- Synthesis of medium-chain glycerides by lipase in organic solvent
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Using commercial lipases from various microbial origins, medium-chain glycerides, such as mono-, di-, and tri-caprin, were synthesized in isooctane from glycerol and capric acid. The enzyme reaction was performed with 0.35 M capric acid, 0.025 M glycerol, and 0.46 g silica gel to remove water in 5 mL of isooctane with 30 mg lyophilized lipase. Of the 21 kinds of lipases, 11 showed good synthetic activities. Lipases from Pseudomonas aeruginosa (Lipase PS), Rhizomucor miehei lipase and Chromobacterium viscosum lipase (Lipase CV) showed high activities for the production of tricaprin, while lipase OF-360 (from Candida rugosa) and lipase D (Rhizopus delemar) were good for dicaprin production. Lipases CC and MY from C. rugosa (C. cylindracea) also showed high activities for dicaprin and tricaprin. Some lipases, especially lipase PS, had high thermal stability over 60°C. The optimal lyophilization pH to dehydrate the lipase coincides with the optimal buffer solution pH for hydrolysis.
- Kwon, Dae Young,Song, Hyo Nam,Yoon, Suk Hoo
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- Enzymatic synthesis of 1,3-dicaproyglycerol by esterification of glycerol with capric acid in an organic solvent system
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In this work, the esterification of glycerol with capric acid catalyzed by an immobilized form of a 1,3-positionally selective lipase (Rhizomucor miehei) showed to be effective for the synthesis of 1,3-dicaprin in n-heptane as the reaction medium. The effects of the reaction parameters were studied using an experimental factorial design of three factors and three levels with two central points. The selected experimental variables were amount of glycerol adsorbed on silica gel (G), biocatalyst load (E) and reaction temperature (T), and the response variables were total conversion of capric acid, acylglycerol fractions, selectivity and yield of dicaprin, and acyl migration reaction. The range of each parameter was selected as follows: G = 50-250 mg, E = 20-40 mg and T = 40-60 C. At optimum conditions 73% capric acid conversion was achieved, with 76% dicaprin selectivity, and selectivity to the specific 1,3-dicaprin of 70% of total products. An adequate selection of the reaction conditions is necessary not only to maximize the conversion of capric acid, but also to minimize the acyl migration reaction and the generation of undesired products. Evidence of kinetically controlled enzymatic acyl migration from sn-3/sn-1 to sn-2 is presented.
- Sanchez, Daniel Alberto,Tonetto, Gabriela Marta,Ferreira, Maria Lujan
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- Selective deuteration for molecular insights into the digestion of medium chain triglycerides
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Abstract Medium chain triglycerides (MCTs) are a unique form of dietary fat that have a wide range of health benefits. They are molecules with a glycerol backbone esterified with medium chain (6-12 carbon atoms) fatty acids on the two outer (sn-1 and sn-3) and the middle (sn-2) positions. During lipid digestion in the gastrointestinal tract, pancreatic lipase stereoselectively hydrolyses the ester bonds of these triglycerides on the sn-1 and sn-3 positions resulting in sn-2 monoglyceride and fatty acids as major products. However, the sn-2 monoglycerides are thermodynamically less stable than their sn-1/3 counterparts. Isomerization or fatty acid migration from the sn-2 monoglyceride to sn-1/3 monoglyceride may occur spontaneously and would lead to glycerol and fatty acid as final products. Here, tricaprin (C10) with selectively deuterated fatty acid chains was used for the first time to monitor chain migration and the stereoselectivity of the pancreatic lipase-catalyzed hydrolysis of ester bonds. The intermediate and final digestion products were studied using NMR and mass spectrometry under biologically relevant conditions. The hydrolysis of the sn-2 monocaprin to glycerol and capric acid did not occur within biologically relevant timescales and fatty acid migration occurs only in limited amounts as a result of the presence of undigested diglyceride species over long periods of time in the digestion medium. The slow kinetics for the exchange of the sn-2 fatty acid chain and the stereoselectivity of pancreatic lipase on MCTs is relevant for industrial processes that involve enzymatic interesterification and the production of high-value products such as specific structured triacylglycerols, confectionery fats and nutritional products.
- Salentinig, Stefan,Yepuri, Nageshwar Rao,Hawley, Adrian,Boyd, Ben J.,Gilbert, Elliot,Darwish, Tamim A.
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- Separation of acylglycerides obtained by enzymatic esterification using solvent extraction
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New avenues to add value to glycerol are currently being explored. One of them is the synthesis of structured lipids through glycerol esterification. In this work we have analyzed the recovery and purification of dicaprin obtained by esterification of glycerol with capric acid (C) in heptane, mediated by Lipozyme RM IM. This is an intermediate step to obtain lipids MLM. In the first stage, the diglyceride synthesis MGM (being G a central HC-OH) was carried out. When M = C, the diglyceride is CGC. Recovery of the diglyceride CGC is required to carry out the esterification of the sn-2 position with palmitic acid (P), thus obtaining the triglyceride CPC. Different solvents were evaluated using Ecofac 1.0 (a molecular design software solvent) through a theoretical approach to explore the best solvents for the acylglycerides separation. Then, the performance of the selected solvents to separate dicaprin from mono and tricaprin was experimentally studied in a liquid-liquid extraction process. Previously, the remaining fatty acid had been neutralized. With liquid-liquid extraction in three simple steps, using ethanol/water, 94 % of the dicaprin obtained by enzymatic esterification was recovered with a purity of 89 % (wt%). It was also possible to obtain dicaprin with a purity of 97 % but with a yield of 56 %.
- Sanchez, Daniel Alberto,Tonetto, Gabriela Marta,Ferreira, Maria Lujan
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- Glyceride synthesis in a solvent-free system
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Synthesis of partial glycerides in a solvent-free system has been investigated with various acyl donors and glycerol as substrates and a 1,3-specific immobilized lipase to catalyze the reaction. Capric acid was the most efficient acyl donor, compared with ethyl caprate and tricaprin. However, to obtain a high yield of dicaprin and a low amount of tricaprin, ethyl caprate was the acyl donor of choice. The composition of the product mixture was determined by the ratio of ethyl caprate to glycerol; a molar ratio of 3:1 was optimum for dicaprin synthesis. The water content in glycerol did not influence the final yield of dicaprin, but initial production of capric acid increased with increasing water content. The reaction was found to be controlled entirely by external mass transfer. The yield of diglyceride could be increased from 70 to 90% by lowering the reaction temperature, so that the diglyceride precipitated during the reaction.
- Fureby,Adlercreutz,Mattiasson
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- LIPID PRODRUGS OF NEUROSTEROIDS
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The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.
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Paragraph 00544
(2021/08/13)
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- LIPID PRODRUGS OF PREGNANE NEUROSTEROIDS AND USES THEREOF
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The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.
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Paragraph 00436; 00438
(2020/02/23)
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- LIPID PRODRUGS OF JAK INHIBITORS AND USES THEREOF
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The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, and methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.
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Paragraph 00603; 00605
(2020/09/12)
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- LIPID PRODRUGS OF BTK INHIBITORS AND USES THEREOF
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The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, and methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.
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Paragraph 00405; 00612; 00614
(2020/09/12)
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- LIPID PRODRUGS OF GLUCOCORTICOIDS AND USES THEREOF
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The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, and methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.
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Paragraph 00596; 00598
(2020/09/12)
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- LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS
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The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.
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Paragraph 00561; 00563
(2019/03/17)
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- 1-O-Alkyl (di)glycerol ethers synthesis from methyl esters and triglycerides by two pathways: Catalytic reductive alkylation and transesterification/reduction
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From available and bio-sourced methyl esters, monoglycerides or oleic sunflower refined oil, the corresponding 1-O-alkyl (di)glycerol ethers were obtained in both high yields and selectivity by two different pathways. With methyl esters, a reductive alkylation with (di)glycerol was realized under 50 bar hydrogen pressure in the presence of 1 mol% of Pd/C and an acid co-catalyst. A second two step procedure was evaluated from methyl esters or triolein and consisted of a first transesterification to the corresponding monoglyceride with a BaO/Al2O3 catalyst, then its reduction to the desired glycerol monoether with a recyclable heterogeneous catalytic system Pd/C and Amberlyst 35 under H2 pressure. In addition, a mechanism for the reaction was also proposed.
- Sutter, Marc,Dayoub, Wissam,Metay, Estelle,Raoul, Yann,Lemaire, Marc
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supporting information
p. 786 - 797
(2013/04/24)
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- Diaryldiazepine Prodrugs for the Treatment of Neurological and Psychological Disorders
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The present invention provides prodrug compounds of diaryldiazepine drug compounds.
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Page/Page column 69
(2011/07/29)
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- TREATMENT OF NEURODEGENERATIVE CONDITIONS
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A method is provided for treating a patient in need of therapy for a neurodegenerative disease comprising administering to that patient a therapeutically effective dose of a lipid glyceride comprising a glycerol moiety and a fatty acid moiety, the fatty acid moiety being selected from the group consisting of γ-linolenic acid, dihomo-γ-linolenic acid and arachidonic acid characterised in that the selected fatty acid moiety is attached to the glycerol moiety at its sn-2 position. Preferably the method is that wherein the lipid is administered for a duration and at a dose sufficient to maintain or elevate TGF-β1 levels in the patient to therapeutic levels.
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Page/Page column 29-31; 38
(2008/06/13)
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- Chemoenzymatic synthesis of structured triacylglycerols by highly regioselective acylation
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A highly efficient two-step chemoenzymatic synthesis of structured triacylglycerols comprising a pure n-3 polyunsaturated fatty acid at the mid-position and a pure saturated fatty acid located at the end-positions is described. In the first step an immobilized Candida antarctica lipase was observed to display an excellent regioselectivity toward the end-positions of glycerol at 0-4°C using vinyl esters as acylating agents. The n-3 fatty acids were introduced into the remaining mid-position highly efficient and in excellent yields using EDCI coupling agent.
- Halldorsson, Arnar,Magnusson, Carlos D.,Haraldsson, Gudmundur G.
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p. 9101 - 9109
(2007/10/03)
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- Chemoenzymatic synthesis of structured triacylglycerols
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Six regioisomerically pure structured triacylglycerols possessing a medium-chain fatty acid (C8, C10 or C12) at the primary positions and pure eicosapentaenoic acid or docosahexaenoic acid at the secondary position of the glycerol moiety were prepared in two steps by a chemoenzymatic approach using lipase.
- Halldorsson, Arnar,Magnusson, Carlos D,Haraldsson, Gudmundur G
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p. 7675 - 7677
(2007/10/03)
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- Enzymatic synthesis of symmetrical 1,3-diacylglycerols by direct esterification of glycerol in solvent-free system
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1,3-Diacylglycerols were synthesized by direct esterification of glycerol with free fatty acids in a solvent-free system. Free fatty acids with relatively low melting points (45°C) such as unsaturated and medium-chain saturated fatty acids were used. With stoichiometric ratios of the reactants and water removal by evaporation at 3 mm Hg vacuum applied at 1 h and thereafter, the maximal 1,3-diacylglycerol content in the reaction mixture was: 84.6% for 1,3-dicaprylin, 84.4% for 1,3-dicaprin, 74.3% for 1,3-dilinolein, 71.7% for 1,3-dieicosapentaenoin, 67.4% for 1,3-dilaurin, and 61.1% for 1,3-diolein. Some of the system's parameters (temperature, water removal, and molar ratio of the reactants) were optimized for the production of 1,3-dicaprylin, and the maximal yield reached 98%. The product was used for the chemical synthesis of 1,3-dicapryloyl-2-eicosapentaenoylglycerol. The yield after purification was 42%, and the purity of the triacylglycerol was 98% (both 1,3-dicapryloyl-2-eicosapentaenoylglycerol and 1,2-dicapryloyl-3-eicosapentaenoylglycerol included) by gas chromatographic analysis, of which 90% was the desired structured triacylglycerol (1,3-dicapryloyl-2-eicosapentaenoylglycerol) as determined by silver ion high-performance liquid chromatographic analysis.
- Rosu, Roxana,Yasui, Mamoru,Iwasaki, Yugo,Yamane, Tsuneo
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p. 839 - 843
(2007/10/03)
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- Synthesis and evaluation of the anti-inflammatory effects of niflumic acid lipophilic prodrugs in brain edema
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Five new lipophilic prodrugs of the non-steroidal anti-inflammatory drug, niflumic acid (Nifluril, CAS 4394-00-7), were synthetized and evaluated on the experimental brain edema (injection of phospholipase A2). The effect of these drugs in comparison with dexamethasone which elicits a marked effect on clinical and experimental brain edema was evaluated. Niflumic acid was vectorised by cholesterol, hexadecanol and by three 1,3-diacylglycerols. The anti-inflammatory activity of these compounds on experimental brain edema was evaluated by determination of the prostaglandin E2 (PGE2) brain tissue concentration. Niflumic acid reduced the prostaglandin E2 production more significantly than dexamethasone. Niflumic acid prodrug forms (1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyl]glycer ol and 1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyloxybutan oyl]glycerol also showed a marked anti-inflammatory activity at low concentrations.
- El Kihel, Laila,Bourass, Jilali,Richomme, Pascal,Petit, Jean Yves,Letourneux, Yves
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p. 1040 - 1044
(2007/10/03)
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- Glycerides with anti-inflammatory properties
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Triglycerides carrying hydrocarbon acyl moieties in the 1- and 3-positions and the 2-methyl-1,3-benzodioxan-4-on-2-yl moiety in the 2-position exhibit excellent anti-inflammatory properties.
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