- Cooperative hierarchical self-assembly of peptide dendrimers and linear polypeptides into nanoarchitectures mimicking viral capsids
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Peptidesomes are nanoparticles that are built by a two-step self-assembly of globular peptide dendrimers with lysine endgroups (red spheres in picture) and poly(L-leucine) carrying one glutamic acid residue (blue lines with red dot). These viral-capsid-mimicking nanoarchitectures exhibit high gene transfection efficacy and thus are promising nonviral vectors for biomedical applications. Copyright
- Xu, Xianghui,Yuan, Hui,Chang, Jing,He, Bin,Gu, Zhongwei
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Read Online
- Novel conditions for the Juliá-Colonna epoxidation reaction providing efficient access to chiral, nonracemic epoxides
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The addition of a phase-transfer catalyst significantly accelerates the Juliá-Colonna epoxidation reaction yielding chiral, nonracemic epoxy ketones. Furthermore, a reliable procedure for the preparation of highly active poly-L-leucine catalyst is reported.
- Geller, Thomas,Gerlach, Arne,Krüger, Christa M.,Militzer, H.-Christian
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Read Online
- A scalable synthesis of L-leucine-N-carboxyanhydride
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Due to its relevance in the synthesis of well-defined oligopeptides, the L-leucine-N-carboxyanhydride (leucine-NCA) synthesis was selected for fine chemical scale-up with a scope on application on larger scales. The heterogeneous gas-solid-liquid nature of the leucine-NCA synthesis implied a mass transfer limited reaction rate towards phosgenation and was investigated on bench scale. Upon scale increase, the liquid-gas mass transport of HCl is drastically reduced, retarding the reaction and consequently rendering the process unsuitable for scale-up. Addition of an HCl scavenger such as (+)-limonene prevented side reactions thus allowing a cost reduction, a considerably faster reaction, and minimization of the amount of phosgene source used. The modified leucine-NCA synthesis has successfully been made scalable, maintaining high product purity on a 1.0 dm3 scale.
- Smeets,Van Der Weide,Meuldijk,Vekemans,Hulshof
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Read Online
- PEG-polyaminoacid based micelles for controlled release of doxorubicin: Rational design, safety and efficacy study
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A library of amphiphilic monomethoxypolyethylene glycol (mPEG) terminating polyaminoacid co-polymers able to self-assemble into colloidal systems was screened for the delivery and controlled release of doxorubicin (Doxo). mPEG-Glu/Leu random co-polymers were generated by Ring Opening Polymerization from 5 kDa mPEG-NH2 macroinitiator using 16:0:1, 8:8:1, 6:10:1, 4:12:1 γ-benzyl glutamic acid carboxy anhydride monomer/leucine N-carboxy anhydride monomer/PEG molar ratios. Glutamic acid was selected for chemical conjugation of Doxo, while leucine units were introduced in the composition of the polyaminoacid block as spacer between adjacent glutamic repeating units to minimize the steric hindrance that could impede the Doxo conjugation and to promote the polymer self-assembly by virtue of the aminoacid hydrophobicity. The benzyl ester protecting the γ-carboxyl group of glutamic acid was quantitatively displaced with hydrazine to yield mPEG5kDa-b-(hydGlum-r-Leun). Doxo was conjugated to the diblock co-polymers through pH-sensitive hydrazone bond. The Doxo derivatized co-polymers obtained with a 16:0:1, 8:8:1, 6:10:1 Glu/Leu/PEG ratios self-assembled into 30–40 nm spherical nanoparticles with neutral zeta-potential and CMC in the range of 4-7 μM. At pH 5.5, mimicking endosome environment, the carriers containing leucine showed a faster Doxo release than at pH 7.4, mimicking the blood conditions. Doxo-loaded colloidal formulations showed a dose dependent cytotoxicity on two cancer cell lines, CT26 murine colorectal carcinoma and 4T1 murine mammary carcinoma with IC50 slightly higher than those of free Doxo. The carrier assembled with the polymer containing 6:10:1 hydGlu/Leu/PEG molar ratio {mPEG5kDa-b-[(Doxo-hydGlu)6-r-Leu10]} was selected for subsequent in vitro and in vivo investigations. Confocal imaging on CT26 cell line showed that intracellular fate of the carrier involves a lysosomal trafficking pathway. The intratumor or intravenous injection to CT26 and 4T1 subcutaneous tumor bearing mice yielded higher antitumor activity compared to free Doxo. Furthermore, mPEG5kDa-b-[(Doxo-hydGlu)6-r-Leu10] displayed a better safety profile when compared to commercially available Caelyx.
- Brunato, Silvia,Mastrotto, Francesca,Bellato, Federica,Bastiancich, Chiara,Travanut, Alessandra,Garofalo, Mariangela,Mantovani, Giuseppe,Alexander, Cameron,Preat, Veronique,Salmaso, Stefano,Caliceti, Paolo
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- Synthesis of α-Amino Acid N-Carboxyanhydrides
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A simple phosgene- and halogen-free method for synthesizing α-amino acid N-carboxyanhydrides (NCAs) is described. The reaction between Boc-protected α-amino acids and T3P reagent gave the corresponding NCA derivatives in good yield and purity with no detectable epimerization. The process is safe, is easy-to-operate, and does not require any specific installation. It generates nontoxic, easy to remove byproducts. It can apply to the preparation of NCAs for the on-demand on-site production of either little or large quantities.
- Laconde, Guillaume,Amblard, Muriel,Martinez, Jean
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supporting information
p. 6412 - 6416
(2021/08/30)
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- Polyamino acid carrier with acid-sensitive connecting arm in middle as well as preparation method and application of polyamino acid carrier
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The invention discloses a polyamino acid carrier with an acid-sensitive connecting arm in the middle as well as a preparation method and application of the polyamino acid carrier. The polyamino acid carrier contains a hydrophilic part, a hydrophobic part and a responsive connecting arm; a specific disulfide bond is introduced into the carrier design, the disulfide bond can be controllably broken into sulfydryl in vitro, the small molecule with the sulfydryl fragment or the gene with sulfydryl inherent on the surface is bonded with the protein drug again, and a covalent disulfide bond is formedto complete chemical bonding delivery of the drug. The polyamino acid carrier and the drug are bonded in a covalent bond manner, so that the drug can be stably transported in systemic circulation. When the carrier reaches high-metabolism and high-reducibility parts such as tumors or inflammations, disulfide bonds are broken again under the condition of high glutathione (GSH), and the activity ofthe drug is released and recovered. Therefore, the purposes of firstly masking the drug activity, then stably delivering the drug in vivo and recovering accurate regulation and control of the drug activity after the drug reaches a target position are achieved.
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Paragraph 0050-0053; 0054-0055
(2020/09/20)
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- METHOD FOR PRODUCING AMINO ACID-N-CARBOXYLIC ACID ANHYDRIDE
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PROBLEM TO BE SOLVED: To provide: a method for safely and efficiently producing amino acid-N-carboxylic acid anhydride; and a method for producing peptide by using the obtained amino acid-N-carboxylic acid anhydride. SOLUTION: The method for producing an amino acid-N-carboxylic acid anhydride according to the present invention is characterized in that the amino acid-N-carboxylic acid anhydride is represented by the following formula (II), and a step of irradiating a composition containing a halogenated methane and an amino acid compound represented by the following formula (I) with high energy light in the presence of oxygen is included. [In the formula, R1 represents an amino acid side chain group in which the reactive group is protected, and R2 represents H or the like.]. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0067-0068; 0078
(2020/08/07)
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- METHOD OF SYNTHESIZING N-CARBOXYANHYDRIDE USING FLOW REACTOR
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PROBLEM TO BE SOLVED: To provide a synthesis method that allows high-yield continuous production of a compound of interest in synthesis and production of N-carboxyanhydride (NCA) and the like using a flow reactor. SOLUTION: In a synthesis method using a flow reactor 100, a basic solution adjusted in advance to a pH of 7-14 becomes acidic with a pH of 0-7, or an acidic solution adjusted in advance to a pH of 0-7 becomes basic with a pH of 7-14, within 60 seconds after the start of mixture of at least two ingredient solutions. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0092-0096; 0123-0124
(2020/03/26)
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- Papain-catalysed mechanochemical synthesis of oligopeptides by milling and twin-screw extrusion: Application in the Juliá-Colonna enantioselective epoxidation
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The oligomerisation of l-amino acids by papain was studied in a mixer ball mill and in a planetary ball mill. The biocatalyst proved stable under the ball milling conditions providing the corresponding oligopeptides in good to excellent yields and with a variable degree of polymerisation. Both parameters were found to be dependent on the reaction conditions and on the nature of the amino acid (specifically on its side-chain size and hydrophobicity). In addition, the chemoenzymatic oligomerisation was demonstrated by utilising twin-screw extrusion technology, which allowed for a scalable continuous process. Finally, the synthesised oligo(l-Leu) 2b proved to be active as a catalyst in the Juliá-Colonna enantioselective epoxidation of chalcone derivatives.
- Ardila-Fierro, Karen J.,Crawford, Deborah E.,K?rner, Andrea,James, Stuart L.,Bolm, Carsten,Hernández, José G.
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supporting information
p. 1262 - 1269
(2018/03/26)
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- Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides: Basic-to-Acidic Flash Switching in a Microflow Reactor
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Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.
- Otake, Yuma,Nakamura, Hiroyuki,Fuse, Shinichiro
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supporting information
p. 11389 - 11393
(2018/08/28)
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- Enantioselective One-Pot Synthesis of α,β-Epoxy Ketones via Aerobic Oxidation of Cyclopropanols
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An efficient, mild, and environmentally benign method was developed for the asymmetric synthesis of 2-oxyranyl ketones from easily available tertiary cyclopropanols. The one-pot protocol includes the aerobic oxidation of cyclopropanol derivatives catalyzed by Mn(III) complexes followed by the poly-l-leucine-assisted stereoselective elimination of water from the intermediate peroxides with DBU to afford the corresponding epoxy ketones in high yields and good-to-excellent enantioselectivities (up to 97%).
- Elek, Gábor Zoltán,Borovkov, Victor,Lopp, Margus,Kananovich, Dzmitry G.
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supporting information
p. 3544 - 3547
(2017/07/17)
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- Large-scale synthesis of α-amino acid-N-carboxyanhydrides
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Hetero- and homopolymers prepared from α-amino acid-N-carboxyanhydrides (NCAs) monomers are widely useful products. The preparation of pure NCA monomers has been extensively studied in the past. Purification methods including repeated crystallizations, extraction, and flash column chromatography have been devised. However, these methods are not easily amendable to large-scale NCA preparations. This article describes the synthesis of numerous highly purified NCAs on a >100 g scale using a simple filtration step through diatomaceous earth (celite). The resulting NCAs provided polyethylene glycol (PEG)–amino acid triblock polymers devoid of low-molecular-weight by-products that were routinely observed when unfiltered batches of NCAs were used. Also disclosed is the preparation of NCAs at ambient temperature. Traditionally, NCA reactions using a phosgene source are heated. This study shows these reactions can be driven by the slight exotherm that forms upon reagent mixing. This eliminates the need for an external heating source, simplifying large-scale reactions.
- Semple, J. Edward,Sullivan, Bradford,Sill, Kevin N.
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- Revisiting the Juliá-Colonna enantioselective epoxidation: Supramolecular catalysis in water
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We describe an efficient epoxidation process leading to chiral epoxyketones using the reusable homo-oligopeptide poly-l-leucine (PLL) in pure water, without any organic co-solvent. A range of substituted epoxyketones can be accessed with good conversions and high enantioselectivities. Based on the experimental results and computational studies, we propose a mechanism that demonstrates the importance of both the α-helical structure and the presence of a hydrophobic groove of the homo-oligopeptide catalyst for reactivity and selectivity.
- Bérubé, Christopher,Barbeau, Xavier,Lagüe, Patrick,Voyer, Normand
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supporting information
p. 5099 - 5102
(2017/07/12)
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- Primary ammonium/tertiary amine-mediated controlled ring opening polymerisation of amino acid N-carboxyanhydrides
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Stable commercial primary ammonium chlorides were combined with tertiary amines to initiate the controlled ring opening polymerisation of amino acid N-carboxyanhydrides to yield polypeptides with defined end group structure, predetermined molar mass and narrow molar mass distribution.
- Vacogne, Charlotte D.,Schlaad, Helmut
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supporting information
p. 15645 - 15648
(2015/11/02)
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- Dual-pH sensitive charge-reversal polypeptide micelles for tumor-triggered targeting uptake and nuclear drug delivery
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A novel dual-pH sensitive charge-reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(l-lysine)-block-poly(l-leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3-dimethylmaleic anhydride to form β-carboxylic amide, making the polypeptides self-assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell-penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH-sensitive β-carboxylic amides.
- Han, Shi-Song,Li, Ze-Yong,Zhu, Jing-Yi,Han, Kai,Zeng, Zheng-Yang,Hong, Wei,Li, Wen-Xin,Jia, Hui-Zhen,Liu, Yun,Zhuo, Ren-Xi,Zhang, Xian-Zheng
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p. 2543 - 2554
(2015/06/08)
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- COPOLYMERS FOR STABLE MICELLE FORMULATIONS
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The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same. Compositions herein are useful for drug-delivery applications.
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Paragraph 0351; 0352; 0353
(2014/09/29)
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- Novel shell-cross-linked micelles with detachable PEG corona for glutathione-mediated intracellular drug delivery
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A series of novel disulfide-containing triblock copolymers, poly(ethylene glycol)-b-poly(l-lysine)-b-poly(rac-leucine) (PEG-SS-PLys-PLeu), were prepared. In an aqueous solution, the copolymers could self-assemble to form core-shell-corona micelles with a disulfide-linked detachable PEG corona, since the PLys middle shell with primary amine groups was linked by a disulfide-containing cross-linker. The morphology and stability of self-assembled micelles were characterized by TEM, DLS and SEM. In the intracellular environment, the micelles underwent destruction of the cross-linked shell with detachment of the PEG corona due to the cleavage of disulfide bonds, followed by the collapse of micelles. The in vitro drug release in response to GSH was further studied. Interestingly, it was found that the micelles not only exhibited reduced drug loss in extracellular environments, but also drastically accelerated drug release at the cytoplasmic GSH level, leading to enhanced growth inhibition of HeLa cells. The glutathione-responsive micelles might have great potential in intracellular drug delivery.
- Wang, Kang,Liu, Yun,Yi, Wen-Jie,Li, Cao,Li, Yong-Yong,Zhuo, Ren-Xi,Zhang, Xian-Zheng
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p. 692 - 699
(2013/03/13)
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- BLOCK COPOLYMERS FOR STABLE MICELLES
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The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same. Compositions herein are useful for drug-delivery applications.
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Paragraph 0386; 0387
(2013/11/05)
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- Porphyrin-functionalized amphiphilic diblock copolypeptides for photodynamic therapy
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A series of amphiphilic diblock copolypeptides (ADCs), 5-(4-aminophenyl)- 10,15,20-triphenyl-porphyrin (APP) conjugated poly(L-leucine)-block-polylysine (APP-LnKm) with different molar ratios of L-leucine unit and lysine unit were designed and synthesized. The optimized composition of the polypeptide was determined to be APP-L109K186, which has high fluorescence quantum yield and could self-assemble into micelles in an aqueous medium with mean particle size 109K186 shows no significant dark cytotoxicity when the concentration is below 200 mg L-1 for HepG2 and HeLa cells. In contrast, the polymer exhibits apparent phototoxicity with low IC 50 values toward HepG2 and HeLa cells, implying that the potential high photodynamic therapy efficacy of the polymer. Copyright
- Li, Ze-Yong,Wang, Hui-Yuan,Li, Cao,Zhang, Xiao-Lu,Wu, Xiao-Jun,Qin, Si-Yong,Zhang, Xian-Zheng,Zhuo, Ren-Xi
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experimental part
p. 286 - 292
(2011/10/08)
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- Sheddable micelles based on disulfide-linked hybrid PEG-polypeptide copolymer for intracellular drug delivery
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A novel reduction-sensitive sheddable micelle based on disulfide-linked hybrid PEG-polypeptide mPEG-SS-Pleu was demonstrated for intracellular drug delivery. These micelles are composed of an mPEG shell and polypeptide core, characterized by FT-IR, 1H NMR, fluorescence techniques, TEM, and DLS. Interestingly, they would undergo a fast sheddable process when encounter the reduction sensitive condition, indicated by the aggregation phenomena in the presence of DTT, a reduction agent, which could cleave the disulfide bond between the micellar core and shell and consequently leading to the aggregation of hydrophobic core. Cytotoxicity study revealed that copolymers in this system have good biocompatibility and their self-assembled micelles showed a high drug loading efficiency for DOX, a hydrophobic drug model, and released DOX quantitatively in response to the intracellular level of reducing potential. Cellular uptake experiments demonstrated that the fluorescently labeled micelles could be successfully internalized into human liver carcinoma HepG2 cells, evidenced by confocal laser scanning microscopy. Above results indicate that the copolymers may have great potential in drug delivery to achieve improved cancer therapy.
- Ren, Tian-Bin,Xia, Wen-Juan,Dong, Hai-Qing,Li, Yong-Yong
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experimental part
p. 3580 - 3586
(2012/05/20)
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- Organo-Soluble Chitosan Salts and Chitosan-Derived Biomaterials Prepared Thereof
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Organo-soluble chitosan salts, method for preparing organo-soluble salts, chitosan-derived materials prepared with organo-soluble chitosan salts, and methods for preparing chitosan-derived materials are disclosed.
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Page/Page column 17
(2011/06/28)
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- New amphiphilic biodegradable β-cyclodextrin/poly(l-leucine) copolymers: Synthesis, characterization, and micellization
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A new amphiphilic biodegradable β-cyclodextrin/poly(l-leucine) (β-CD-PLLA) copolymer was synthesized by ring-opening polymerization of N-carboxy-l-alanine anhydride (LL-NCA) in N,N-dimethylformamide (DMF) initiated by mono-6-amino-β-cyclodextrin (H2N-β-CD). The structures of the copolymers were determined by IR, 1H NMR and GPC. The fluorescence technique was used to determine the critical micelle concentrations (CMC) of copolymer micelle solution. The diameter and distribution of micelles were characterized by dynamic light scattering (DLS) and its shape was observed by transmission electron microscopy (TEM). The results showed that LL-NCA could be initiated by H2N-β-CD to produce the copolymer. These copolymers could self-assemble into nano-micelles in water. The CMC of copolymer solution and the size of micelle reduced with increasing proportion of the hydrophobic part. TEM images demonstrated the micelles are all spherical. Such block copolymers could be expected to find applications in drug delivery systems and other biomedical fields.
- Zhang, Guolin,Liang, Fang,Song, Ximing,Liu, Daliang,Li, Mengjiang,Wu, Qiuhua
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experimental part
p. 885 - 890
(2011/12/02)
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- High potency and broad-spectrum antimicrobial peptides synthesized via ring-opening polymerization of α-Aminoacid-N-carboxyanhydrides
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Antimicrobial peptides (AMPs), particularly those effective against methicillin-resistant Staphylococcus aureus (S. aureus) and antibiotic-resistant Pseudomonas aeruginosa (P. aeruginosa), are important alternatives to antibiotics. Typical peptide synthesis methods involving solid-phase sequential synthesis are slow and costly, which are obstacles to their more widespread application. In this paper, we synthesize peptides via ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCA) using a transition metal initiator. This method offers high potential for inexpensive synthesis of substantial quantities of AMPs. Lysine (K) was chosen as the hydrophilic amino acid and alanine (A), phenylalanine (F), and leucine (L) as the hydrophobic amino acids. We synthesized five series of AMPs (i.e., P(KA), P(KL), P(KF), P(KAL), and P(KFL)), varied the hydrophobic amino acid content from 0 to 100%, and determined minimal inhibitory concentrations (MICs) against clinically important Gramnegative and Gram-positive bacteria and fungi (i.e., Escherichia coli (E. coli), P. aeruginosa, Serratia marcescens (S. marcescens), and Candida albicans (C. albicans). We found that P(K10F 7.5L7.5) and P(K10F15) show the broadest activity against all five pathogens and have the lowest MICs against these pathogens. For P(K10F7.5L7.5), the MICs against E. coli, P. aeruginosa, S. marcescens, S. aureus, and C. albicans are 31 μg/mL, 31 μg/mL, 250 μg/mL, 31 μg/mL, and 62.5 μg/mL, while for P(K10F15) the respective MICs are 31 μg/mL, 31 μg/mL, 250 μg/mL, 31 μg/mL, and 125 μg/mL. These are lower than the MICs of many naturally occurring AMPs. The membrane depolarization and SEM assays confirm that the mechanism of microbe killing by P(K10F 7.5L7.5) copeptide includes membrane disruption, which is likely to inhibit rapid induction of AMP-resistance in pathogens.
- Zhou, Chuncai,Qi, Xiaobao,Li, Peng,Chen, Wei Ning,Mouad, Lamrani,Chang, Matthew W.,Leong, Susanna Su Jan,Chan-Park, Mary B.
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experimental part
p. 60 - 67
(2010/12/18)
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- A tripodal peptidic titanium phosphonate as a homochiral porous solid medium for the heterogeneous enantioselective hydration of epoxides
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A porous, homochiral titanium-phosphonate material based on a tripodal peptide scaffold was used as a heterogeneous reaction medium for the enantioselective hydration (>99%) of styrene oxide. This titanium-phosphonate material, which was shown to contain confined chiral spaces, was prepared by polymerization of L-leucine onto a tris(2-aminoethyl)amine initiator, followed by capping with phosphonate groups and completed by non-aqueous condensation with titanium isopropoxide. Circular dichroism confirmed that the peptide tethers yielded a secondary structure. X-ray powder diffraction and transmission electron microscopy supported by a semi-empirical model showed the likely formation of a porous, lamellar material that was quantified by nitrogen adsorption.
- Milo, Anat,Neumann, Ronny
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supporting information; experimental part
p. 2159 - 2165
(2010/12/18)
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- POLYMER MICELLES CONTAINING ANTHRACYLINES FOR THE TREATMENT OF CANCER
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The present invention provides micelles having an anthracycline encapsulated therein, the micelles comprising a multiblock copolymer. The invention further provides methods of preparing and using said micelles, and compositions thereof.
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Page/Page column 59
(2010/11/17)
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- HYBRID BLOCK COPOLYMER MICELLES WITH MIXED STEREOCHEMISTRY FOR ENCAPSULATION OF HYDROPHOBIC AGENTS
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The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same.
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Page/Page column 94
(2008/12/08)
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- PROCESS FOR THE PREPARATION OF N-CARBOXYANHYDRIDES
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The invention relates to a process for the preparation of N-carboxyanhydrides by reaction of the corresponding amino acid with phosgene, diphosgene and/or triphosgene in a solvent medium, characterized in that the reaction is a least partially carried out in the presence of an unsaturated organic compound which has one or more ethylenic double bonds. The N-carboxyanhydrides are thus obtained with better yields and an improved purity.
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Page/Page column 6
(2008/06/13)
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- Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion
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The recent advance of particle size engineering in nanometer ranges has widened the formulation opportunities of relatively water-insoluble drugs. However, the 'nanoformulation' suffers from a lack of systematic understanding about the requirements of polymeric stabilizers. Furthermore, the polymers that can be used for the preparation of nanocrystals are so limited that finding a proper stabilizer for a given formulation is often difficult. In this study, amino acid copolymers whose properties can systematically be tailored are developed, and their morphological and compositional effects are investigated. Copolymers containing lysine (K) as their hydrophilic segments, and phenylalanine (F) or leucine (L) as their hydrophobic segments successfully produce stable nanocrystals (200-300 nm) in water, while copolymers of K and alanine (A) could not generate nanosized particles. Not the morphology but the hydrophobicity of copolymers seems to be a critical parameter in the preparation of drug nanocrystals by wet comminution. The effective stabilization performance of copolymers requires the hydrophobic moiety content to be higher than 15 mol%. Comminution for only 5 min is long enough for nanocrystal preparation, and the crystallinity of drug is found intact after the processing.
- Lee, Jonghwi,Lee, Soo-Jeong,Choi, Ji-Yeun,Yoo, Ji Youn,Ahn, Cheol-Hee
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p. 441 - 449
(2007/10/03)
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- Scale-up studies for the asymmetric Julia-Colonna epoxidation reaction
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The asymmetric Julia-Colonna epoxidation reaction under triphasic/PTC conditions has been successfully scaled-up to a one-hundred gram substrate level providing the corresponding epoxy ketone with high optical purity (up to 97% ee) and in good yield (75-78%). The amount of polyamino acid catalyst could be reduced leading to a simplified reaction work-up. In order to minimise the overall reaction time baffled reactors with pitched-blade impellers have been employed.
- Gerlach, Arne,Geller, Thomas
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p. 1247 - 1249
(2007/10/03)
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- Influence of polymerization degree of poly-l-leucine catalyst and substituent effect on the Julia-Colonna asymmetric epoxidation of benzalacetophenones
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The Julia-Colonna asymmetric epoxidation reaction of substituted benzalacetophenone afforded the corresponding epoxide with high yield and high enantioselectivity, catalyzed by the specified length of poly-l-leucine (chain length n > 15). Poly-l-leucine catalysts have been prepared by the polymerization reaction of l-leucine-NCA with initiators (BnONa, n-BuNH2, H2O) and characterized by the MALD1-TOF Mass and IR analysis.
- Takagi, Ryukichi,Begum, Shahnaz,Siraki, Akiko,Yoneshige, Arata,Koyama, Kin-ichirou,Ohkata, Katsuo
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p. 129 - 141
(2007/10/03)
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- A Facile Synthesis of N-Carboxyanhydrides and Poly(α-amino acid) Using Di-tert-butyltricarbonate
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A facile synthesis of N-carboxyanhydrides and poly(α-amino acid) using di-tert-butyltricarbonate (DBTC) is discussed. A one-pot synthesis of poly(amino acid) from an amino acid and DBTC as a dehydrating agent is also discussed. It is found that ring-opening polymerization of α-amino acid-N-carboxyanhydrides (NCA) is advantageous over the polycondensation because ring-opening polymerization, which is a chain polymerization is capable of providing polypeptides with precise topology. Results show that the system is suitable to synthesize NCA and poly(amino acid) from amino acids having acid-sensitive protecting groups.
- Nagai, Atsushi,Sato, Daisuke,Ishikawa, Junichi,Ochiai, Bungo,Kudo, Hiroto,Endo, Takeshi
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p. 2332 - 2334
(2007/10/03)
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- Rapid assembly and synthetic applications of a supported poly-α-amino acid containing phosphine groups
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A simple method for the rapid multiplication of the number of available amine sites on a polymer bead, using lysine N-carboxyanhydride, is described. The product may be functionalised with a phosphine and employed in a catalytic reaction. (C) 2000 Elsevier Science Ltd.
- Edwards,Shipton,Wills
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p. 8615 - 8619
(2007/10/03)
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- 2-thiosubstituted carbapenems
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Carbapenem antibiotic compounds of the general formula: STR1 wherein the moiety STR2 is a 4, 5 or 6 membered mono, di- or tri- substituted oxygen or sulfur containing ring; wherein Z is oxygen, sulfur, sulfoxide and sulfone, pharmaceutical compositions thereof useful for the treatment of bacterial infections, processes for preparing the compounds and new intermediates useful in the process.
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- A new simple and quantitative synthesis of α-aminoacid-N-carboxyanhydrides (oxazolidines-2,5-dione)
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Nitrosation of chiral N-carbamoylaminoacids with a mixture of NO and O2 gives, with the same configuration and in quantitative yield the corresponding α-aminoacid-N-carboxyanhydrides (NCA), well known precursors of peptides. The by products of this reaction are N2 and H2O. Copyright (C) 1996 Elsevier Science Ltd.
- Collet, Helene,Bied, Catherine,Mion, Louis,Taillades, Jacques,Commeyras, Auguste
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p. 9043 - 9046
(2007/10/03)
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- Friedel-Crafts α-Aminoacylation of Alkylbenzene with a Chiral N-Carboxy-α-amino Acid Anhydride without Loss of Chirality
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A Friedel-Crafts-type α-aminoacylation of alkylbenzene with N-carboxy anhydrides of five L-α-amino acids was developed.Five new α-aminoalkyl p-methylphenyl ketones and other α-aminoalkyl aryl ketones were obtained and isolated as free bases or hydrochloride salts.The chiralities of the original L-α-amino acids were retained during this acylation.
- Itoh, Osamu,Honnami, Toshiya,Amano, Akira,Murata, Kouichi,Koichi, Youta,Sugita, Toshio
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p. 7334 - 7338
(2007/10/02)
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- Urethane-protected amino acid-N-carboxyanhydrides
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Urethane-protected NCAs and MTAs are prepared by reacting an NCA or NTA with a haloformate in an inert diluent, under anhydrous conditions and in the presence of a tertiary nitrogen-containing base having an atom or functional group sufficiently electron rich and positioned relative to the nitrogen of said base so as to render said atom or group capable of complexing with the H--N group of said N-carboxyanhydride or N-thiocarboxyanhydride but able to generate N-carboxyanhydride or N-thiocarboxyanhydride anionic complexes capable of reacting with the haloformate.
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- Urethane-protected amino acid-N-carboxyanhydrides
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The invention relates to urethane-protected amino acid-N-carboxyanhydride and N-thiocarboxyanhydride compounds which are useful in peptide, polypeptide and protein synthesis. Disclosed herein is the preparation and use of these novel compounds.
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- Electroactive Poly(amino acids). Part 2. Copolymers of Nε-4-Nitrobenzoyl-L-lysine with Inactive Amino Acids: Modified Electrodes with these Polymers and Poly(pyrrole) and with Poly(1-pyrrole)
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Co-polymerization of the N-carboxyanhydrides derived from Nε-4-nitrobenzoyl-L-lysine (NBL) and one of the amino acids, Nε-4-benzoyl-L-lysine, L-leucine, and glycine afforded elecroactive materials.These can be adsorbed onto platinum from dimethylacetamide solution.The electrochemical response of the adsorbed layers quickly deteriorates to give broad peaks on continuous cyclic voltammetry.Determination of the response is thought to be due to a combination of poor adhesion and conformational changes which accompany charging and discharging of the film.Poly(1- pyrrole) forms a coherent film on platinum.It shows a good response due to the nitro group on continuous cyclic voltammetry.The height of this response falls with time due to loss of electroactive material.Poly(NBL) also forms a film by adsorption onto a 20-60 nm thick layer of poly(pyrrole) and the composite gives a response on continuous cyclic voltammetry that is much more stable than any of the previous cases.Coating platinum with poly(NBL) and then with poly(pyrrole) also gives a stable composite.
- Grimshaw, James,Perera, Sarath D.
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p. 1711 - 1718
(2007/10/02)
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- ENANTIOMERIC QUANTIFICATIONS OF AMINO ACIDS THROUGH THEIR Nα-ACYL AMIDES BY GAS CHROMATOGRAPHY.
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Apparent separation of 1.1 or higher on Chiralsil Val III can be obtained for Nα-acyl N-alkyl aminoacid amides allowing the use of short capillary gas chromatographic columns.A clean derivatization protocol without racemization is described, proceding through the NCA derivatives that are prepared from "in situ" silylated amino acids with trimethylsilyl cyanide.
- Hosten, N.,Anteunis, M. J. O.
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- THE PREPARATION OF N-CARBOXYANHYDRIDES OF α-AMINO ACIDS USING BIS(TRICHLOROMETHYL)CARBONATE
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A syntheis of the N-carboxyanhydrides (NCA's) of several α-amino acids using bis(trichloromethyl)carbonate, 1, is reported.The triphosgene is used to supply phosgene in situ in stoichiometric amounts; it is particularly effective for preparing NCA's of amino acids with long, aliphatic side chains.
- Daly, William H.,Poche, Drew
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p. 5859 - 5862
(2007/10/02)
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- Asymmetric Syntheses via Heterocyclic Intermediates, XVIII. - On the Enantioselective Synthesis of (2R)-Serine Methyl Esters or (2R)-Serines Starting with the Bis(lactim) Ether of cyclo-(-L-Val-Gly)
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The lithiated bis(lactim) ether 8a furnishes with aldehydes and ketones in good yields the addition products 11 with (3R) configuration.The asymmetric inductions at C-3 of 11 (d.e. values) amount to more than 95 percent with ketones, with aldehydes they are somewhat smaller.With unsymmetrical ketones or aldehydes C-3' also becomes a chiral center.For the (3R)-major diastereomers the "second induction" at C-3' varies from about 4 t about 87 percent (for benzaldehyde or isobutyraldehyde, respectively), preferably the (3R,3'S) epimers are formed. - Acid hydrolysis of 11 yields (besides methyl L-valinate) the (2R)-serine methyl esters 26.Their e.e. values correspond with the d.e. values of 11. - Dehydratation of 11 furnishes the "Hofmann olefins" 32 and/or the "Saytzeff olefins" 33 which can be transformed in various ways into optically active amino acids.
- Schoellkopf, Ulrich,Groth, Ulrich,Gull, Martin-Reinhold,Nozulak, Joachim
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p. 1133 - 1151
(2007/10/02)
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- SYNTHETIC ENZYMES-4. HIGHLY ENANTIOSELECTIVE EPOXIDATION BY MEANS OF POLYAMINOACIDS IN A TRIPHASE SYSTEM: INFLUENCE OF STRUCTURAL VARIATIONS WITHIN THE CATALYSTS.
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The asymmetric epoxidation of chalcone and other electron-poor olefins in a triphase system (water-organic solvent-polyaminoacid) affords optically active oxiranes.The influence of the molecular structure of catalysts and of their secondary conformation on the enantioselectivity of the reaction has also been examined.
- Colonna, Stefano,Molinari, Henriette,Banfi, Stefano,Julia, Sebastian,Masana, Jaume,Alvarez, Angel
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p. 1635 - 1642
(2007/10/02)
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- Block copolypeptides. 1. Synthesis and solid state conformational studies.
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Triblock copolypeptides of gamma-benzyl L-glutamate (G) and L-leucine or L-valine of high molecular weight have been prepared. The solubilites and solution conformation were determined and compared with random copolymers of similar composition as well as the appropriate homopolypeptides. Characterization of the secondary structure in the solid state was undertaken as part of an investigation into the solid state properties of this new class of materials. Infrared and solid state measurements indicate that the G and L-leucine blocks assume an alpha-helical conformation and L-valine blocks a beta-sheet structure. Polarized infrared measurements showed the chain axis in oriented films to be parallel to the orientation direction. Further solid state characterization of the tertiary structure and mechanical properties of the block copolypeptides will be reported in succeeding papers.
- Hayashi,Walton,Anderson
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p. 346 - 351
(2007/10/08)
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