- Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E
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Vitamin E refers to a group of saturated tocopherol (T) isomers and the biologically more active unsaturated tocotrienol (T3) isomers. PEGylated α-tocopherol, commercially known as Vitamin E TPGS, has been used as an emulsifier and therapeutic agent for children with vitamin E deficiency. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. The current work was therefore undertaken to synthesize and characterize the water soluble polyethylene glycol (PEG 350 and 1000) derivatives of T and T3. Yield and the identity of the synthesized products were confirmed by 1H NMR, mass spectroscopy, HPLC, and thermal analysis. The self-assembly of the PEGylated vitamin E isomers in water at critical micelle concentrations (CMC) was further confirmed by size, zeta, and Cryo-TEM image analysis. While stable at pH 7.4, PEG conjugates were found to rapidly hydrolyze at pH 1.2. Our data showed that PEGylated T3 isomers were significantly more active as inhibitors for P-glycoprotein than PEGylated T. The in vitro cytotoxicity of the conjugates was also tested against a large panel of normal and tumorigenic cells. Of the conjugates, γ-T3PGS 1000 and δ-T3PGS 1000 were found to have the least toxicity against non-tumorigenic breast and pancreatic cell lines, which may be advantageous for its use as functional excipients in drug delivery. The results from the current work have demonstrated the feasibility of synthesizing PEGylated conjugates of vitamin E isomers and highlighted the potential use of these conjugates in drug delivery as functional and safer excipients especially for γ-T3PGS 1000 and δ-T3PGS 1000 conjugate.
- Abu-Fayyad, Ahmed,Nazzal, Sami
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- Synthesis of ionic biologically active conjugates from trolox and α-tocopherol succinates
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Six ionic conjugates with nitroxyl radical amino-TEMPO and diethanolamine as the amines were synthesized from trolox and α-tocopherol succinates. The water solubility of the synthesized ammonium salts was determined. It was shown that formation of the trolox succinate salts increased the water solubility whereas this phenomenon was not observed for α-tocopherol succinates.
- Yushkova, Yu. V.,Morozov,Chernyak,Grigor’ev
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- Encapsulation of enzymes in metal ion-surfactant nanocomposites for catalysis in highly polar solvents
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We described a method to encapsulate enzymes in metal ion-surfactant nanocomposites. The nanobiocatalyst displayed highly retained activity (～100%) and much improved stability in protein-denaturing organic solvents. As a demonstration, the encapsulated lipase exhibited much higher activity and stability in the synthesis of vitamin E succinate in dimethyl sulfoxide.
- Cao, Xun,Ni, Yan,Zhang, Alei,Xu, Sheng,Chen, Kequan,Ouyang, Pingkai
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- Aqueous phase preparation method of isoxazoline compound participating in vitamin E micro-micelle
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The invention provides an aqueous phase synthesis method of the isoxazoline compound represented by the formula (III), wherein the benzaldehyde oxime represented by the formula (I) is a substrate, and the aqueous solution of the surfactant in the mass concentration 1 wt % - 5 wt % is N - chlorosuccinimide. Under the common action of the basic substance, the olefinic compound represented by the formula (II) is reacted 6 - 16h at room temperature, and the resulting reaction liquid is subjected to post-treatment to obtain the isoxazoline compound represented by the formula (III). Water serves as a reaction solvent, the use amount of the organic solvent is reduced, and zero emission of the solvent is realized.
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Paragraph 0036-0038
(2021/11/21)
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- Method for reducing by hydrolysis producing high content of natural vitamin E industrial production method
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An industrialized production method for producing high-content natural vitamin E by utilizing a hydrolysis reduction process comprises: (1) dissolving low-content natural mixed tocopherols in proper amount of a solvent, adding succinic anhydride and performing esterification reaction under an alkaline condition, so as to generate corresponding natural tocopherol esters; (2) performing reduced-pressure distillation on the product obtained in the step (1) to remove the solvent, adding an extraction reagent and performing extraction, water washing, crystallization and separation, so as to obtain natural tocopherol succinate with high content; (3) hydrolyzing natural tocopherol succinate obtained in the step (2) under an alkaline condition, and reducing to generate natural tocopherols; and (4) performing extraction, water washing, separation and distillation on the natural tocopherols obtained through hydrolysis in the step (3), so as to obtain the natural vitamin E (mixed tocopherols) with the high content up to 90% or more.
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Paragraph 0039-0040
(2017/03/08)
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- Using imidazolium-based ionic liquids as dual solvent-catalysts for sustainable synthesis of vitamin esters: Inspiration from bio- and organo-catalysis
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Vitamin E (VE) has significant biological activities and thus its acylation to increase its stability is of extreme interest. We developed an efficient and sustainable approach using imidazolium-based ionic liquids as dual solvent-catalysts for the esterification between α-tocopherol (the most active form of VE) and succinic anhydride. Although in literature it is reported that lipase can catalyze this reaction, hereby we demonstrate that the reaction observed in DMSO and DMF is catalyzed by the histidyl residues of the protein. Histidine and its analogue containing an imidazole ring were tested as organocatalysts for the production of α-tocopherol succinate. In light of the imidazole organocatalysis, commercially-available 3-alkyl-1-methyl imidazolium ILs [CnC1Im][X-] were investigated as dual solvent-catalysts for the esterification of α-tocopherol with succinic anhydride, and provided satisfactory yields and reaction rates. [C5C1Im][NO3-] can be recycled by water extraction, instead of organic solvent extraction to separate α-tocopherol succinate from [C5C1Im][NO3-], with an average yield of 94.1% for 4 subsequent batches, while the catalytic activity of the recycled ILs showed almost no loss after 4 batches. The developed protocol for the synthesis of α-tocopherol esters and IL recycling bears industrial potential due to the ease of use and the efficient recycling.
- Tao, Yifeng,Dong, Ruijuan,Pavlidis, Ioannis V.,Chen, Biqiang,Tan, Tianwei
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supporting information
p. 1240 - 1248
(2016/03/09)
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- Structure-Based Rational Design of Prodrugs to Enable Their Combination with Polymeric Nanoparticle Delivery Platforms for Enhanced Antitumor Efficacy
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Drug-loaded nanoparticles (NPs) are of particular interest for efficient cancer therapy due to their improved drug delivery and therapeutic index in various types of cancer. However, the encapsulation of many chemotherapeutics into delivery NPs is often hampered by their unfavorable physicochemical properties. Here, we employed a drug reform strategy to construct a small library of SN-38 (7-ethyl-10-hydroxycamptothecin)-derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine-tuned the polarity of the SN-38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self-assembly into biodegradable poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-PLA) nanoparticulate structures. Our strategy combining the rational engineering of prodrugs with the pre-eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality.
- Wang, Hangxiang,Xie, Haiyang,Wu, Jiaping,Wei, Xuyong,Zhou, Lin,Xu, Xiao,Zheng, Shusen
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supporting information
p. 11532 - 11537
(2016/02/19)
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- Anticancer activity of vitamin e-derived compounds in murine c6 glioma cells
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A small library of vitamin E analogues, with a free acid group linked to the chroman core through an amide, ether or ester bond, was synthesized and evaluated for their anticancer potency on C6 murine glioma cells. Several compounds showed antitumor activity better than temozolomide, the mostly commonly used drug in the treatment of gliomas.
- Mazzini, Francesco,Betti, Michele,Canonico, Barbara,Netscher, Thomas,Luchetti, Francesca,Papa, Stefano,Galli, Francesco
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scheme or table
p. 540 - 543
(2010/12/19)
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- Modulating the therapeutic activity of nanoparticle delivered paclitaxel by manipulating the hydrophobicity of prodrug conjugates
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A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.
- Ansell, Steven M.,Johnstone, Sharon A.,Tardi, Paul G.,Lo, Lily,Xie, Sherwin,Shu, Yu,Harasym, Troy O.,Harasym, Natashia L.,Williams, Laura,Bermudes, David,Liboiron, Barry D.,Saad, Walid,Prud'homme, Robert K.,Mayer, Lawrence D.
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experimental part
p. 3288 - 3296
(2009/04/07)
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- Bioprecursors for percutaneous application
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The invention concerns a bioprecursor of formula (I), wherein A1 and A2 represent independently of each other a radical derived from a molecule capable of being used in dermatology or in cosmetology; X and Y represent independently of each other a hydrogen atom, a hydroxy group or a C1-C20 alkyl group; and n represents an integer between 0 and 10.
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