- Remarkable Salt Effects in the Highly Enhanced Enantioselective Hydrolysis of Amino Acid Esters with the Active Tripeptide in the Vesicular System
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The remarkably high enantioselectivity (kLa,obsd/kDa,obsd = 67) was attained along with the large rate-enhancement of the L-form substrate for the hydrolytic cleavage of N-dodecanoyl-D(L)-Phe-PNP by controlling the ionic strength ( = 0.03 M, 1 M = 1 mol dm-3) in the vesicular system.
- Goto, Koichi,Imamura, Chikara,Yamamoto, Shinichi,Matsumoto, Yoko,Ueoka, Ryuichi
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- Enantioselective ester hydrolysis by an achiral catalyst co-embedded with chiral amphiphiles into a vesicle membrane
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Co-embedding of an amphiphilic non-chiral hydrolysis catalyst with amphiphilic chiral additives into the membrane of a phospholipid vesicle induces different rates of ester hydrolysis for enantiomeric amino acid esters.
- Poznik,K?nig
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- Steric-control for the enantioselective hydrolysis of amino acid esters with membrane-bound enzyme models
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The apparently complete stereoselectivity (K(L)(a,obsd)/k(D)(a,obsd)=(∞) for the hydrolysis of enantiomeric substrate (p-nitrophenyl n-dodecanoyl-D(L)-phenyalaninate; C(t2)-D(L)-Phe-PNP) catalyzed by active tripeptide (N-(benzyloxycarbonyl)-L-phenylalanyl-L- histidyl-L-leucine; Z-PheHisLeu) was attained by regulating the composition of coaggregates, ionic strength, and temperature, in coaggregate systems composed of vesicular and micellar surfactants. This can be related to the optimization of conformation in the Z-PheHisLeu catalyst to react with amino acid esters by changing of physical properties of coaggregates.
- Tanoue, Osamu,Baba, Manabu,Tokunaga, Yusuke,Goto, Koichi,Matsumoto, Yoko,Ueoka, Ryuichi
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- CHEMICAL UNCOUPLERS OF RESPIRATION AND METHODS OF USE THEREOF
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Uncoupling of respiration is a well-recognized process that increases respiration and heat production in cells. Provided herein are chemical uncouplers of respiration that are compounds of Formula (I). Also provided are methods for preventing or treating metabolic disorders and modulating metabolic processes using compound of Formula (I).
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Paragraph 0246; 0249; 0262
(2020/11/27)
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- In search of bioinspired hydrogels from amphiphilic peptides: A template for nanoparticle stabilization for the sustained release of anticancer drugs
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The development of potent stimuli-responsive hydrogels has rapidly expanded in the last decades due to their diversified applications in the field of biomedicines. In accordance with this drift, herein, we aimed at modulating a series of amphiphilic peptide analogues with the general formula Me-(CH2)14-CO-NH-CH(X)-COOH, where X = CH2Ph in hydrogelators I (l-Phe) and II (d-Phe) and X = CH2Ph(OH) in hydrogelator III (l-Tyr), which displayed an excellent propensity to immobilize water at room temperature with a minimum gelation concentration of 0.04%/0.05%/0.02% w/v for hydrogelators I-III, respectively, regardless of their configuration at the C-terminal centre. To validate this threshold concentration difference, we performed computational analysis that demonstrated the ability of the side-chains of hydrogelators I and III to remain highly planar with the methylene units of the amphiphile and aromatic rings, promoting favourable correspondence through van der Waals forces and pi-pi stacking. Consequently hydrogelators I and III self-assembled in an ordered organisation superior to hydrogelator II. Furthermore, the spectroscopic and microscopic experiments revealed that the hydrogelators manifested a β-sheet conformation and nanofibrous morphology at the supramolecular level. As observed visually and additionally confirmed by differential scanning calorimetry (DSC) and rheological measurements, the hydrogels exhibited thermo-reversibility, injectability and high mechanical strength. Importantly, these biomaterials were also found to be resistant towards proteolytic degradation and non-cytotoxic in the cell line HEK 293 using a dose-dependant cell viability assay. To date, the development of a structured approach for the release of drugs in a predictable manner from an optimised formulation, using peptide-based hydrogel nanoparticles as a delivery system remains in its infancy. Hence, we developed hydrogel nanoparticles (HNPs) with our fabricated amphiphilic peptides that exploited the weak noncovalent interactions for their fabrication, unlike other cross-linked polymers that require strong covalent or ionic bonds for their formation. Interestingly, the as-synthesized nanoparticles showed an unprecedented ability to release the anticancer drugs 5-fluoro uracil/doxorubicin at physiological conditions depending on the physico-chemical parameters of the drugs. We believe that the reported injectable, biocompatible, amphiphilic peptide-based hydrogels hold future promise as a potential tool to transport drugs to a targeted site at a greater concentration, thus relieving the patient from surgical injury and simultaneously aiding in a faster recovery.
- Mehra, Radha Rani,Tiwari, Priyanka,Basu, Anindya,Duttkonar, Anita
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p. 11666 - 11678
(2019/07/31)
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- Discovery of Hydrolysis-Resistant Isoindoline N -Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration
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N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice.
- Lin, Hua,Long, Jonathan Z.,Roche, Alexander M.,Svensson, Katrin J.,Dou, Florence Y.,Chang, Mi Ra,Strutzenberg, Timothy,Ruiz, Claudia,Cameron, Michael D.,Novick, Scott J.,Berdan, Charles A.,Louie, Sharon M.,Nomura, Daniel K.,Spiegelman, Bruce M.,Griffin, Patrick R.,Kamenecka, Theodore M.
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supporting information
p. 3224 - 3230
(2018/04/23)
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- COMPOSITIONS IN THE FORM OF AN INJECTABLE AQUEOUS SOLUTION COMPRISING AMYLIN, AN AMYLIN RECEPTOR AGONIST OR AN AMYLIN ANALOG, AND A CO-POLYAMINO ACID
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An injectable aqueous solution, of which the pH is from 6.0 to 8.0, comprising at least: a) amylin, an amylin receptor agonist or an amylin analog; b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic radicals Hy having the following formula I: [in-line-formulae]?GpR?r?GpA?a?GpC)p ??I[/in-line-formulae] wherein the composition does not comprise a basal insulin of which the isoelectric point pI is from 5.8 to 8.5. It also relates to a composition wherein it moreover comprises a prandial insulin.
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Paragraph 0543-0546; 0623-0626
(2018/07/31)
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- Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
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An injectable aqueous solution, the pH of which is from 6.0 to 8.0, having at least: a) human glucagon, and b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy. In an embodiment, the compositions have, in addition, a gastrointestinal hormone.
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Paragraph 0554; 0555; 0556; 0557; 0635; 0636; 0637; 638
(2018/01/09)
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- METHODS FOR IDENTIFICATION, ASSESSMENT, PREVENTION, AND TREATMENT OF METABOLIC DISORDERS USING PM20D1 AND N-LIPIDATED AMINO ACIDS
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The present invention relates to methods for identifying, assessing, preventing, and treating metabolic disorders and modulating metabolic processes using PM20D1 and N- lipidated amino acids.
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Page/Page column 129; 130
(2017/05/17)
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- Preparation of dual responsive low-molecular-weight hydrogel for long-lasting drug delivery
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A novel low-molecular-weight hydrogel (LMWG) was fabricated by oligopeptide and phenylboronic acid to obtain a smart molecular hydrogel with dual glucose and pH response for long-term drug delivery in this study. Dual glucose and pH responsiveness of the blank molecular hydrogel was first evaluated by on-line tracking the dynamics curves using UV spectroscopy. Model drugs of phenformin for antidiabetes and doxorubicin for anticancer were selected to evaluate the drug carry and glucose/pH responsive drug release of the molecular hydrogel. The results showed the drug-loaded LMWG had good sustaining and long-lasting drug delivery in physiological or pathological environment.
- Tao, Ning,Li, Guotao,Liu, Miaochang,Gao, Wenxia,Wu, Huayue
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p. 3173 - 3180
(2017/05/08)
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- Structure-activity relationship study of syringolin A as a potential anticancer agent
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A detailed structure-activity relationship of syringolin A (1), which is a promising antitumor natural product, was described. We previously developed syringolin A analog 2 as a potent proteasome inhibitor by the structure-based drug design of syringolin A. In this Letter, we synthesized a range of analogs of 2, having a different length of the lipophilic chain and substituted aryl group, and their cytotoxicity against human cancer cells was evaluated. It turned out that these modifications greatly affected the cytotoxicity. Further optimization would lead to develop a novel proteasome inhibitor.
- Chiba, Takuya,Matsuda, Akira,Ichikawa, Satoshi
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supporting information
p. 4872 - 4877
(2015/10/28)
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- Self-assembly of azobenzene-based two-component gels
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An azobenzene derivative was found to form a two-component gelator with lauroyl or stearoyl phenylalanine although phenylalanine units failed to gel the solvent. During gelation, the yellow sols turned into red gels, implying a sharp color change in the system. In gel, molecules self-assembled into one-dimensional nanofibers. Circular dichroism spectral results indicated that the chirality of phenylalanine was passed on to the azobenzene moiety, which formed a right-handed helical stacking in the gel phase. UV-vis experiments and NMR spectra revealed that the azobenzene derivative and lauroyl phenylalanine formed a complex with a ratio of 1:4. The critical gelation concentrations and gel-to-sol phase transition temperatures were dependent on the ratio of the two compounds. Moreover, the response of two-component gels to mechanical stimulus could result in a gel-to-sol transition. The gels can again self-heal after resting, which is a process that can be reversed numerous times. This journal is
- Zhang, Yuan,Xue, Pengchong,Yao, Boqi,Sun, Jiabao
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p. 5747 - 5753
(2015/01/08)
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- Molecular mechanism of physical gelation of hydrocarbons by fatty acid amides of natural amino acids
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A variety of fatty acid amides of different naturally occurring l-amino acids have been synthesized and they are found to form gels with various hydrocarbons. The gelation properties of these compounds were studied by a number of physical methods including FTIR spectroscopy, X-ray diffraction, scanning electron microscopy, differential scanning calorimetry, rheology, and it was found that gelation depended critically on the fatty acid chain length and the nature of the amino acid. Among them l-alanine based gelators were found to be the most efficient and versatile gelators as they self-assemble into a layered structure to form the gel network. Mechanisms for the assembly and formation of gels from these molecules are discussed.
- Pal, Asish,Ghosh, Yamuna K.,Bhattacharya, Santanu
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p. 7334 - 7348
(2008/02/04)
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- Isolation and total synthesis of gymnastatin N, a POLO-like kinase 1 active constituent from the fungus Arachniotus punctatus
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A high throughput screen against POLO-like kinase 1 (Plk1), an anti-cancer target, identified an active extract from the fungus Arachniotus punctatus. Bioassay guided fractionation led to the isolation of the new natural product, gymnastatin N (1) and the known compound aranorosinol A (2) with IC50 values of 13 and 118 μM, respectively. A 12′-hydroxy analog of gymnastatin N, 3, was also isolated as a minor component. Gymnastatin N (1) was found to be a 52:48 mixture of (1S,6′R) and (1R,6′R) diastereomers, by synthesis of the four possible diastereomers and comparison of the optical rotation and chiral HPLC profile of each diastereoisomer with the natural product. Analogues of 1 were synthesized and evaluated against the Plk1 assay and these SAR studies suggested that the diene and free carboxylic acid moieties might be responsible for its bioactivity. Graphical Abstract.
- Phoon, Chee Wee,Somanadhan, Brinda,Heng, Sabrina Cher Hui,Ngo, Anna,Ng, Siew Bee,Butler, Mark S.,Buss, Antony D.,Sim, Mui Mui
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p. 11619 - 11628
(2007/10/03)
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- Steric-control for the enantioselective hydrolysis of amino acid esters in hybrid membrane systems.
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The enantioselective hydrolysis of the amino acid esters, p-nitrophenyl-N-dodecanoyl-D(L)-phenylalaninates (C(12)-D(L)-Phe-PNP) catalyzed by active tripeptide, N-(benzyloxycarbonyl)-L-phenylalanyl-L-histidyl-L-leucine (Z-PheHisLeu) in the presence of coag
- Tanoue, Osamu,Ichihara, Hideaki,Goto, Koichi,Matsumoto, Yoko,Ueoka, Ryuichi
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p. 224 - 226
(2007/10/03)
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- Fairly marked enantioselectivity for the hydrolysis of amino acid esters by chemically modified enzymes
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The hydrolysis (deacylation) of enantiomeric substrates by the chemically modified enzymes decanoyl-α-chymotrypsin and decanoyl-trypsin was studied. Reaction activity for decanoyl-α-chymotrypsin was lower than that for the native enzyme, although intriguingly the enantioselectivity was markedly enhanced as compared with the native enzyme. In particular, the apparently complete enantioselective catalysis was attained for the hydrolytic cleavage of p-nitrophenyl N-dodecanoyl- D(L)-phenylalaninates. The enhancement of enantioselectivity, however, was not observed for decanoyl-trypsin. These results suggest that the chemically modified α-chymotrypsin by addition of hydrophobic groups has promoted enantioselectivity for the hydrolysis of hydrophobic esters.
- Yano, Yoshihiro,Shimada, Kenji,Okai, Jiro,Goto, Koichi,Matsumoto, Yoko,Ueoka, Ryuichi
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p. 1314 - 1318
(2007/10/03)
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- Self-assembled organogels formed by mono-chain L-alanine derivatives
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The mono-chain L-alanine derivatives self-assemble into bilayer aggregates in a number of organic liquids and gelatinize the liquids.
- Luo,Liu,Liang
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p. 1556 - 1557
(2007/10/03)
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- Synthesis of novel chiral lipophilic pyridyl-containing β-amino alcohol ligands and enantioselective hydrolysis of α-amino acid esters by chiral metallomicelles
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Seven novel chiral lipophilic pyridyl-containing β-amino alcohol ligands have been synthesized by coupling of 6-alkoxymethyl-2- chloromethylpyridine 3 with the corresponding chiral β-amino alcohols or L- cysteine. Their metal ion complexes have been inves
- You, Jingsong,Yu, Xiaoqi,Liu, Ke,Tao, Lin,Xiang, Qingxiang,Xie, Rugang
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p. 243 - 254
(2007/10/03)
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- Enantioselective hydrolysis of long chain α-amino acid esters by chiral sulfur-containing macrocyclic metallomicelles
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A novel chiral lipophilic sulfur-containing macrocyclic ligand 5 with bis-pendant alcohols in the proximity of the coordination center has been synthesized. Its metal ion complexes have been investigated as catalysts for the enantioselective hydrolysis of long chain α-amino acid esters in aqueous comicellar solution with Brij35. Large rate accelerations (up to 220 times) and moderate enantioselectivities (up to 4.85 (k(S)/k(R))) employing the macrocyclic 5-Cu2+ have been observed, whereas the acyclic 3-Cu2+ exhibits less reactivity and stereoselectivity. Taking the analogous ligand 4, lacking the hydroxy groups leads to a dramatic rate decrease, and an inversion of enantioselectivity is observed. The pKa value of the hydroxyl bound to Cu2+ is determined to be pKa=7.2 under our micellar reaction conditions.
- You, Jingsong,Yu, Xiaoqi,Li, Xingshu,Yan, Qianshun,Xie, Rugang
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p. 1197 - 1203
(2007/10/03)
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- Mechanism of Enantioselective Ester Cleavage by Histidine-Containing Dipeptides at a Micellar Interface
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Chiral p-nitrophenyl esters derived from the amino acid phenylalanine are cleaved by histidine-containing dipeptides at a micellar interface.High enantioselectivities (up to kL/kD = 30.4 at 0 deg C) are observed.Both the substrates and the catalysts contain an alternating sequence of hydrophobic and hydrophilic groups.Due to the need for hydration of the hydrophilic groups, the hydrophobic groups cannot dissolve completely into the micellar hydrocarbon phase.The kinetic data suggest that the micellar interface is capable of discriminating between transition states that have different hydrophilic and hydrophobic properties.One of the diastereomeric transition states is characterized by a hydrogen bond between the amide CO group of the ester and an NH group of the histidine-containing dipeptide.Upon formation of this hydrogen bond these polar CO and NH groups lose their hydrophilicity which allows the transfer of the adjacent apolar groups to the micellar hydrocarbon phase.The other diastereomeric transition state cannot form this hydrogen bond and the hydrophobic groups remain hydrated.Consequently, the latter transition state is of higher energy.The kinetic data reveal that it is important to prevent steric hinderance between the reactants in order to allow the unhindered formation of the hydrogen bond.
- Cleij, Marco C.,Drenth, Wiendelt,Nolte, Roeland J. M.
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p. 3883 - 3891
(2007/10/02)
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- Membrane Matrix for the Hydrolysis of Amino Acid Esters with Marked Enantioselectivity
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The stereoselective hydrolysis of the long-chain substrate (p-nitrophenyl n-dodecanoyl-D(L)-phenylalaninate, D(L)-S12) in surfactant aggregates has been found to be easily controlled by changing the reaction temperature, amino acid sequence in peptide cat
- Ueoka, Ryuichi,Matsumoto, Yoko,Moss, Robert A.,Swarup, Shanti,Sugii, Atsushi,et al.
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p. 1588 - 1595
(2007/10/02)
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- MARKED CHANGES IN THE CIRCULAR DICHROISM OF THE TRIPEPTIDE CATALYST RELATED TO ENHANCHED ENANTIOSELECTIVE HYDROLYSIS IN MICELLAR SYSTEMS
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The enantioselectivity for the hydrolytic cleavage of p-nitrophenyl N-dodecanoyl -D(L)-phenylalaninates in the micellar systems was augmented by using the active tripeptide (Z-L-Phe-L-His-L-Leu), which showed an α-helix-like CD curve, combined with a mark
- Ueoka, Ryuichi,Matsumoto, Yoko,Nagamine, Katsuyuki,Yasui, Hidehisa,Harada, Kumiko,Sugii, Atsushi
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p. 3070 - 3073
(2007/10/02)
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- Aggregation Behavior of Amphiphiles Functionalized with Dipeptide Segments and Enantioselective Ester Hydrolysis in Their Bilayer Membranes
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Four amphiphiles having dipeptide segments, which consist of one histidyl residue and another amino acid residue, and the dihexadecyl moiety for the double-chain segment (N+C5AlaHis2C16, N+C5LeuHis2C16, N+C5PheHis2C16, and N+C5HisAla2C16) were synthesized, and the aggregate morphology of them was characterized by electron microscopy and differential scanning calorimetry.The amphiphiles, which have the histidyl residue bound to the dihexadecylamine component (N+C5AlaHis2C16, N+C5LeuHis2C16, and N+C5PheHis2C16) formed both multi- and single-walled aggregates in the aqueous dispersion state, while their sonicated solutions involved only single-walled vesicles.On the other hand, the amphiphile, which has the alanyl residue bound to the dihexadecylamine component (N+C5HisAla2C16) afforded tubular aggregates in the aqueous dispersion.The hydrolysis of enantiomeric esters of various hydrophobic nature, which was carried out in the single-walled vesicles, showed relatively small enantioselectivity.The reasons for such catalytic performance of the vesicles were discussed from the kinetic and mechanistic viewpoints; the kinetic analysis being carried out on the basis of the organic pseudo-phase concept.
- Murakami, Yukito,Nakano, Akio,Ikeda, Hidetsugu,Imori, Toru,Akiyoshi, Kazunari
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p. 172 - 180
(2007/10/02)
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- MARKED TEMPERATURE EFFECT ON THE ENANTIOSELECTIVE HYDROLYSIS IN ARTIFICAL MEMBRANES
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The enantioselectivity was markedly elevated at temperatures somewhat higher than the phase transitions for the hydrolysis of hydrophobic amino acid esters (p-nitrophenyl N-dodecanoyl-D(L)-phenylalaninate by a hydrophobic dipeptide (tetradecanoyl-L-histidyl-L-leucine) in the artificial membrane (dialkyldimethylammonium bromides) systems.
- Ueoka, Ryuichi,Matsumoto, Yoko,Nagamatsu, Toshiro,Hirohata, Shoichi
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p. 583 - 586
(2007/10/02)
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- STUDIES ON THERMODYNAMICS FOR THE HYDROLYSIS. II. THE TEMPERATURE EFFECT ON THE STEREOSELECTIVE DEACYLATION OF AMINO ACID ESTERS IN BILAYER AND MICELLAR SYSTEMS.
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Stereoselective deacylations of p-nitrophenyl N-acyl-D(or L)-phenylalaninates(D(or L)-S//n; n equals 2, 12, and 16) and N-benzyloxycarbonyl-D(L)-phenylalaninates(D(L)-ZS) by the bilayer and micellar catalytic systems of L-histidine derivatives (LauHis, My
- Matsumoto,Ueoka
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p. 3370 - 3375
(2007/10/02)
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- Dermatological compositions containing an acylamino-carboxylic acid or an alkyl ester thereof
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Topical dermatological compositions containing an acylamino-carboxylic acid compound of the formula STR1 wherein R1 is hydrogen, alkyl of 1 to 3 carbon atoms, trifluoromethyl, phenyl, halo-phenyl, nitro-phenyl or biphenylyl, R2 is hydrogen or alkyl of 1 to 3 carbon atoms, R3 is hydrogen, alkyl of 1 to 6 carbon atoms, methylthio-(alkyl of 1 to 6 carbon atoms) or benzyl, R4 is alkyl of 10 to 22 carbon atoms, n is 0, 1 or 2, R5 is alkyl of 8 to 22 carbon atoms, phenyl or biphenylyl, and R6 is hydrogen or alkyl of 1 to 3 carbon atoms; the compositions are useful for the care of the skin.
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