- Dual-responsive star-shaped polypeptides for drug delivery
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Core cross-linked star-shaped polypeptides based on poly(l-glutamic acid)-poly(l-phenylalanine-co-l-cystine) copolymer have been successfully synthesized and thoroughly characterized. The star polypeptides can self-assemble to form 50 nm micelles in aqueous medium, which respond rapidly to both pH change within the physiologically relevant pH range and a reduction environment mimicking the intracellular space. Water-soluble doxorubicin hydrochloride and hydrophobic resveratrol are loaded into the star polypeptides micelles through electrostatic and hydrophobic interactions respectively. The drug loading content can be controlled by tuning the composition of the star polypeptides. The in vitro release studies indicate dual sensitivity enabled rapid drug release at pH 5.5 and 10 mM dithiothreitol (DTT), mimicking the intracellular environment. Furthermore, the star polypeptides are biocompatible and interact well with cells in vitro. Confocal fluorescence microscopy and flow cytometry assays show these star polypeptides can be quickly internalized and effectively deliver the drugs into HeLa cells to inhibit cell growth.
- Wang, Wenlong,Zhang, Liang,Liu, Mengtao,Le, Yuan,Lv, Shanshan,Wang, Jiexin,Chen, Jian-Feng
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- Synthesis of poly(ethylene glycol)/polypeptide/poly(D, L -lactide) copolymers and their nanoparticles
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Core-shell structured nanoparticles of poly(ethylene glycol) (PEG)/polypeptide/poly(D,L-lactide) (PLA) copolymers were prepared and their properties were investigated. The copolymers had a poly(L-serine) or poly(L-phenylalanine) block as a linker between a hydrophilic PEG and a hydrophobic PLA unit. They formed core-shell structured nanoparticles, where the polypeptide block resided at the interface between a hydrophilic PEG shell and a hydrophobic PLA core. In the synthesis, poly(ethylene glycol)-b-poly(L-serine) (PEG-PSER) was prepared by ring opening polymerization of N-carboxyanhydride of O-(tert-butyl)-L-serine and subsequent removal of tert-butyl groups. Poly(ethylene glycol)-b-poly(L-phenylalanine) (PEG-PPA) was obtained by ring opening polymerization of N-carboxyanhydride of L-phenylalanine. Methoxy-poly(ethylene glycol)-amine with a MW of 5000 was used as an initiator for both polymerizations. The polymerization of D,L-lactide by initiation with PEG-PSER and PEG-PPA produced a comb-like copolymer, poly(ethylene glycol)-b-[poly(L-serine)-g-poly(D,L-lactide)] (PEG-PSER-PLA) and a linear copolymer, poly(ethylene glycol)-b-poly(L-phenylalanine)-b-poly(D,L-lactide) (PEG-PPA-PLA), respectively. The nanoparticles obtained from PEG-PPA-PLA showed a negative zeta potential value of -16.6 mV, while those of PEG-PSER-PLA exhibited a positive value of about 19.3 mV. In pH 7.0 phosphate buffer solution at 36 °C, the nanoparticles of PEG/polypeptide/PLA copolymers showed much better stability than those of a linear PEG-PLA copolymer having a comparable molecular weight.
- Lee, Hyunpyo,Park, Jun Beum,Chang, Ji Young
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- Investigation of N-carbamoylamino acid nitrosation by {NO + O2 in the solid-gas phase. Effects of NOx speciation and kinetic evidence for a multiple-stage process
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Nitrosation of N-carbamoylamino acids (CAA) by gaseous NO + O2, an interesting synthetic pathway to amino acid N-carboxyanhydrides (NCA), alternative to the phosgene route, was investigated on N-carbamoyl-valine either in acetonitrile suspension or solventless conditions, and compared to the classical nitrosating system NaNO2 + CF3COOH (TFA), the latter being quite less efficient in terms of either rate, stoichiometric demand, or further tractability of the product. The rate and efficiency of the NO + O2 reaction mainly depends on the O2/NO ratio. Evaluation of the contribution of various nitrosating species (N 2O3, N2O4, HNO2) through stoichiometric balance showed the reaction to be effected mostly by N 2O3 for O2/NO ratios below 0.3, and by N 2O4 for O2/NO ratios above 0.4. The relative contribution of (subsequently formed) HNO2 always remains minor. Differential scanning calorimetry (DSC) monitoring of the reaction in the solid phase by either HNO2 (from NaNO2 + TFA), gaseous N 2O4 or gaseous N2O3, provides the associated rate constants (ca. 0.1, 2 and 108 s-1 at 25°C, respectively), showing that N2O3 is by far the most reactive of these nitrosating species. From the DSC measurement, the latent heat of fusion of N2O3, 2.74 kJ ·mol-1 at -105 °C is also obtained for the first time. The kinetics was investigated under solventless conditions at 0°C, by either quenching experiments or less tedious, rough calorimetric techniques. Auto-accelerated, parabolic-shaped kinetics was observed in the first half of the reaction course, together with substantial heat release (temperature increase of ca. 20°C within 1-2 min in a 20-mg sample), followed by pseudo-zero-order kinetics after a sudden, important decrease in apparent rate. This kinetic break is possibly due to the transition between the initial solid-gas system and a solid-liquid-gas system resulting from water formation. Overall rate constants increased with parameters such as the specific surface of the solid, the O 2/NO ratio, or the presence of moisture (or equivalently the hydrophilicity of the involved CAA), however without precise relationship, while the last two parameters may directly correlate to the increasing acidity of the medium. Copyright
- Lagrille, Olivier,Taillades, Jacques,Boiteau, Laurent,Commeyras, Auguste
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- Complete surface control of peptide nanospheres with detachable and attachable polymer brush layers
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The surfaces of biodegradable peptide nanospheres with density-controllable poly(ethylene glycol) (PEG) brush layers were amenable to high levels of control, from hydrophilic 'stealth' properties to hydrophobic adsorptive properties depending on the PEG density in response to environmental conditions - 'intelligent' properties that are expected to be useful for novel drug delivery systems.
- Waku, Tomonori,Matsumoto, Masahiro,Matsusaki, Michiya,Akashi, Mitsuru
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- Biodegradable hybrid polymer micelles for combination drug therapy in ovarian cancer
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The co-delivery of drug combination at a controlled ratio via the same vehicle to the cancer cells is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and increased therapeutic potency. In an attempt to develop such multidrug vehicle this work focuses on functional biodegradable and biocompatible polypeptide-based polymeric micelles. Triblock copolymers containing the blocks of ethylene glycol, glutamic acid and phenylalanine (PEG-PGlu-PPhe) were successfully synthesized via NCA-based ring-opening copolymerization and their composition was confirmed by 1H NMR. Self-assembly behavior of PEG-PGlu 90-PPhe25 was utilized for the synthesis of hybrid micelles with PPhe hydrophobic core, cross-linked ionic PGlu intermediate shell layer, and PEG corona. Cross-linked (cl) micelles were about 90 nm in diameter (ξ-potential = -20 mV), uniform (narrow size distribution), and exhibited nanogels-like behavior. Degradation of cl-micelles was observed in the presence of proteolytic enzymes (cathepsin B). The resulting cl-micelles can incorporate the combination of drugs with very different physical properties such as cisplatin (15 w/w% loading) and paclitaxel (9 w/w% loading). Binary drug combination in cl-micelles exhibited synergistic cytotoxicity against human ovarian A2780 cancer cells and exerted a superior antitumor activity by comparison to individual drug-loaded micelles or free cisplatin in cancer xenograft model in vivo. Tunable composition and stability of these hybrid biodegradable micelles provide platform for drug combination delivery in a broad range of cancers.
- Desale, Swapnil S.,Cohen, Samuel M.,Zhao, Yi,Kabanov, Alexander V.,Bronich, Tatiana K.
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- Supramolecular hydrogels with reverse thermal gelation properties from (Oligo)tyrosine containing block copolymers
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Novel block copolymers comprising poly(ethylene glycol) (PEG) and an oligo(tyrosine) block were synthesized in different compositions by N-carboxyanhydride (NCA) polymerization. It was shown that PEG2000-Tyr 6 undergoes thermoresponsive hydrogelation at a low concentration range of 0.25-3.0 wt % within a temperature range of 25-50 C. Cryogenic transmission electron microscopy (Cryo-TEM) revealed a continuous network of fibers throughout the hydrogel sample, even at concentrations as low as 0.25 wt %. Circular dichroism (CD) results suggest that better packing of the β-sheet tyrosine block at increasing temperature induces the reverse thermogelation. A preliminary assessment of the potential of the hydrogel for in vitro application confirmed the hydrogel is not cytotoxic, is biodegradable, and produced a sustained release of a small-molecule drug.
- Huang, Jin,Hastings, Conn L.,Duffy, Garry P.,Kelly, Helena M.,Raeburn, Jaclyn,Adams, Dave J.,Heise, Andreas
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- Synthesis of novel copolymer: Poly(p-dioxanone-co-l-phenylalanine)
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In order to expand the application of poly(p-dioxanone) or PPDO in biomedical area, a series of novel copolymers were synthesized successfully by one-step, melted copolymerization of p-dioxanone (PDO) and l-phenylalanine N-carboxyanhydride (l-Phe-NCA) monomers. With the in-feed molar ratio of l-Phe-NCA/PDO equal to 1/20, the conversions of the two kinds of monomers were calculated from 1H NMR. The average molecular weight and polydispersity of the copolymer increase with the increasing reaction time and catalyst concentration. However, the conversions of the two kinds of monomers did not change with the reaction conditions. A three-step mechanism is presented and proved by high resolution 1H NMR and IR spectrums.
- Wang, Bing,Ma, Chi,Xiong, Zuo-Chun,Xiong, Cheng-Dong,Zhou, Quan-Hua,Chen, Dong-Liang
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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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- Self-assembled spin-labeled nanoparticles based on poly(amino acids)
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The development of detectable nanoparticles for controlled drug delivery systems has tremendous practical importance regarding the monitoring of drug pathway in organism. Self-assembly amphiphilic block-copolymer poly(l-glutamic acid)-b-poly(l-phenylalanine) (pGlu-b-pPhe) was chosen for the preparation of discussed nanoparticles. The synthesis of blocks was carried out using ring-opening polymerization (ROP) of N-carboxyanhydrides of mentioned amino acids. To introduce the spin label at C-terminal position of hydrophilic block, (4-amino-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4-amino-TEMPO) was applied as ROP initiator and the polymerization of hydrophobic block was carried out with previously synthesized macroinitiator. The results obtained by transmission electron microscopy clearly showed that TEMPO-pGlu-b-pPhe polymer was really capable to self-assembling in aqueous solutions followed by polymersome formation. The mean size of nanoparticles was increased in a range of TEMPO-pGlu43-b-pPhe12 43-b-pPhe29 43-b-pPhe49 as 60 200 280 nm, respectively. EPR spectroscopy of the solutions of spin-labeled homopolymer TEMPO-p-γ-Glu(Bzl), block copolymers TEMPO-p-γ-Glu(Bzl)-b-pPhe and suspension of polymersomes formed from TEMPO-p-Glu-b-pPhe was performed and the results were compared. It was proved that in the case of nanoparticles EPR detectable spin labels are located on polymersome surface. The experiments in cell culture demonstrated the absence of cytotoxicity of labeled nanoparticles. Additionally, it was shown that TEMPO-label can be detected inside the cell by EPR method.
- Hubina,Pogodaev,Sharoyko,Vlakh,Tennikova
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- An in vivo evaluation of amphiphilic, biodegradable peptide copolymers as siRNA delivery agents
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A series of amphiphilic, biodegradable polypeptide copolymers were prepared for the delivery of siRNA (short interfering ribonucleic acid). The molecular weight (or polymer chain length) of the linear polymer was controlled by reaction stoichiometry for the 11.5, 17.2, and 24.6 kDa polypeptides, and the highest molecular weight polypeptide was prepared using a sequential addition method to obtain a polypeptide having a molecular weight of 38.6 kDa. These polymers were used to prepare polymer conjugate systems designed to target and deliver an apolipoprotein B (ApoB) siRNA to hepatocyte cells and to help delineate the effect of polymer molecular weight or polymer chain length on siRNA delivery in vivo. A clear trend in increasing potency was found with increasing molecular weight of the polymers examined (at a constant polymer:siRNA (w/w) ratio), with minimal toxicity found. Furthermore, the biodegradability of these polymer conjugates was examined and demonstrates the potential of these systems as siRNA delivery vectors.
- Barrett, Stephanie E.,Abrams, Marc T.,Burke, Rob,Carr, Brian A.,Crocker, Louis S.,Garbaccio, Robert M.,Howell, Bonnie J.,Kemp, Eric A.,Kowtoniuk, Robert A.,Latham, Andrew H.,Leander, Karen R.,Leone, Anthony M.,Patel, Mihir,Pechenov, Sergey,Pudvah, Nicole T.,Riley, Sean,Sepp-Lorenzino, Laura,Walsh, Eileen S.,Williams, J. Michael,Colletti, Steven L.
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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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- 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 0063-0065; 0072
(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 0092-0104
(2020/03/26)
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- Co-delivery of Cu(I) chelator and chemotherapeutics as a new strategy for tumor theranostic
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Chelating Cu from tumors has been verified as an effective and promising strategy for cancer therapy through antiangiogenesis. However, systematic removal Cu by injecting with Cu chelators will result unavoidable side effects, since Cu is indispensable to the body. In this work, a micelle targeting to tumors' newborn vessels based on a polypeptide was developed to co-load DOX and Probe X, which can go through an “OFF-to-ON” procedure to report the Cu+-capture events in vivo in a real-time way by giving near infrared (NIR) fluorescence and photoacoustic signal. By co-delivering antiangiogenesis and chemotherapeutic reagents, the tumor can be significantly suppressed, meanwhile with a low systematic toxicity. Hopefully, this work can offer new insights in designing sophisticated antitumor strategy.
- Chen, Hongyi,Chen, Qinjun,Chu, Yongchao,Guo, Qin,Guo, Zhongyuan,Jiang, Chen,Jiang, Liping,Li, Chao,Liu, Peixin,Sun, Tao,Yu, Haijun,Zhang, Guangping,Zhang, Yiwen,Zhang, Yujie,Zhou, Wenxi
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p. 483 - 496
(2020/03/03)
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- Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification
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A novel, broadly applicable method for amide C-N and ester C-O bond formation is presented based on formylpyrrolidine (FPyr) as a Lewis base catalyst. Herein, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group activation, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is distinguished by excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover, high levels of functional group compatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT, yields are considerably improved (for instance from 26 to 91%) and esterification is facilitated for the first time in synthetically useful yields. These significant enhancements are rationalized by activation by means of acid chlorides instead of less electrophilic acid anhydride intermediates.
- Huy, Peter H.,Mbouhom, Christelle
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p. 7399 - 7406
(2019/08/20)
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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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- Highly efficient antibacterial diblock copolypeptides based on lysine and phenylalanine
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A series of amphiphilic diblock copolypeptides (K30-b-F15, K30-b-F30, and K30-b-F45) were synthesized via N-carboxy-α-amino-anhydride ring-opening polymerization. The copolypeptides had excellent antibacterial efficacy to both Gram positive (S. aureus) and Gram negative (E. coli) bacteria. The minimum inhibitory concentrations (MICs) against E. coli and S. aureus are 8?μg?mL?1 and 2?μg?mL?1, respectively, lower than most natural and artificial antimicrobial peptides (AMPs). The morphological changes of the bacteria treated with diblock copolypeptides were investigated by transmission electron microscopy; the results proved that the diblock copolypeptides had a similar antibacterial pore-forming mechanism to natural cationic peptides. This was confirmed by laser scanning confocal microscope images. CCK-8 results and the MICs showed that the diblock copolypeptides have high selectivity to bacteria, which suggested that the diblock copolypeptides could be excellent candidates to replace traditional antibiotics in future.
- Su, Xiaokai,Zhou, Xinyu,Tan, Zhengzhong,Zhou, Chuncai
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- A method of manufacturing an amino acid-N-carboxyanhydride
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PROBLEM TO BE SOLVED: To provide a method for producing an amino acid-N-carboxy anhydride by which the amino acid-N-carboxy anhydride can be synthesized via a series of steps without requiring isolation and purification of an amino acid carbamate being a precursor, midway through production. SOLUTION: The production method includes the steps of: (1) mixing an amino acid (for example, L-valine, L-phenylalanine etc.), an onium salt (for example, tetrabutyl ammonium hydrogensulfate etc.), a carbonate (for example, diphenyl carbonate etc.), water, and an organic solvent (for example, methyl isobutyl ketone etc.), making them react with one another, and preparing a reaction solution; (2) adding an acid for removing a reaction residue originating from the onium salt to the obtained reaction solution; (3) removing water included in the reaction solution to which the acid has been added; (4) heating the reaction solution from which water has been removed; and (5) obtaining the amino acid-N-carboxy anhydride by crystallizing it from the heated reaction solution. COPYRIGHT: (C)2012,JPOandINPIT
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Paragraph 0092
(2016/12/22)
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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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- Multifunctional biocompatible and biodegradable folic acid conjugated poly(ε-caprolactone)-polypeptide copolymer vesicles with excellent antibacterial activities
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Cancer patients after chemotherapy may also suffer bacterial attack due to badly decreased immunity. Although with high bacterial efficacy, conventional antibiotics are prone to inducement of drug resistance and may be not suitable for some cancer patients. In contrast, antibacterial peptides are highly effective in inhibiting bacteria without inducing resistance in pathogens. Presented in this article is a novel kind of highly effective antibacterial peptide-based biocompatible and biodegradable block copolymer vesicle. The copolymer is poly(ε-caprolactone)-block-poly[phenylalanine-stat-lysine-stat-(lysine-folic acid)] [PCL19-b-poly[Phe12-stat-Lys9-stat-(Lys-FA)6]], which can self-assemble into vesicles in aqueous solution. The biocompatible and biodegradable PCL forms the vesicle membrane, whereas the poly[Phe12-stat-Lys9-stat-(Lys-FA)6] block constitutes the vesicle coronas. Compared to the individual polymer chains, the vesicles showed enhanced antibacterial activities against both Gram-positive and Gram-negative bacteria (16 μg mL-1) due to the locally concentrated antibacterial poly[Phe12-stat-Lys9-stat-(Lys-FA)6] coronas, which may avoid the inducement of antibiotic-resistant bacteria and side effects of multidrug interactions. Furthermore, folic acid is introduced into the vesicle coronas for potential further applications such as cancer-targeted drug delivery. Moreover, the amino groups can be further functionalized when necessary. This low cytotoxic, biocompatible, biodegradable, and antibacterial vesicle (without antibiotic resistance) may benefit patients after tumor surgery because it is highly anti-inflammatory, and it is possible to deliver the anticancer drug to tumor cells simultaneously.
- Wang, Mingzhi,Zhou, Chuncai,Chen, Jing,Xiao, Yufen,Du, Jianzhong
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p. 725 - 734
(2015/04/27)
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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 0360; 0361; 0362
(2014/09/29)
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- Synthesis of sterically hindered N-acylated amino acids from N-carboxyanhydrides
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Sterically hindered N-acyl, gem-disubstituted amino acids are easily prepared via the addition of organometallic reagents to N-carboxyanhydrides (NCA). The process tolerates a wide variety of functional groups and allows the synthesis of amide products not readily accessible by traditional acylation chemistry. The existence of an isocyanate intermediate was established by in situ IR spectroscopy.
- Schaefer, Gabriel,Bode, Jeffrey W.
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supporting information
p. 1526 - 1529
(2014/04/03)
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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 0392; 0393
(2013/11/05)
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- SYNTHESIS OF DIAMIDO GELLANTS BY USING AMINO ACID N-CARBOXYANHYDRIDES
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The invention relates to a method for the synthesis of a compound according to formula I comprising the following steps: a) reacting a N-carboxyanhydride according to formula II and a N-carboxy- anhydride according to formula III with a diamine according to formula IV and b) adding an acid to the reaction to adjust the pH value of the reaction to 2-C20 alkyl group, a C6-C20 aryl group, or a C7 -C20 alkylaryl group; and R1 and R2 can be identical or different and represent a hydrogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 thioether group, a C6-C20 aryl group, a C7-C20 alkylaryl group, a C7-C20 alkylhydroxyaryl group, a C4-C20 alkylheteroaryl group with 1 to 4 heteroatoms; or a C1-C4 alkylcarboxylic moiety, which may be an acid, an amide, or which may be esterified with a C1-C6 alkyl group or a C7-C20 alkylaryl group.
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Page/Page column 9; 10
(2014/01/07)
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- Thermosensitive hydrogel from oligopeptide-containing amphiphilic block copolymer: Effect of peptide functional group on self-assembly and gelation behavior
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We reveal that a slight change in the functional group of the oligopeptide block incorporated into the poloxamer led to drastically different hierarchical assembly behavior and rheological properties in aqueous media. An oligo(l-Ala-co-l-Phe-co-β-benzyl l-Asp)-poloxamer-oligo(β-benzyl-l- Asp-co-l-Phe-co-l-Ala) block copolymer (OAF-(OAsp(Bzyl))-PLX-(OAsp(Bzyl))-OAF, denoted as polymer 1), which possessed benzyl group on the aspartate moiety of the peptide block, was synthesized through ring-opening polymerization. The benzyl group on aspartate was then converted to carboxylic acid to yield oligo(l-Ala-co-l-Phe-co-l-Asp)-poloxamer-oligo(l-Asp-co-l-Phe-co-l-Ala) (OAF-(OAsp)-PLX-(OAsp)-OAF, denoted as polymer 2). Characterization of the peptide secondary structure in aqueous media by circular dichroism revealed that the oligopeptide block in polymer 1 exhibited mainly an α-helix conformation, whereas that in polymer 2 adopted predominantly a β-sheet conformation at room temperature. The segmental dynamics of the PEG in polymer 1 remained essentially unperturbed upon heating from 10 to 50 C; by contrast, the PEG segmental motion in polymer 2 became more constrained above ca. 35 C, indicating an obvious change in the chemical environment of the block chains. Meanwhile, the storage modulus of the polymer 2 solution underwent an abrupt increase across this temperature, and the solution turned into a gel. Wet-cell TEM observation revealed that polymer 1 self-organized to form microgel particles of several hundred nanometers in size. The microgel particle was retained as the characteristic morphological entity such that the PEG chains did not experience a significant change of their chemical environment upon heating. The hydrogel formed by polymer 2 was found to contain networks of nanofibrils, suggesting that the hydrogen bonding between the carboxylic acid groups led to an extensive stacking of the β sheets along the fibril axis at elevated temperature. The in vitro cytotoxicity of the polymer 2 aqueous solution was found to be low in human retinal pigment epithelial cells. The low cytotoxicity coupled with the sol-gel transition makes the corresponding hydrogel a good candidate for biomedical applications.
- Chiang, Ping-Ray,Lin, Tsai-Yu,Tsai, Hsieh-Chih,Chen, Hsin-Lung,Liu, Shih-Yi,Chen, Fu-Rong,Hwang, Yih-Shiou,Chu, I-Ming
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p. 15981 - 15991
(2014/04/03)
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- Polypeptide dendrimers: Self-assembly and drug delivery
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Amphiphilic dendritic poly(glutamic acid)-b-polyphenylalanine copolymers were synthesized using generation 3 dendritic poly(glutamic acid) as the macroinitiator in the ring-opening polymerization of NCA-Phe. The block copolymers self-assembled micelles with polyphenylalanine segments as core and dendritic poly(glutamic acid) segments as shell. The biocompatibility of the micelles was studied. The release of the anticancer drug doxorubicin from the micelles was investigated in vitro. The results showed that the sustaining release of the drug could last for 60 h. The micellar drug release system was efficient in inhibiting the proliferation of HepG2 liver cancer cells, 75% cancer cells were killed under appropriate in vitro incubation.
- Xu, Xianghui,Li, Caixia,Li, Haiping,Liu, Rong,Jiang, Chao,Wu, Yao,He, Bin,Gu, Zhongwei
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experimental part
p. 326 - 333
(2012/01/15)
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- Dual-vectors of anti-cancer drugs and genes based on pH-sensitive micelles self-assembled from hybrid polypeptide copolymers
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A series of amphiphilic pH-sensitive hybrid polypeptide copolymers, poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-phenylalanine) (PEG-PLL-PLP) were synthesized. The copolymers could self-assemble into micelles with PLP as the hydrophobic core and PEG-PLL as the hydrophilic shell, as evidenced by 1HNMR and TEM. These micelles exhibited obvious pH response in hydrodynamic diameter and pH-dependent drug release behavior, attributed to the protonation/deprotonation of amino groups in PLL segments. The copolymers could further condense plasmid DNA efficiently. Importantly, the polymer/DNA complexes showed high transfection efficiency in 293T cells under optimized conditions. This study suggested the copolymers may have great potential in both drug and gene delivery. The Royal Society of Chemistry 2011.
- Li, Yong-Yong,Hua, Shou-Hu,Xiao, Wang,Wang, Hui-Yuan,Luo, Xiao-Hua,Li, Cao,Cheng, Si-Xue,Zhang, Xian-Zheng,Zhuo, Ren-Xi
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experimental part
p. 3100 - 3106
(2011/10/08)
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- Revolutionary phosgene-free synthesis of α-amino acid N-carboxyanhydrides using diphenyl carbonate based on activation of α-amino acids by converting into imidazolium salts
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The phosgene-free synthesis of α-amino acid n-carboxyanhydrides using diphenyl carbonate based on activation of α-amino acids by converting into imidazolium salts was reported. 1-Ethyl-3-methylimidazolium bromide (4.77 g, 25.0 mmol) was dissolved in water (25 mL) and was passed through a column of Amberlite IRA 400 CL (50 cm3) using 250 mL of water as an eluent to synthesize amino acid imidazolium salt. A solution of L-phenylalanine imidazolium salt (550 mg, 2.0 mmol) in acetonitrile (15 mL) was added dropwise to a solution of diphenyl-carbonate (427 mg, 2.00 mmol) in acetonitrile (5 mL) at room temperature, and the reaction mixture was stirred at room temperature to synthesize urethane derivative. The results showed that all of the obtained imidazolium salts were soluble in chloroform, dichloromethane, 2-butanone acetonitrile, and not soluble in tetrahydrofuran.
- Koga, Koichi,Sudo, Atsushi,Endo, Takeshi
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experimental part
p. 4351 - 4355
(2011/11/30)
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- Supramolecular hydrogels based on L-phenylalanine derivatives with a positively charged terminal group
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A new hydrogelator based on l-phenylalanine with a long hydrophobic chain and positively charged terminus was synthesized, and its gelation behavior in H2O was investigated. Polarized optical microscopy (POM), field emission scanning electron microscopy (FE-SEM), and X-ray diffraction (XRD) results indicate that the hydrogelator self-assembles into fibres-like aggregates which then lead to the formation of a hydrogel. 1H-NMR and CD spectra of hydrogels and aqueous solution revealed that intermolecular H-bonding between the amide groups was the driving force for gelation. A luminescence study, in which ANS (8-anilinonaphthalene-1-sulfonic acid) was used as a probe, indicated that the hydrophobic interactions between long chains were the driving force for gelation. Consequently, it was proved that the hydrogelator self-assembles into fibre-like aggregates and then forms supramolecular hydrogels through the H-bonding and hydrophobic interactions.
- Fu, Xin-Jian,Zhang, Hua,Zhou, Si-Kai,Liu, Shao-Bing,Guo, Fu-Quan,Wang, Hong,Yang, Ya-Jiang
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scheme or table
p. 158 - 168
(2010/04/01)
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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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- Disulfide-cross-linked PEG-poly(amino acid)s copolymer micelles for glutathione-mediated intracellular drug delivery
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We report biocompatible, cell-permeable core-shell-corona polymer micelles bearing glutathione-cleavable shell cross-links, which allow the facilitated release of entrapped anticancer drugs at cytoplasm in response to an intracellular glutathione level. The Royal Society of Chemistry 2008.
- Koo, Ahn Na,Lee, Hong Jae,Kim, Sung Eun,Chang, Jeong Ho,Park, Chiyoung,Kim, Chulhee,Park, Jae Hyung,Lee, Sang Cheon
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supporting information; experimental part
p. 6570 - 6572
(2009/04/20)
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- A virus-mimetic nanogel vehicle
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Delivering the goods: A pH-sensitive nanogel consists of a hydrophobic copolymer core and two layers of hydrophilic shell (see picture). The core is loaded with a model anticancer drug, doxorubicin (DOX). The nanogel infects tumor cells in a receptor-dependent manner, kills the cells, and migrates to neighboring cells like a virus. BSA = bovine serum albumin, F = folate, PEG = polyethylene glycol. (Figure Presented).
- Lee, Eun Seong,Kim, Dongin,Youn, Yu Seok,Oh, Kyung Taek,Bae, You Han
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p. 2418 - 2421
(2008/12/23)
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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 7
(2008/06/13)
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- Salicylanilide esterification: unexpected formation of novel seven-membered rings
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Novel benzoxazepines were prepared upon esterification of biologically active salicylanilides with some N-protected amino acids. While the desired conjugates of the salicylanilides with the amino acids were obtained when sterically more demanding amino acids were used, benzoxazepines were formed as a result of a seven-exo-trig cyclization in the case of N-protected glycine and alanine. The structures of the products were confirmed by 2D NMR methods, and further transformations of the acyclic conjugates provided additional support for the proposed mechanism of cyclization.
- Imramovsky, Ale?,Vin?ová, Jarmila,Férriz, Juana Monreal,Kune?, Ji?í,Pour, Milan,Dole?al, Martin
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p. 5007 - 5011
(2007/10/03)
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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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- Esterification of amino acids and mono acids using triphosgene
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Alkyl esters of several amino acids and acids were prepared using triphosgene [trichloromethyl carbonate, TPA (2)].
- Rivero,Heredia,Ochoa
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p. 2169 - 2175
(2007/10/03)
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- N-Carboxy-L-phenylalanine anhydride
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The molecules of the title compound, 4-benzyl-1,3-oxazolidene-2,5-dione, C10H9NO3, are linked by intermolecular hydrogen bonds between the imino group of the five-membered ring and an adjacent carbonyl O-atom, along the c axis. The benzyl groups are stacked in a layer and the five-membered rings are arranged in another layer sandwiched by the benzyl group layer. This sandwich structure should explain the high polymerizability of the title compound in the solid state.
- Kanazawa, Hitoshi
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p. 469 - 470
(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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- Syntheses and catalytic activities of new cytochrome P-450 model compounds. Effect of peptide chains
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As cytochrome P-450 model compounds with structures similar to heme proteins, we designed and synthesized novel porphyrin iron (III) chloride complexes, 11 and 12, which have three peptide chains (3PCs) and four peptide chains (4PCs), and evaluated their catalytic activities. The asymmetric porphyrin complexes are derived from etioporphyrin and peptide chains equivalent to proteins were provided by ring-opening polymerization of N-carboxy L-amino acid anhydride (L-Phe-NCA, γ-BLG-NCA, and N(ε)-benzyloxycarbonyl-L-Lys-NCA) initiated by amino groups on meso positions. The new asymmetric porphyrin complex, 11 or 12, was used for asymmetric epoxidations of styrene as is done by cytochrome P-450. The iron complex achieved the induction of asymmetry, although it has no special conformation, and gave S-styrene oxide in excess (ca. 60%ee). It was found, furthermore, that asymmetric induction was affected by the kind of amino acid residue, the number of peptide chains, and length of peptide chains.
- Ohkatsu,Watanabe,Goto,Wakita
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p. 742 - 747
(2007/10/02)
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- New routes to 1,4-benzodiazepin-2,5-diones
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1,4-benzodiazepin-2,5-diones have been synthesized in good overall yields by two routes, the first one by cyclisation of dipeptides prepared from Boc anthranilic acid and α-amino acid methyl esters, the second one by reaction of N-carboxy α-amino acid anhydrides with Boc anthranilic acid.
- Akssira,Boumzebra,Kasmi,Dahdouh,Roumestant,Viallefont
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p. 9051 - 9060
(2007/10/02)
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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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- 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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