- Efficient synthesis of the cholinephosphate phospholipid headgroup
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In search of an efficient method to prepare cholinephosphate headgroups in phospholipids under mild conditions (where the diacylglycerol moiety is not subject to oxidation), a method was developed for phosphorylation using a trialkyl phosphite and I2. The active intermediate is a phosphoryl iodide formed by oxidation of the phosphite with I2. 2-Bromoethanol, dimethyl chlorophosphite, and an alcohol (diglyceride) are converted to a phosphate triester in a one-pot reaction with high yield. In the second reaction, the phosphate triester is demethylated, and the ethyl bromide group is converted to choline by treatment with aqueous trimethylamine. This procedure is applied to the synthesis of hexadecylphosphocholine, and 1,2-didecanoyl-1-deoxy-1-thio-sn-glyceryo-3-phosphocholine.
- Hendrickson, Elizabeth K.,Hendrickson, H.Stewart
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- Multi-Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry
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Herein we report for the first time, an advanced continuous flow synthesis of the blockbuster Leishmaniasis drug miltefosine from simple starting materials by a sequence involving four steps of chemical transformation including a continuous mechanochemical step. First three reaction steps were performed in simple tubular reactors in a telescopic mode, while in the last step the product precipitated from the 3rd step was used for a continuous mechanochemical synthesis of miltefosine. When compared to a typical batch protocol that takes 15 h, miltefosine was obtained in 58 % overall yield in flow synthesis mode at the laboratory scale in a total residence time 34 min at synthesis rate of 10 g/hr, which is sufficient to treat 4800 patients per day.
- Patil, Niteen B.,Atapalkar, Ranjit S.,Chavan, Subhash P.,Kulkarni, Amol A.
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supporting information
p. 17695 - 17699
(2021/10/29)
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- An effective reagent to functionalize alcohols with phosphocholine
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Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is the synthesis of miltefosine, the lone oral drug approved to treat leishmaniasis. Due to its prohibitive expense ($1500 per g), miltefosine is not accesable for the majority of the world's patients. Based on the described reaction sequence, this drug can be produced for $25 per g.
- Xu, Lianyan L.,Berg, Lawrence J.,Jamin Keith,Townsend, Steven D.
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supporting information
p. 767 - 770
(2020/02/11)
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- Synthesis and Evaluation of Antitumor Alkylphospholipid Prodrugs
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Purpose: Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs of promising APLs (miltefosine, perifosine, and erufosine) were synthesized so as to decrease their membrane activity and improve their toxicity profile while preserving their antineoplastic potency. Methods: The synthesis of the pro-APLs was straightforwardly achieved in one step starting from the parent APLs. The critical aggregation concentration of the prodrugs, their hydrolytic stability under various pH conditions, their blood compatibility and cytotoxicity in three different cell lines were determined and compared to those of the parent antitumor lipids. Results: The APL prodrugs display antitumor activity which is similar to that of the parent alkylphospholipids but without associated hemolytic toxicity. Conclusion: The pro-APL compounds may be considered as intravenously injectable derivatives of APLs. They could thus address one of the major issues met in cancer therapies involving antitumor lipids and restricting their utilization to oral and topical administration because of limited maximum tolerated dose.
- Gaillard, Boris,Lebeau, Luc,Remy, Jean-Serge,Pons, Fran?oise
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- BODP - A versatile reagent for phospholipid synthesis
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Benzyloxydichlorophosphine (BODP) has been found to be a convenient reagent for the synthesis of phospholipids. A series of artificial ether and ester phospholipids have been prepared in good to high yields. Georg Thieme Verlag Stuttgart New York.
- Zaffalon, Pierre-Leonard,Zumbuehl, Andreas
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p. 778 - 782
(2011/04/22)
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- Dialkylamino and nitrogen heterocyclic analogues of hexadecylphosphocholine and cetyltrimetylammonium bromide: Effect of phosphate group and environment of the ammonium cation on their biological activity
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A series of dialkylamino and nitrogen heterocyclic analogues of hexadecylphosphocholine and cetyltrimethylammonium bromide have been synthesized. The prepared compounds exhibit significant cytotoxic, antifungal and antiprotozoal activities. Alkylphosphocholines possess higher antifungal activity against Candida albicans in comparison with quaternary ammonium compounds. However, quaternary ammonium compounds exhibit significant higher activity against human tumor cells and Acanthamoeba lugdunensis compared to alkylphosphocholines. In addition, their haemolytic toxicity has been investigated. The relationship between structure and biological activity of the tested compounds is discussed.
- Lukac, Milos,Mojzis, Jan,Mojzisova, Gabriela,Mrva, Martin,Ondriska, Frantisek,Valentova, Jindra,Lacko, Ivan,Bukovsky, Marian,Devinsky, Ferdinand,Karlovska, Janka
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experimental part
p. 4970 - 4977
(2010/02/27)
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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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- Mucosal formulation
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A mucosal formulation for administration to mucosal membranes, such as in the mouth, nasal passage, stomach, vagina, etc., is disclosed. The mucosal formulation contains a lipid-pharmaceutical agent complex formed from phospholipids possessing a hydrophobic moiety that orients into a hydrophobic phase and a polar head moiety that orients towards the aqueous phase (i.e., “amphipathic” lipids). When placed in an aqueous medium (e.g., vaginal fluid), the phospholipids form liposomes or other small lipid vesicles (e.g., micelles) that may then be used to deliver pharmaceutical agents into a living organism.
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Page/Page column 8
(2010/11/28)
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- Novel alkyl phospholipid derivatives and uses thereof
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The present invention provides novel alkyl phospholipid derivatives that are useful for treating various diseases including tumors and/or pathophysiological conditions in mammals, preferably humans, that are caused by microorganisms, in particular fungi, protozoa, bacteria and/or viruses. Such alkyl phospholipids can be employed as single drugs or in the course of combination therapies, in particular for the treatment of leishmaniasis, trypanosomiasis and/or malaria.
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Page/Page column 60
(2010/11/27)
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- Synthesis and properties of alkyl phosphorylcholine amphiphiles with a linear and an asymmetrically branched alkyl chain
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Alkyl phosphorylcholine amphiphiles bearing one linear chain and one asymmetrically branched alkyl chain were successfully synthesized using 2-chloro-2-oxo-1,3,2-dioxaphospholane in tetrahydrofuran or ethyl acetate. 1H and 31PNMR studies revealed that the linear alkyl phosphorylcholines (Cn-PC) provide aqueous micelles in D2O and reverse micelles in CDCl3, while the branched alkyl phosphorylcholines (ISOFOLn-PC) give vesicles in D2O. The critical micelle concentrations (CMCs) of Cn-PC were measured by fluorescence dye solubilization methods: the CMCs of C12-PC, C 14-PC, C16-PC, and C18-PC were 1.6, 0.38, 0.16, and 0.11 mM, respectively, in water at 25 °C. The critical association concentrations (CACs) of ISOFOLn-PC, ISOFOLn-PC, and ISOFOL24-PC were 0.068, 0.005, and 0.077 mM, respectively, in water at 25 °C. The vesicle size of ISOFOLn-PC in aqueous solution was measured by the dynamic light scattering method. The mean diameter of ISOFOLn-PC vesicles was approximately 30 nm and the size distribution was relatively monodisperse. The ISOFOLn-PC vesicles formed were colloidally stable in water over the period of several weeks.
- Kang, Eui-Chul,Kataoka, Shingo,Kato, Kenji
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p. 1558 - 1564
(2007/10/03)
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- Process for the preparation of alkylphosphocholines and the production thereof in pure form
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A process for the preparation of C14 -C18 -alkylphosphocholines by reacting an n-alkanol with a chain length of C14 -C18 with phosphorus oxychloride in an inert solvent or also without solvent in the presence or absence of a basic substance in a single vessel process and subsequent reaction of the reaction product in an inert solvent with a choline salt in the presence of a basic substance to form phosphoric acid diester chloride, subsequent hydrolysis and isolation of alkylphosphocholine as well as optionally purification using a mixed-bed ion exchanger or in successive steps with an acid ion exchanger and a basic ion exchanger.
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- Antitumor phospholipids: A one-pot introduction of a phosphocholine moiety into lipid hydroxy acceptors
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A high-yielding, 3-step, one-pot conversion of lipid hydroxy acceptors 2 into clinically useful alkylphosphocholines 1 is reported. Reaction of 2 with ethylene chlorophosphite gave phosphite 3, which underwent oxidation and ring opening with bromine in CH2Cl2 to give (2-bromoethyl)phosphate ester 4; hydrolysis of the P-Br bond and quaternization of 4 with aqueous trimethylamine generated 1.
- Erukulla, Ravi Kumar,Byun, Hoe-Sup,Bittman, Robert
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p. 5783 - 5784
(2007/10/02)
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- Synthesis and biological activity of some lysing and fusogenically active phosphocholine derivatives
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2-Hexadecylglycerophosphocholine (1) and its 1-O-methyl, 1-O-ethyl and 1-O-benzyl (4) derivatives as well as some n-alkanol phosphocholines were synthetized and tested for haemolytic activity. Most potent (LD50 approximately equal to 5.10(-6) mol/l) were 1 and the hexadecanol and octadecanol phosphocholines (7 and 8). 1, 4 and 7 were tested for fusogenic activity against vegetable protoplasts. When used at sublytic concentrations (0.01 - 0.05 mmol), these compounds were as efficient as polyethylene glycol.
- Nuhn,Kertscher,Dobner,Braune,Kluge
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p. 706 - 708
(2007/10/02)
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