ara-CDP-dipalmitin are promising new prodrugs of ara-C with improved efficacy.
- Hong,An,Schliselfeld,Buchheit,Nechaev,Kirisits,West
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p. 1793 - 1798
(2007/10/02)
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- Synthesis of Glycerophosphonolipids Containing Aminoalkylphosphonic Acids
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1,2-Di-O-octadecyl- and 1,2-di-O-hexadecanoyl-sn-glycerol 3-(2-aminoethyl)phosphonate (21) and (22) and the (3-aminopropyl)phosphonate analogues (23) and (24) were prepared with the aim of obtaining enzyme (lipase)-stable liposomes.New reactions were devised and classic methodologies were modified in order to transform D-mannitol (6) into optically pure 1,2-di-O-substituted sn-glycerols (12) and (13) (R=C18H37 and C15H31CO).Benzyloxycarbonylaminoalkylphosphonic acids (5a) and (5b) were then coupled with the glycerols by means of condensing reagents such as 2,4,6-triisopropylbenzenesulphonyl chloride.The resulting N-protected lipids were catalitically hydrogenated to furnish compounds (21)-(24) in overall yields of 10-20 percent from compound (6).
- Yamauchi, Kiyoshi,Une, Fumiyoshi,Tabata, Sachio,Kinoshita, Masayoshi
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p. 765 - 770
(2007/10/02)
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