- A new approach to phospholipid synthesis using tetrahydropyranyl glycerol: Rapid access to phosphatidic acid and phosphatidylcholine, including mixed-chain glycerophospholipid derivatives
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Phospholipid synthesis using tetrahydropyranyl glycerol was investigated to produce chiral diglycerides, phosphorylated, and target phospholipid compounds. The synthetic compounds were used for the establishment of structure activity relationships with respect to phospholipid-phospholipid and phospholipid-protein interactions. The synthesis involves regioselective incorporation of three different substituents at the three glycerol positions that normally requires the use of multiple protecting groups. An efficient general route to phosphatidylcholine and phosphatidic acid is applicable to the preparation of a wide range of structurally related glycerophospholipid derivatives. The investigation resulted a facile and efficient method for the preparation of a wide range of diacylglycerols and phospholipids, including phospholipid acid, symmetric and mixed chain phosphatidylcholines.
- Rosseto, Renato,Bibak, Niloufar,Hajdu, Joseph
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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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Read Online
- Development of isotope-enriched phosphatidylinositol-4- And 5-phosphate cellular mass spectrometry probes
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Synthetic phosphatidylinositol phosphate (PtdInsPn) derivatives play a pivotal role in broadening our understanding of PtdInsPnmetabolism. However, the development of such tools is reliant on efficient enantioselective and regioselective synthetic strategies. Here we report the development of a divergent synthetic route applicable to the synthesis of deuterated PtdIns4Pand PtdIns5Pderivatives. The synthetic strategy developed involves a key enzymatic desymmetrisation step using Lipozyme TL-IM. In addition, we optimised the large-scale synthesis of deuteratedmyo-inositol, allowing for the preparation of a series of saturated and unsaturated deuterated PtdIns4Pand PtdIns5Pderivatives. Experiments in MCF7 cells demonstrated that these deuterated probes enable quantification of the corresponding endogenous phospholipids in a cellular setting. Overall, these deuterated probes will be powerful tools to help improve our understanding of the role played by PtdInsPnin physiology and disease.
- Joffrin, Amélie M.,Saunders, Alex M.,Barneda, David,Flemington, Vikki,Thompson, Amber L.,Sanganee, Hitesh J.,Conway, Stuart J.
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p. 2549 - 2557
(2021/03/01)
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- 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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- The key entity of a DCAR agonist, phosphatidylinositol mannoside Ac1PIM1: Its synthesis and immunomodulatory function
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Ac1PIM1is a potential biosynthetic intermediate for phosphatidylinositol mannosides (PIMs) fromMycobacterium tuberculosis. We achieved the first synthesis of Ac1PIM1by utilizing an allyl-type protecting group strategy and regioselective phosphorylation of inositol. A very potent agonist of an innate immune receptor DCAR, which is better than previously known agonists, is demonstrated.
- Arai, Yohei,Fujimoto, Yukari,Matsumaru, Takanori,Torigoe, Shota,Yamasaki, Sho
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p. 3659 - 3663
(2020/06/03)
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- Total Synthesis of an Immunogenic Trehalose Phospholipid from Salmonella Typhi and Elucidation of Its sn-Regiochemistry by Mass Spectrometry
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Diphosphatidyltrehalose (diPT) is an immunogenic glycolipid, recently isolated from Salmonella Typhi. Despite rigorous structure elucidation, the sn-position of the acyl chains on the glycerol backbone had not been unequivocally established. A stereoselective synthesis of diPT and its regioisomer is reported herein. Using a hybrid MS3 approach combining collisional dissociation and ultraviolet photodissociation mass spectrometry for analysis of the regioisomers and natural diPT, the regiochemistry of the acyl chains of this abundant immunostimulatory glycolipid was established.
- Mishra, Vivek K.,Buter, Jeffrey,Blevins, Molly S.,Witte, Martin D.,Van Rhijn, Ildiko,Moody, D. Branch,Brodbelt, Jennifer S.,Minnaard, Adriaan J.
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supporting information
p. 5126 - 5131
(2019/07/03)
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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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supporting information
p. 1999 - 2009
(2017/10/16)
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- Synthesis and biological activity of phosphoglycolipids from Thermus thermophilus
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An extreme thermophile, Thermus thermophilus, has very unique glycolipids on the cell surface. The acidic immunostimulatory phosphoglycolipid of T. thermophilus was synthesized for the first time, with newly developed glycosylation methods using 3-nitropyridyl (3NPy) and 4,6-dimethoxy-1,3,5- triazin-2-yl (DMT) glycosides as glycosyl donors. The analogues of the phosphoglycolipid, which include a diastereomer possessing the opposite configuration at the diacyl glycerol moiety, were also synthesized. The biological activities of the synthesized compounds were elucidated with cytokine inductions (IL-6 and TNF-α). A synthetic phosphoglycolipid with a natural-type diacyl glycerol configuration showed apparent immunostimulatory activity, whereas its diastereomer did not. The present study revealed that the configuration at the diacyl glycerol moiety of the phosphoglycolipids is important for immunostimulation, suggesting the existence of the particular receptor/recognizing protein that can recognize the stereochemistry of the glycerol part.
- Fujimoto, Yukari,Mitsunobe, Kunihiro,Fujiwara, Satoko,Mori, Motoko,Hashimoto, Masahiro,Suda, Yasuo,Kusumoto, Shoichi,Fukase, Koichi
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supporting information
p. 5034 - 5041
(2013/08/23)
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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 10
(2011/10/04)
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- Synthesis and biological evaluation of phosphatidylinositol phosphate affinity probes
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The synthesis of the complete family of phosphatidylinositol phosphate analogues (PIPs) from five key core intermediates A-E is described. These core compounds were obtained from myo-inositol orthoformate 1 via regioselective DIBAL-H and trimethylaluminium-mediated cleavages and a resolution-protection process using camphor acetals 10. Coupling of cores A-E with phosphoramidites 34 and 38, derived from the requisite protected lipid side chains, afforded the fully-protected PIPs. Removal of the remaining protecting groups was achieved via hydrogenolysis using palladium black or palladium hydroxide on carbon in the presence of sodium bicarbonate to afford the complete family of dipalmitoyl- and amino-PIP analogues 42, 45, 50, 51, 58, 59, 67, 68, 76, 77, 82, 83, 92, 93, 99 and 100. Investigations using affinity probes incorporating these compounds have identified novel proteins involved in the PI3K intracellular signalling network and have allowed a comprehensive proteomic analysis of phosphoinositide interacting proteins. The Royal Society of Chemistry 2010.
- Conway, Stuart J.,Gardiner, James,Grove, Simon J. A.,Johns, Melloney K.,Lim, Ze-Yi,Painter, Gavin F.,Robinson, Diane E. J. E.,Schieber, Christine,Thuring, Jan W.,Wong, Leon S.-M.,Yin, Meng-Xin,Burgess, Antony W.,Catimel, Bruno,Hawkins, Phillip T.,Ktistakis, Nicholas T.,Stephens, Leonard R.,Holmes, Andrew B.
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scheme or table
p. 66 - 76
(2010/04/29)
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- Synthesis and biological evaluation of a novel cardiolipin affinity matrix
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Cardiolipin (1) is a dimeric phospholipid found in the mitochondrial membranes of both plants and animals. In order to understand better its role, we report the preparation of an immobilised analogue (2) using phosphoramidite chemistry; the probe has been used successfully to bind a recombinant protein containing a cardiolipin-binding domain.
- Johns, Melloney K.,Yin, Meng-Xin,Conway, Stuart J.,Robinson, Diane E. J. E.,Wong, Leon S.-M.,Bamert, Rebecca,Wettenhall, Richard E. H.,Holmes, Andrew B.
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experimental part
p. 3691 - 3697
(2009/10/23)
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- 4(2)-Methoxyphenyl glycerol ethers in the synthesis of nonracemic di-O,O-acylglycerols
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Effective methods for the synthesis of nonracemic 4-and 2-methoxyphenyl glycerol ethers from nonracemic 3-chloropropanediols and by direct resolution of the racemate, respectively, were developed. Some existing discrepancies related to the to chiroptical properties of their derivatives were eliminated. Both ethers were used to synthesize nonracemic 3-O-aryloxy-1,2-di-O',O'-palmitoyl glycerols.
- Bredikhina,Novikova,Efremov,Sharafutdinova,Bredikhin
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experimental part
p. 2320 - 2323
(2010/02/15)
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- A facile and convenient chemoenzymatic synthesis of optically active O-(4-methoxyphenyl)-glycidol and 1,2-diacyl-sn-glycerol
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A convenient preparation of the (R)- and (S)-enantiomers of O-(4-methoxyphenyl)-glycidol by a one-pot reduction of ketone 3 and in situ lipase mediated resolution is described. Activated moist aluminium oxide in the presence of Pseudomonas cepacia lipase immobilized on ceramic particles (PS-C) has been found effective for the transesterification leading to a high degree of enantioselectivity. These chiral glycidols were further used as a chiral precursor for the synthesis of biologically important 1,2-O-diacyl-sn-glycerol under mild reaction conditions. The present method is facile for the synthesis of chiral glycidols in high enantioselectivity when compared to the previously reported methods.
- Kamal, Ahmed,Sandbhor, Mahendra,Shaik, Ahmad Ali,Malik, M. Shaheer
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p. 1855 - 1859
(2007/10/03)
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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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- A new approach to the stereospecific synthesis of phospholipids. The use of L-glyceric acid for the preparation of diacylglycerols, phosphatidylcholines, and related derivatives
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A new stereospecific synthesis of phospholipid derivatives of 1,2- diacyl-sn-glycerols is reported. The synthesis is based on (1) the use of L- glyceric acid as the stereocenter for construction of the optically active phospholipid molecule, (2) preparation of 3-triphenylmethyl-sn-glycerol as the key intermediate for sequential introduction of the primary and secondary acyl functions leading to the chiral diglycerides, and (3) elaboration of the sn-3-phosphodiester headgroup via phosphorylation using 2-chloro-2-oxo-1,3,2- dioxaphospholane, followed by ring opening of the five-membered phosphorus heterocycle with trimethylamine, ammonia, as well as oxygen and sulfur nucleophiles. The sequence has been shown to be suitable for the preparation of both symmetric and mixed-chain diacylglycerols with saturated and unsaturated acyl substituents. Phospholipid headgroups including phosphocholine, phosphoethanolamine, phosphoethanol, and phosphoethylthioacetate functions have been prepared. Application of the method to the synthesis of functionalized phosphatidylcholines has also been demonstrated by incorporating spectroscopically active spin-labeled and fluorescent reporter groups via postsynthetic derivatization of chain terminal ω-aminoalkyl functions of the acyl substituents of the compounds. The synthetic methods developed have a great deal of flexibility, providing convenient routes to a wide range of structurally variable phospholipids for physicochemical, enzymological, and cell-biological studies.
- Roodsari, Farzaneh S.,Wu, Dongpei,Pum, Gregory S.,Hajdu, Joseph
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p. 7727 - 7737
(2007/10/03)
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- An improved synthesis of 1-β-D-arabinofuranosylcytosine 5'-phosphate- L-1,2-diacylglycerols
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5'-O-MMTr-cytosine arabinoside was prepared on a large scale from 5'-O- MMTr-cytidine with diphenyl carbonate via 5'-protected cytidine - 2',3'- carbonate - aracytidine-2',2-anhydro derivative at a 67 % yield. The synthesis of 1,2-L-dipalmitoyl-sn-glycerol, 1,2-L-distearoyl-sn-glycerol and 1,2-L-dioleoyl-sn-glycerol described here using 9-fluorenylmethoxycarbonyl (FMOC) group for protection of 3-position of glycerol which can be selectively removed by Et3N treatment on the overall 60-70 % yield based on 1,2,-isopropilidene-sn-glycerol. These glycerols were phosphorylated first with 2-chlorophenyl-phosphoro-bis-triazolide quantitatively in order to avoid acyl migration, then the glycerophosphate intermediates were condensed with 2',3',N4-trileulinyl-1-β-D-arabinofuranosylcytosine in the presence of 2- mesytilenesulphonyl chloride (MsCl) and 1-methylimidazole (MeIm)- which was used in the coupling of nucleotides- in an 85-95 % yield compared with the low yielding diester method of Ryu. Deblocking was carded out in two steps with tetrabutylammonium fluoride (TBAF) and hydrazine hydrate, producing target compounds (14a, 14b, 14c) at a 50 % yield.
- Nyilas, Agnes
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p. 1953 - 1967
(2007/10/03)
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- A new protecting group: 9-fluorenylmethoxycarbonyl (FMOC) in the synthesis of 1,2-diacylglycerols
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The synthesis of 1,2-L-dipalmitoyl-sn-glycerol, 1,2-L-distearoyl-sn-glycerol and 1,2-L-dioleoyl-sn-glycerol are described here using 9-fluorenylmethoxycarbonyl (FMOC) group for protection of the 3-position of glycerol which can be selectively removed by Et3N treatment on the overall 60-70% yield based on 1,2-isopropylidene-sn-glycerol. Little or no acyl migration occured during deprotection and purification.
- Nyilas, Agnes
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p. 171 - 174
(2007/10/03)
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- A new protocol for the removal of dimethoxytrityl ether groups derived from primary alcohols
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A range of primary alcohol dimethoxytrityl ethers were deprotected by using ultrasound at ambient temperature (yields 69-100%). The new procedure may find utility in the synthesis of materials of biological interest, such as oligonucleotides.
- Wang, Yikang,McGuigan, Christopher
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p. 3829 - 3833
(2007/10/03)
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- Cosmetic composition
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A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from glutamine derivatives and salts thereof. The composition preferably also comprises an activity enhancer which may be chosen from hair growth stimulants, penetration enhancers and cationic polymers.
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- Synthesis of phosphotriester analogues of the phosphoinositides PtdIns(4,5)P2 and PtdIns(3,4,5)P3
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A synthetic route was developed for the preparation of novel O-(3-aminopropyl) tethered phosphotriester analogs (5) of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5,)P2, or PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3, or PIP3) using the coupling reagent 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite. The phosphotriester ligand design introduced a reactive aminopropyl group at the polar lipid head of the ring-phosphorylated phosphoinositides, allowing a reporter moiety to be positioned at the surface of the bilayer and in the vicinity of the phosphorylated inositol. Such reporter groups may interact with membrane-proximal regions of PIP2- and PIP3-binding proteins recruited to membrane sites by electrostatic interactions between the phosphates of the phospholipid and basic regions of the proteins. Following a convergent strategy, phosphitylation of an optically-pure 1,2-O-diacyl-sn-glycerol with 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite was followed by coupling with protected inositol precursors to give adducts 8 in 80% to 95% yield. The 2-cyanoethyl phosphotriester was stable during the subsequent reaction steps and could be conveniently converted to the 3-aminopropyl group during the final hydrogenolysis of the benzyl protecting groups. Benzophenone-containing photoaffinity probes of the phosphotriester 11a and 11b were also synthesized. Alternatively, the versatile cyanoethyl group could be removed using diisopropylethylamine prior to hydrogenolysis, thereby furnishing the corresponding phosphodiesters, PIP3 and PIP2 (13a and 13b).
- Gu, Qu-Ming,Prestwich, Glenn D.
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p. 8642 - 8647
(2007/10/03)
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- Synthesis and properties of photoactivatable phospholipid derivatives designed to probe the membrane-associate domains of proteins
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The total syntheses of photoactivatable phospholipidic probes 1 and 2 are described. These probes contain either an aryldiazonium function at their polar head (probes 1a and 1b) or an diazocyclohexadienonyl group attached to the end of one fatty acid side chain (probe 2) and have been designed to probe the lipid/water interface and the hydrophobic core of the membrane, respectively. The synthetic schemes include the possibility of incorporating a radio-labeled atom (tritium) for further labeling investigations. Both probes were stable in the dark under physiological conditions and could be efficiently photodecomposed at wavelengths above 300 nm, leading to the generation of highly reactive species, aryl cations and cyclohexadienonyl carbene, respectively. In addition, these probes displayed UV-absorption spectra which are compatible with tryptophan-mediated energy transfer photoactivation, which can lead potentially to an efficient mapping of the membrane-associate protein domains.
- Alcaraz, Marie-Lyne,Peng, Ling,Klotz, Philippe,Goeldner, Maurice
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p. 192 - 201
(2007/10/03)
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- Cosmetic composition containing DOPA derivatives
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A composition for topical application to human hair or skin contains a chemical analogue of dihydroxyphenyl alanine (DOPA). This chemical analogue can be absorbed by skin or by a hair follicle and metabolised in-vivo, thus leading to the formation of melanin in skin or to the growth of melanin-pigmented hair. Consequently the composition can give controlled skin darkening to mimic sun-induced tanning or can bring about the growth of dar hair in place of the grey or white hair.
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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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- Cosmetic composition
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A composition suitable for topical application to mammalian skin or hair for inducing, maintaining or increasing hair growth comprises a glycosaminoglycanase inhibitor chosen from aldonomonolactones, alduronomonolactones and acylated monosaccharides, and a cosmetically acceptable vehicle for the inhibitor; the total amount of the inhibitor present in the composition being sufficient to increase hair growth in the rat, when said composition is applied topically thereto over a period of no more than 3 months, by at least 10% more than that obtainable using a control composition from which the said inhibitor has been omitted, in accordance with the Rat Hair Growth Test.
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- Cosmestic composition
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A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from glutamic acid derivatives and salts thereof. The composition preferably also comprises an activity enhancer which may be chosen from hair growth stimulants, penetration enhancers and cationic polymers.
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- Method of growing hair
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A method for inducing, maintaining or increasing hair growth which is achieved by topically applying a preserved composition to mammalian skin and hair in a mammal having need thereof, the composition comprising a hexosaccharic acid, salts and esters thereof, in an amount sufficient to induce, maintain or increase hair growth.
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- Hair growth composition containing citric acid esters
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Triesters of citric acid are used for inducing, maintaining or increasing hair growth. Compositions for topical application to mammalian hair or scalp comprise an effective amount of from 1% to 99% by weight of an ester of citric acid having the structure (1): where, R1, R2 and R3 each independently represent a branched or unbranched alkyl, alkenyl, aryl, alkylaryl or arylalkyl group, each said group having from 1 to 18 carbon atoms, R4 represents -H, or a branched or unbranched saturated or unsaturated acyl, alkyl, aryl, alkylaryl or aylalkyl group having from 1 to 18 carbon atoms, in the presence of a cosmetically acceptable vehicle for the citric acid ester and in the absence of solid absorbent for the ester;, said effective amount of said ester being sufficient to increase hair growth in the rat, when said composition is applied topically thereto over a period of no more than three months, by at least 10% more than that obtainable using a control composition from which the said ester has been omitted, in accordance with the Rat Hair Growth Test.
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- Cosmetic composition
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A composition suitable for topical application to mammalian skin or hair comprises: (a) a growth factor chosen from: (i) transforming growth factor alpha (TGF-α), (ii) transforming growth factor beta (TGF-β), (iii) insulin-like growth factor-1 (IGF-1), (iv) fragments thereof of one or more of said growth factors, and (v) mixtures thereof of said growth factors or fragments of said growth factors; and (b) a cosmetically acceptable vehicle for the growth factor or fragments thereof; the total amount of growth factor being sufficient to increase hair growth in the rate, when the composition is applies topically thereto over a period of no more than 3 months, by at least 10% more than that obtainable using a control composition from which the said growth factor has been omitted, in accordance with the Rat Hair Growth Test.
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- Lactams, their synthesis and use in cosmetic compositions
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A composition suitable for topical application to mammalian skin or hair for inducing, maintaining or increasing hair growth comprises: (i) a chemical inhibitor of glycosidase activity chosen from lactams having the structure: STR1 where A1 and A6 are --H, --CH3, STR2 --CH2 OT or STR3 A1 and A6 being the same or different, and at least one of which being the group: STR4 in a lactam ring; and where Q is --OT', --NHT' or a lactam linkage to A1 or A6 ; the Q groups being the same or different, and at least one of which is involved in a lactam linkage; and where T is the same or different and is chosen from --H, --Cp H2p+1 or a metal ion, T' is --H or --COCp H2p+1, and p is an integer of from 1 to 22; provided that: where any of the Q groups is --OT' or --NHT', then that group or groups can be of either stereochemical configuration with respect to the plane of the ring; and (ii) a cosmetically acceptable vehicle for the chemical inhibitor. Certain novel lactams are also claimed.
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- Carbohydrate lactam derivatives and their use in cosmetic compositions
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A composition suitable for topical application to mammalian skin or hair for inducing, maintaining or increasing hair growth comprises: (i) a chemical inhibitor of glycosidase activity chosen from lactams having the structure: where A1 and A6 are -H, -CH3,, - , or A1 and A6 being the same or different, and at least one of which being the group:, , , in a lactam ring;, and where Q is -OT?, -NHT? or a lactam linkage to A1 or A6;, the Q groups being the same or different, and at least one of which is involved in a lactam linkage;, and where T is the same or different and is chosen from, -H, -CpH2p+1or a metal ion,T? is -H or -COCpH2p+1, and, p is an integer of from 1 to 22;, provided that:, where any of the Q groups is, -OT? or -NHT?,then that group or groups can be of either stereochemical configuration with respect to the plane of the ring; and (ii) a cosmetically acceptable vehicle for the chemical inhibitor. Certain novel lactams are also claimed.
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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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- Process for preparing 1,2-diacyl-sn-glycerols
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The object of the present invention is a novel and simple process for the production of 1,2-diacyl-sn-glycerols, wherein the acyl groups may be the same or different. According to the invention D-mannitol is reacted with benzene boronic acid or a derivative thereof to form a D-mannitol-monobenzeneboronate which compound is acylated either to form, after removal of the benzeneboronate protective group, a 1,2,5,6-tetraacyl-D-mannitol with four identical acyl groups, or is acylated selectively in two stages, by first acylating the 1,6-hydroxy groups of the boronate protected D-mannitol to form, after removal of the boronate protection, a 1,6-diacyl-D-mannitol, which then is repeatedly reacted with a benzene boronic acid or a derivative thereof and then acylated in the 2- and 5-positions. After removal of the boronate protective group, the tetra-acylated D-mannitol obtained either in the one-stage or two-stage process is split by oxidation to form a 1,2-diacyl-glyceraldehyde which in turn is reduced to the corresponding 1,2-diacyl-sn-glycerol. By means of the invention it is thus possible to prepare 1,2-diacyl-sn-glycerols in which the acyl groups can be the same or different.
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- ORD and CD studies of saturated glycerides.
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A convenient method for transforming 3-acyl-sn-glycerols into 1-acyl-2,3-diacyl'-sn-glycerols, antipodes of 1,2-diacyl'=3-acyl-sn-glycerols, of relatively high optical purity, via the 1,2-dimesyl-3-acyl-sn-glycerols has been worked out. ORD and CD curves of optically active triglycerides and also some mono- and diglycerides have been studied in detail. The curo 200 nm or below. A Cotton effect from the n yeilds ets* transtition of the ester chromophore was observed at 215-220 nm, which was negative for triglyceritical rotations could be observed in triglycerides with very small differences in chain length, such as 1,2-dilauroyl-3-myristoyl-sn-glycerol.
- Gronowitz,Herslof
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p. 174 - 188,178, 179, 186
(2007/10/07)
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