- A novel phenylalanine ammonia-lyase from Pseudozyma antarctica for stereoselective biotransformations of unnatural amino acids
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A novel phenylalanine ammonia-lyase of the psychrophilic yeast Pseudozyma antarctica (PzaPAL) was identified by screening microbial genomes against known PAL sequences. PzaPAL has a significantly different substrate binding pocket with an extended loop (26 aa long) connected to the aromatic ring binding region of the active site as compared to the known PALs from eukaryotes. The general properties of recombinant PzaPAL expressed in E. coli were characterized including kinetic features of this novel PAL with L-phenylalanine (S)-1a and further racemic substituted phenylalanines rac-1b-g,k. In most cases, PzaPAL revealed significantly higher turnover numbers than the PAL from Petroselinum crispum (PcPAL). Finally, the biocatalytic performance of PzaPAL and PcPAL was compared in the kinetic resolutions of racemic phenylalanine derivatives (rac-1a-s) by enzymatic ammonia elimination and also in the enantiotope selective ammonia addition reactions to cinnamic acid derivatives (2a-s). The enantiotope selectivity of PzaPAL with o-, m-, p-fluoro-, o-, p-chloro- and o-, m-bromo-substituted cinnamic acids proved to be higher than that of PcPAL.
- Varga, Andrea,Csuka, Pál,Sonesouphap, Orlavanah,Bánóczi, Gergely,To?a, Monica Ioana,Katona, Gabriel,Molnár, Zsófia,Bencze, László Csaba,Poppe, László,Paizs, Csaba
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p. 185 - 194
(2020/04/28)
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- Investigation of Taniaphos as a chiral selector in chiral extraction of amino acid enantiomers
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Finding chiral selector with high stereoselectivity to a variety of amino acid enantiomers remains a challenge and warrants further research. In this work, Taniaphos, a chiral ligand with rotatable spatial configuration, was employed as a chiral extractant to enantioseparate various amino acid enantiomers. Phenylalanine (Phe), homophenylalanine (Hphe), 4-nitrophenylalanine (Nphe), and 3-chloro-phenylglycine (Cpheg) were used as substrates to evaluate the extraction efficiency. The results revealed that Taniaphos-Cu exhibited good abilities to enantioseparate Phe, Hphe, Nphe, and Cpheg with the highest separation factors (α) of 3.13, 2.10, 2.32, and 2.14, respectively. Taniaphos-Cu is more conducive to combine with D-amino acid in extraction. The influences of pH, Taniaphos-Cu, and concentration and extraction temperature on extraction were comprehensively evaluated. The highest performance factors (pf) for Phe, Hphe, Nphe, and Cpheg at optimal extraction conditions were 0.08892, 0.1250, 0.09621, and 0.08021, respectively. The recognition mechanism between Taniaphos-Cu and amino acid enantiomers was discussed. The coordination interaction between Taniaphos-Cu and -COO?, π-π interaction between Taniaphos-Cu and amino acid enantiomers are important acting forces in chiral extraction. The steric-hindrance between -NH2 and -OH lead to Taniaphos-Cu-D-Phe is more stable than Taniaphos-Cu-L-Phe. This work provided a chiral extractant that has good abilities to enantioseparate various amino acid enantiomers.
- Xiao, Wenjie,Chen, Shuhuan,Liu, Xiong,Ma, Yu
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p. 292 - 302
(2021/03/29)
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- A PROCESS FOR THE SYNTHESIS OF MELPHALAN
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The invention relates to a process for the preparation of Melphalan (4-[bis(2-5 chloroethyl)amino]-L-phenylalanine of formula (I) said process comprising the reaction of a 4-amino-L-phenylalanine protected at the carboxy and amino aminoacidic groups with an agent able to convert the aromatic amino group into a group of formula: -N(CH2CH2OS(O)nO-)2, wherein n is 1 or 2 followed by conversion of the –-N(CH2CH2OS(O)nO-)2 group into a -N(CH2CH2Cl)2 group. The invention also provides novel intermediates useful for the preparation of Melphalan.
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Page/Page column 13
(2021/07/02)
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- Self-assembling behaviour of a modified aromatic amino acid in competitive medium
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Aromatic amino acid, specifically phenylalanine (Phe), is one of the most studied building blocks in peptide synthesis due to its importance in biology. It is reported in the literature that Phe-containing peptides have a high tendency to form different self-assembled materials due to efficient aromatic-aromatic interactions. In this article, we have tuned the supramolecular interactions of phenylalanine by making it electron-deficient upon introduction of the nitro group in the ring. The presence of the nitro group has a profound influence on the self-assembly process. It has been observed that 4-nitrophenylalanine (4NP) is a highly efficient gelator compared with the native phenylalanine in DMSO solvent in terms of minimum gelation concentration and it forms hydrogen bonding mediated crystals in water. The change of self-assembling patterns of 4NP in these solvents was studied using X-ray diffraction, UV-Vis spectroscopy, FE-SEM and other techniques. With the help of different experimental data and density functional theory (DFT), we have simulated the theoretical structure of 4NP in DMSO. The theoretical structure of 4NP in DMSO is different compared with that of crystals in water. We then studied the self-assembly process of 4NP in the mixed solvent of DMSO (polar aprotic) and water (polar protic). Different competitive non-covalent interactions of solvents as well as the ratio of the solvent mixture guide the final self-assembly state of 4NP. This journal is
- Aswal, Vinod K.,Misra, Souvik,Mondal, Sanjoy,Nanda, Jayanta,Ray, Debes,Sepay, Nayim,Singh, Pijush
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p. 6599 - 6607
(2020/08/03)
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- Bi-enzymatic Conversion of Cinnamic Acids to 2-Arylethylamines
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The conversion of carboxylic acids, such as acrylic acids, to amines is a transformation that remains challenging in synthetic organic chemistry. Despite the ubiquity of similar moieties in natural metabolic pathways, biocatalytic routes seem to have been overlooked for this purpose. Herein we present the conception and optimisation of a two-enzyme system, allowing the synthesis of β-phenylethylamine derivatives from readily-available ring-substituted cinnamic acids. After characterisation of both parts of the reaction in a two-step approach, a set of conditions allowing the one-pot biotransformation was optimised. This combination of a reversible deaminating and irreversible decarboxylating enzyme, both specific for the amino acid intermediate in tandem, represents a general method by which new strategies for the conversion of carboxylic acids to amines could be designed.
- Weise, Nicholas J.,Thapa, Prasansa,Ahmed, Syed T.,Heath, Rachel S.,Parmeggiani, Fabio,Turner, Nicholas J.,Flitsch, Sabine L.
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p. 995 - 998
(2020/01/21)
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- Nitration of Tyrosine in the Mucin Glycoprotein of Edible Bird's Nest Changes Its Color from White to Red
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The edible bird's nest (EBN) of the swiftlet Aerodramus fuciphagus, a mucin glycoprotein, is usually white in color, but there also exist the more desirable red or "blood" EBN. The basis of the red color has been a puzzle for a long time. Here, we show that the nitration of the tyrosyl residue to the 3-nitrotyrosyl (3-NTyr) residue in the glycoprotein is the cause of the red color. Evidence for the 3-NTyr residue comes from (a) the quantitative analysis of 3-NTyr in EBN by enzyme-linked immunosorbent assay, (b) the ultraviolet-visible absorption spectra of red EBN as a function of pH being similar to 3-nitrotyrosine (3-NT), (c) the change in the color of red EBN from yellow at low pH to red at high pH just like 3-NT, and (d) strong Raman nitro bands at 1330 cm-1 (symmetric -NO2 stretch) and 825 cm-1 (-NO2 scissoring bend) for red EBN. The high concentrations of nitrite and nitrate in red EBN are also explained.
- Shim, Eric Kian-Shiun,Lee, Soo-Ying
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p. 5654 - 5662
(2018/05/30)
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- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
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A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
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p. 1067 - 1078
(2018/08/01)
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- Chiral GAP catalysts of phosphonylated imidazolidinones and their applications in asymmetric Diels-Alder and Friedel-Crafts reactions
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The design and synthesis of recyclable imidazolidinone catalysts using GAP chemistry/technique was described. Their applications in asymmetric Diels-Alder and Friedel-Crafts reactions with α,β-unsaturated aldehydes resulted in excellent yields and higher enantioselectivities than previous processes. As recyclable small molecular catalysts, phosphonylated imidazolidinones can be recovered and reused for up to three runs without costing significant decrease in catalytic activity.
- Qiao, Shuo,Mo, Junming,Wilcox, Cody B.,Jiang, Bo,Li, Guigen
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supporting information
p. 1718 - 1724
(2017/02/23)
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- An Optically Active Polymer for Broad-Spectrum Enantiomeric Recognition of Chiral Acids
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Recognition of enantiomers of chiral acids by anion–π or lone pair–π interactions has not yet been investigated but is a significant and attractive challenge. This study reports an optically active polymer-based supramolecular system with capabilities of discriminating enantiomers of various chiral acids. The polymer featuring alternate π-acidic naphthalenediimides (NDIs) and methyl l-phenylalaninates in the backbone exhibits an unprecedented slow self-assembly process that is susceptible to perturbation by various chiral acids. Thus, the combination of anion–π or lone pair–π interactions and sensitivity of the polymeric self-assembly process to external chiral species endows the system with recognition capabilities. This is the first time that anion–π or lone pair–π interactions have been applied in the recognition of enantiomers of various chiral acids with a single system. The results shed light on new strategies for material design by integrating π-acidic aromatic systems and chiral building blocks to afford relevant advanced functions.
- Yan, Jijun,Kang, Chuanqing,Bian, Zheng,Ma, Xiaoye,Jin, Rizhe,Du, Zhijun,Gao, Lianxun
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supporting information
p. 5824 - 5829
(2017/04/28)
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- Supramolecular self-assembly of chiral polyimides driven by repeat units and end groups
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Pyromellitic diimides (PMDIs) are effective building blocks for the construction of supramolecular systems but are infrequently used in comparison with other electron-deficient aromatic systems. We report PMDI-based chiral polyimides that form polymeric supramolecular systems with unique self-assembly features that show time-dependent spectroscopic behaviour. Extensive investigations revealed the driving forces for the self-assembly of the polyimides. One is the complementary aromatic π-π stacking between electron-accepting PMDI and electron-donating phenyl ring in the polymer backbones, and another is the hydrogen bonding interactions of the end groups. The self-assembly is readily disrupted by guest molecules with strong associations with the PMDI and the end groups. The introduction of flexible arylether diimides into the PMDI-based copolymer backbones and the sequence of PMDIs and arylether diimides in the copolymer backbones significantly influence the self-assembly of the polyimides. The results elucidate the mechanisms of polymeric self-assembly of chiral polyimides, providing important information for the development of materials based on polymeric supramolecular systems with properties and functions regulated by composition, sequence and end groups.
- Yan, Jijun,Kang, Chuanqing,Bian, Zheng,Jin, Rizhe,Ma, Xiaoye,Gao, Lianxun
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supporting information
p. 14723 - 14729
(2017/11/28)
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- Specific molecular marked heavy-metal chelating agent, corresponding rapid chromatographic detection card and application
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The invention relates to a specific molecular marked heavy-metal chelating agent, corresponding detection technologies and application. The heavy-metal chelating agent disclosed by the invention is metal chelating molecules marked by specific marking molecules; after being combined with heavy metal, one ends of the molecules can be identified and captured by an antibody; the marking molecules at the other ends are combined with a corresponding ligand or antibody; therefore, sandwich detection is realized; and the detection technologies comprise an enzyme-linked immune technology and a rapid paper chromatographic technology. By means of the specific molecular marked heavy-metal chelating agent, the corresponding detection technologies and application disclosed by the invention, rapid sandwich detection on metal ion can be realized for the first time; requirements of conventional heavy-metal detection on an expensive instrument can be avoided; and thus, disadvantages of the sensitivity and the specificity of a competition-method heavy-metal rapid detection card can be made up.
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-
Paragraph 0030; 0031; 0039; 0040
(2017/08/28)
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- Synthesis of new tetrazolyl derivatives of L- and D-phenylalanine
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New tetrazolyl derivatives of L- and D-phenylalanine were synthesized by azidation of n-propyl esters of (2S)- and (2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(4-aminophenyl)propionic acids and by a series of subsequent chemical transformations. The structure and individuality of the compounds obtained were confirmed by using a complex of spectral and chromatographic methods.
- Tolstyakov,Tolstobrova,Zarubina,Popova,Protas,Chuprun,Trifonov
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p. 1681 - 1685
(2017/01/28)
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- An unusual peroxo intermediate of the arylamine oxygenase of the chloramphenicol biosynthetic pathway
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Streptomyces venezuelae CmlI catalyzes the six-electron oxygenation of the arylamine precursor of chloramphenicol in a nonribosomal peptide synthetase (NRPS)-based pathway to yield the nitroaryl group of the antibiotic. Optical, EPR, and M?ssbauer studies show that the enzyme contains a nonheme dinuclear iron cluster. Addition of O2 to the diferrous state of the cluster results in an exceptionally long-lived intermediate (t1/2 = 3 h at 4 °C) that is assigned as a peroxodiferric species (CmlI-peroxo) based upon the observation of an 18O2-sensitive resonance Raman (rR) vibration. CmlI-peroxo is spectroscopically distinct from the well characterized and commonly observed cis-μ-1,2-peroxo (μ-η1:η1) intermediates of nonheme diiron enzymes. Specifically, it exhibits a blue-shifted broad absorption band around 500 nm and a rR spectrum with a β(O-O) that is at least 60 cm-1 lower in energy. M?ssbauer studies of the peroxo state reveal a diferric cluster having iron sites with small quadrupole splittings and distinct isomer shifts (0.54 and 0.62 mm/s). Taken together, the spectroscopic comparisons clearly indicate that CmlI-peroxo does not have a μ- η1:η1-peroxo ligand; we propose that a μ- η1:η2-peroxo ligand accounts for its distinct spectroscopic properties. CmlI-peroxo reacts with a range of arylamine substrates by an apparent second-order process, indicating that CmlI-peroxo is the reactive species of the catalytic cycle. Efficient production of chloramphenicol from the free arylamine precursor suggests that CmlI catalyzes the ultimate step in the biosynthetic pathway and that the precursor is not bound to the NRPS during this step.
- Makris, Thomas M.,Vu, Van V.,Meier, Katlyn K.,Komor, Anna J.,Rivard, Brent S.,Münck, Eckard,Que, Lawrence,Lipscomb, John D.
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supporting information
p. 1608 - 1617
(2015/03/05)
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- Synthesis of six phenylalanine derivatives and their cell toxicity effect on human colon cancer cell line HT-29
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Some phenylalanine (Phe) derivatives had important roles in pharmacology and may be used as pharmaceutical materials and pharmaceutical intermediates. In order to understand the cell toxicity of phenylalanine derivatives, we synthesized L-4-bromo-phenylalanine (Brp), L-4-iodophenylalanine (Ip), L-4-nitro-phenylalanine (Np), L-4-sulfonic-phenylalanine (Sp), L-4-phosphophenylalanine (Pp) and L-4-amino-phenylalanine (Np). We used mass spectrometry (MS), Infrared Spectroscopy (IR) or hydrogen-1 nuclear magnetic resonance spectrum (1H-NMR), and high performance liquid chromatography (HPLC) to test the correction of these products, MTT assay and Hoechst 33258 staining to detect their cell toxic effect on human colon cancer cell HT-29 (HT-29 cells). The results showed that these products were correct and the cytotoxicity of Pp>Ip>Sp and Np>Brp, Ap almost had no effect on HT-29 cells. In addition, Pp, Ip and Sp induced cell apoptosis, the other three kinds of phenylalanine derivatives induced neither apoptosis nor necrosis.
- Zhao, Qianyi,Xu, Ting,Li, Menghua,Yang, Ying,Hu, Haopeng,Wang, Shupei,Yan, Wenjuan,Chen, Ran,Zhang, Chunyan,Xu, Cunshuan
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p. 466 - 470
(2015/06/22)
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- The bacterial ammonia lyase EncP: A tunable biocatalyst for the synthesis of unnatural amino acids
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Enzymes of the class I lyase-like family catalyze the asymmetric addition of ammonia to arylacrylates, yielding high value amino acids as products. Recent examples include the use of phenylalanine ammonia lyases (PALs), either alone or as a gateway to deracemization cascades (giving (S)- or (R)-α-phenylalanine derivatives, respectively), and also eukaryotic phenylalanine aminomutases (PAMs) for the synthesis of the (R)-β-products. Herein, we present the investigation of another family member, EncP from Streptomyces maritimus, thereby expanding the biocatalytic toolbox and enabling the production of the missing (S)-β-isomer. EncP was found to convert a range of arylacrylates to a mixture of (S)-α- and (S)-β-arylalanines, with regioselectivity correlating to the strength of electron-withdrawing/-donating groups on the ring of each substrate. The low regioselectivity of the wild-type enzyme was addressed via structure-based rational design to generate three variants with altered preference for either α- or β-products. By examining various biocatalyst/substrate combinations, it was demonstrated that the amination pattern of the reaction could be tuned to achieve selectivities between 99:1 and 1:99 for β:α-product ratios as desired.
- Weise, Nicholas J.,Parmeggiani, Fabio,Ahmed, Syed T.,Turner, Nicholas J.
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supporting information
p. 12977 - 12983
(2015/10/28)
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- Synthesis of D- and L-Phenylalanine Derivatives by Phenylalanine Ammonia Lyases: A Multienzymatic Cascade Process
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The synthesis of substituted D-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization (based on stereoselective oxidation and nonselective reduction). A simple high-throughput solid-phase screening method has also been developed to identify PALs with higher rates of formation of non-natural D-phenylalanines. The best variants were exploited in the chemoenzymatic cascade, thus increasing the yield and ee value of the D-configured product. Furthermore, the system was extended to the preparation of those L-phenylalanines which are obtained with a low ee value using PAL amination.
- Parmeggiani, Fabio,Lovelock, Sarah L.,Weise, Nicholas J.,Ahmed, Syed T.,Turner, Nicholas J.
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p. 4608 - 4611
(2015/04/14)
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- Phenylalanine ammonia lyase catalyzed synthesis of amino acids by an MIO-cofactor independent pathway
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Phenylalanine ammonia lyases (PALs) belong to a family of 4-methylideneimidazole-5-one (MIO) cofactor dependent enzymes which are responsible for the conversion of L-phenylalanine into trans-cinnamic acid in eukaryotic and prokaryotic organisms. Under conditions of high ammonia concentration, this deamination reaction is reversible and hence there is considerable interest in the development of PALs as biocatalysts for the enantioselective synthesis of non-natural amino acids. Herein the discovery of a previously unobserved competing MIO-independent reaction pathway, which proceeds in a non-stereoselective manner and results in the generation of both L- and D-phenylalanine derivatives, is described. The mechanism of the MIO-independent pathway is explored through isotopic-labeling studies and mutagenesis of key active-site residues. The results obtained are consistent with amino acid deamination occurring by a stepwise E1cB elimination mechanism. All manner of things: A competing MIO-independent (MIO=4-methylideneimidazole-5-one) reaction pathway has been identified for phenylalanine ammonia lyases (PALs), which proceeds in a non-stereoselective manner, resulting in the generation of D-phenylalanine derivatives. The mechanism of D-amino acid formation is explored through isotopic-labeling studies and mutagenesis of key active-site residues.
- Lovelock, Sarah L.,Lloyd, Richard C.,Turner, Nicholas J.
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p. 4652 - 4656
(2014/05/20)
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- Equilibrium of chiral extraction of 4-nitro-d,l-phenylalanine with BINAP metal complexes
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The enantioselective extraction of 4-nitro-phenylalanine (Nphy) was studied with metal-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) complexes as the chiral selector. The complex with palladium (BINAP-Pd) exhibits the highest selectivity out of the selectors studied, which is solubilised in the organic phase and preferentially extracts d-Nphy from the aqueous phase. Efficiency of extraction depends, often substantially, on a number of process variables, including types of organic solvents and metal precursors, concentration of ligand, pH, and temperature. A reactive extraction model was established to interpret the experimental data. The equilibrium formation constants and other important parameters required by the model were determined experimentally. The equilibrium formation constants were 6.73 and 1.93 for d-Nphy and l-Nphy. By way of modelling and experiment, an optimal extraction condition with pH of 7 and BINAP-Pd concentration of 1 mmol L-1 was obtained with enantioselectivity (α) of 3.37, which was close to the maximum of 3.48, and a performance factor (pf) of 0.195. The model was verified experimentally with excellent results.
- Liu, Jia-Jia,Wu, Guo-Hui,Tang, Ke-Wen,Liu, Xiong,Zhang, Pan-Liang
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- Equilibrium of chiral extraction of 4-nitro-d,l-phenylalanine with BINAP metal complexes
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The enantioselective extraction of 4-nitro-phenylalanine (Nphy) was studied with metal-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) complexes as the chiral selector. The complex with palladium (BINAP-Pd) exhibits the highest selectivity out of the selectors studied, which is solubilised in the organic phase and preferentially extracts d-Nphy from the aqueous phase. Efficiency of extraction depends, often substantially, on a number of process variables, including types of organic solvents and metal precursors, concentration of ligand, pH, and temperature. A reactive extraction model was established to interpret the experimental data. The equilibrium formation constants and other important parameters required by the model were determined experimentally. The equilibrium formation constants were 6.73 and 1.93 for d-Nphy and l-Nphy. By way of modelling and experiment, an optimal extraction condition with pH of 7 and BINAP-Pd concentration of 1 mmol L-1 was obtained with enantioselectivity (α) of 3.37, which was close to the maximum of 3.48, and a performance factor (pf) of 0.195. The model was verified experimentally with excellent results.
- Liu, Jia-Jia,Wu, Guo-Hui,Tang, Ke-Wen,Liu, Xiong,Zhang, Pan-Liang
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- Design and synthesis of calcium responsive magnetic resonance imaging agent: Its relaxation and luminescence studies
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Calcium concentration modulation both inside and outside cell is of considerable interest for nervous system function in normal and pathological conditions. MRI has potential for very high spatial resolution at molecular/cellular level. Design, synthesis and evaluation of Gd-DO3A-AME-NPHE, a calcium responsive MRI contrast agent is presented. The probe is comprised of a Gd3+-DO3A core coupled to iminoacetate coordinating groups for calcium induced relaxivity switching. In the absence of Ca2+ ions, inner sphere water binding to the Gd-DO3A-AME-NPHE is restricted with longitudinal relaxivity, r1 = 4.37 mM-1 s-1 at 4.7 T. However, addition of Ca2+ triggers a marked enhancement in r1 = 6.99 mM-1 s-1 at 4.7 T (60% increase). The construct is highly selective for Ca2+ over competitive metal ions at extracellular concentration. The r1 is modulated by changes in the hydration number (0.2 to 1.05), which was confirmed by luminescence emission lifetimes of the analogous Eu3+ complex. T1 phantom images establish the capability of complex of visualizing changes in [Ca2+] by MRI.
- Tanwar, Jyoti,Datta, Anupama,Chauhan, Kanchan,Kumaran, S. Senthil,Tiwari, Anjani K.,Kadiyala, K. Ganesh,Pal, Sunil,Thirumal,Mishra, Anil K.
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p. 225 - 232
(2014/06/24)
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- Asymmetric synthesis of 3,3,5,5-tetrasubstituted 1,2-dioxolanes: Total synthesis of epiplakinic acid F
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The first enantioselective total synthesis of epiplakinic acid F (1) was achieved through a pivotal step involving a radical-mediated asymmetric peroxidation of vinylcyclopropanes with molecular oxygen to construct highly substituted 1,2-dioxolanes. Subsequent conversions of the chiral 1,2-dioxolanes led to total synthesis of epiplakinic acid F (1) and the confirmation of its absolute configuration. The enantiomer of epiplakinic acid F methyl ester (2) was also prepared. This journal is the Partner Organisations 2014.
- Tian, Xiang-Yin,Han, Jian-Wei,Zhao, Qiong,Wong, Henry N. C.
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supporting information
p. 3686 - 3700
(2014/06/09)
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- Immunomodulatory peptides
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The invention relates to peptides derivatized with a hydrophilic polymer which, in some embodiments, bind to human FcRn and inhibit binding of the Fc portion of an IgG to an FcRn, thereby modulating serum IgG levels. The disclosed compositions and methods may be used in some embodiments, for example, in treating autoimmune diseases and inflammatory disorders. The invention also relates, in further embodiments, to methods of using and methods of making the peptides of the invention.
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- Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites
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In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.
- Sk?ld, Niklas,Nielsen, Birgitte,Olsen, Jacob,Han, Liwei,Olsen, Lars,Madsen, Ulf,Kristensen, Jesper L.,Pickering, Darryl S.,Johansen, Tommy N.
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p. 5368 - 5377
(2014/12/11)
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- Distinct metabolites for photoreactive l-phenylalanine derivatives in Klebsiella sp. CK6 isolated from rhizosphere of a wild dipterocarp sapling
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Photoaffinity labeling is a reliable analytical method for biological functional analysis. Three major photophores-aryl azide, benzophenone and trifluoromethyldiazirine- are utilized in analysis. Photophore-bearing L-phenylalanine derivatives, which are used for biological functional analysis, were inoculated into a Klebsiella sp. isolated from the rhizosphere of a wild dipterocarp sapling in Central Kalimantan, Indonesia, under nitrogen-limiting conditions. The proportions of metabolites were quite distinct for each photophore. These results indicated that photophores affected substrate recognition in rhizobacterial metabolic pathways, and differential photoaffinity labeling could be achieved using different photophore-containing L-phenylalanine derivatives.
- Wang, Lei,Hisano, Wataru,Murai, Yuta,Sakurai, Munenori,Muto, Yasuyuki,Ikemoto, Haruka,Okamoto, Masashi,Murotani, Takashi,Isoda, Reika,Kim, Dongyeop,Sakihama, Yasuko,Sitepu, Irnayuli R.,Hashidoko, Yasuyuki,Hatanaka, Yasumaru,Hashimoto, Makoto
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p. 8393 - 8401
(2013/08/23)
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- Transformation of l-phenylalanine to (S)-indoline-2-carboxylic acid without group-protection
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(S)-Indoline-2-carboxylic acid was synthesized by use of a nitro amination approach with l-phenylalanine as chiral pool. The first step of the synthesis was nitration of l-phenylalanine, with urea nitrate (UN)/H2SO 4 as nitrating reagent, to give 2,4-dinitro-l-phenylalanine in 75.7 % yield in one-pot synthesis and 69.1 % yield by step-wise nitration. Intramolecular nitro amination of 2,4-dinitro-l-phenylalanine gave (S)-6-nitro-indoline-2-carboxylic acid in 65.7 % yield and more than 99.5 % enantiomeric excess (ee). The title compound, (S)-indoline-2-carboxylic acid, was obtained in 85.9 % yield and high ee by one-pot transformation of (S)-6-nitroindoline-2-carboxylic acid. The total synthesis consisted of three operations and gave the title compound in 42 % yield and more than 99.5 % ee.
- Liu, Jin-Qiang,Chen, Xin-Zhi,Ji, Baoming,Zhao, Bang-Tun
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p. 1143 - 1152
(2013/06/05)
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- CmlI is an N-oxygenase in the biosynthesis of chloramphenicol
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The N-oxygenation of an amine group is one of the steps in the biosynthesis of the antibiotic chloramphenicol. The non-heme di-iron enzyme CmlI was identified as the enzyme catalyzing this reaction through bioinformatics studies and reconstitution of enzymatic activity. In vitro reconstitution was achieved using phenazine methosulfate and NADH as electron mediators, while in vivo activity was demonstrated in Escherichia coli using two substrates. Kinetic analysis showed a biphasic behavior of the enzyme. Oxidized hydroxylamine and nitroso compounds in the reaction were detected both in vitro and in vivo based on LC-MS. The active site metal was confirmed to be iron based on a ferrozine assay. These findings provide new insights into the biosynthesis of chloramphenicol and could lead to further development of CmlI as a useful biocatalyst.
- Lu, Haige,Chanco, Emmanuel,Zhao, Huimin
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supporting information; scheme or table
p. 7651 - 7654
(2012/09/08)
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- Efficient kinetic resolution of amino acids catalyzed by lipase AS 'Amano' via cleavage of an amide bond
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Herein the efficient kinetic resolution of non-natural alpha-amino acids catalyzed by lipase AS 'Amano' via cleaving the amide bond is reported. The starting materials were the corresponding amino acid amides and the amino acids were generated with ees of up to 99% with E values of >600. These results indicated that the lipase AS 'Amano' could be a powerful amide hydrolase for the kinetic resolution of amino acid starting from the corresponding amino acid amides.
- Wang, Bo,Liu, Yanfeng,Zhang, Dela,Feng, Yuhong,Li, Jiacheng
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p. 1338 - 1342,5
(2020/09/16)
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- Microbial enantioselective removal of the N-benzyloxycarbonyl amino protecting group
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In order to deprotect N-carbobenzoxy-l-aminoacids (Cbz-AA) and related compounds, a series of microorganisms was selected from soil by enrichment cultures with Cbz-l-Glu as sole nitrogen source. A lyophilized whole-cell preparation of two Arthrobacter sp. strains grown on Cbz-Glu or Cbz-Gly exhibited a high cleavage activity. The conditions of hydrolysis have been optimized and a quantitative enantioselective deprotection of several Cbz-dl-amino acids was obtained, as well as the deprotection of N-carbamoylester derivatives of several synthetic amino compounds. The preparation of Cbz-d-allylglycine and l-allylglycine in high yield and high optical purity is described as an application of this method.
- Maurs, Michele,Acher, Francine,Azerad, Robert
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- Mechanism-inspired engineering of phenylalanine aminomutase for enhanced β-regioselective asymmetric amination of cinnamates
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Turn to switch: A mutant of phenylalanine aminomutase was engineered that can catalyze the regioselective amination of cinnamate derivatives (see scheme, red) to, for example, β-amino acids. This regioselectivity, along with the X-ray crystal structures, suggests two distinct carboxylate binding modes differentiated by Cβi￡Cipso bond rotation, which determines if β- (see scheme) or α-addition takes place. Copyright
- Wu, Bian,Szymanski, Wiktor,Wybenga, Gjalt G.,Heberling, Matthew M.,Bartsch, Sebastian,Dewildeman, Stefaan,Poelarends, Gerrit J.,Feringa, Ben L.,Dijkstra, Bauke W.,Janssen, Dick B.
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supporting information; experimental part
p. 482 - 486
(2012/03/22)
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- Synthesis and biological evaluation of Matijing-Su derivatives as potent anti-HBV agents
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A series of Matijing-Su (MTS, N-(N-benzoyl-l-phenylalanyl)-O-acetyl-l- phenylalanol) derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity in 2.2.15 cells. The IC50 of compounds 14a (0.71 μM), 13c (2.85 μM), 13b (4.37 μM), etc. and the selective index of 13g (161.01), 13c (90.45), 13a (85.09) etc. of the inhibition on the replication of HBV DNA were better than those of the positive control lamivudine (IC50: 82.42 μM, SI: 41.59). Compounds 13o, 13p, and 16a also exhibited significant anti-HBV activity.
- Qiu, Jingying,Xu, Bixue,Huang, Zhengming,Pan, Weidong,Cao, Peixue,Liu, Changxiao,Hao, Xiaojiang,Song, Baoan,Liang, Guangyi
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experimental part
p. 5352 - 5360
(2011/10/12)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 60
(2010/12/31)
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- A facile chiral pool synthesis of (S)-6-nitroindoline-2-carboxylic acid from l -phenylalanine
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(S)-6-Nitroindoline-2-carboxylic acid, a substructure occurring in numerous biologically active natural products, was synthesized with moderate yield (53%) and high enantiomeric excess (>99.5%) starting from the nitration of l-phenylalanine, which is a commercially available chiral pool compound, followed by successively bromination and intramolecular cyclization. The route was carried out in gram quantities and it is suitable for industrial application due to its convenient reaction conditions and low cost. Georg Thieme Verlag Stuttgart - New York.
- Liu, Jin-Qiang,Qian, Chao,Chen, Xin-Zhi
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scheme or table
p. 403 - 406
(2010/04/02)
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- Synthesis, in vitro progesterone receptors affinity of gadolinium containing mifepristone conjugates and estimation of binding sites in human breast cancer cells
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Novel gadolinium-based mifepristone conjugates were synthesised using various synthetic routes. Moderate antiprogestagenic activity of the new conjugates was observed in human breast cancer cells (T47-D cells) using AP (alkaline phosphatase) assay. The amount of incorporated Gd determined by inductively coupled plasma mass spectroscopy (ICPMS) indicates the number of binding sites per cell. These conjugates might be important compounds to develop receptor-targeted MRI contrast agents as well as other anti-breast cancer therapeutics.
- Saha, Pijus,H?dl, Claudia,Strauss, Wolfgang S.L.,Steiner, Rudolf,Goessler, Walter,Kunert, Olaf,Leitner, Alexander,Haslinger, Ernst,Schramm, H. Wolfgang
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experimental part
p. 1891 - 1898
(2010/05/17)
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- Synthesis and anti-hepatitis B virus activities of Matijing-Su derivatives
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A series of derivatives of Matijing-Su (MTS, N-(N-benzoyl-l-phenylalanyl)-O-acetyl-l-phenylalanol) was synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The IC50 of compounds 9c (1.40 μM), 9g (2.33 μM) and 9n (2.36 μM), etc. and the selective index of 9n (45.93) of the inhibition on the replication of HBV DNA were higher than those of the positive control lamivudine [41.59, (IC50: 82.42 μM)]. Compounds 11d, 12a and 12e also exhibited significant anti-HBV activities.
- Xu, Bixue,Huang, Zhengming,Liu, Changxiao,Cai, Zegui,Pan, Weidong,Cao, Peixue,Hao, Xiaojiang,Liang, Guangyi
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experimental part
p. 3118 - 3125
(2009/09/25)
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- PHENYLALANINE DIPEPTIDE DERIVATIVES, COMPOSITIONS AND USE THEREOF
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Disclosed are a compound of formula I, stereoisomers, pharmaceutically acceptable salts or hydrates thereof, a pharmaceutical composition comprising the smae, a process for preparing the same and use thereof. The compound may also be used to prepare a medicament to treat viral infections, especially to prepare a medicament to treat hepatitis B virus and human immunodeficiency virus with little toxic side effects.
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Page/Page column 12
(2009/10/06)
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- Synthesis and evaluation of some novel isochroman carboxylic acid derivatives as potential anti-diabetic agents
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A series of novel isochroman mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Analysis of structure-activity relationships led to the identification of potent compound 4n which inhibited PTP1B with IC50 value of 51.63 ± 0.91 nM. In general, high potency was associated with a dithiolane ring with a spacer of five carbons to the isochroman ring. Compound 4n has been selected for in vivo evaluation as drug candidate for anti-diabetic activity.
- Lakshminarayana,Rajendra Prasad,Gharat, Laxmikant,Thomas, Abraham,Ravikumar,Narayanan, Shridhar,Srinivasan,Gopalan, Balasubramanian
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experimental part
p. 3147 - 3157
(2009/12/04)
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- Phenylalanine aminomutase-catalyzed addition of ammonia to substituted cinnamic acids: A route to enantiopure α- and β-amino acids
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(Chemical Equation Presented) An approach is described for the synthesis of aromatic α- and β-amino acids that uses phenylalanine aminomutase to catalyze a highly enantioselective addition of ammonia to substituted cinnamic acids. The reaction has a broad scope and yields substituted α- and β-phenylalanines with excellent enantiomeric excess. The regioselectivity of the conversion is determined by substituents present at the aromatic ring. A box model for the enzyme active site is proposed, derived from the influence of the hydrophobicity of substituents on the enzyme affinity toward various substrates.
- Szymanski, Wiktor,Wu, Bian,Weiner, Barbara,De Wildeman, Stefaan,Feringa, Ben L.,Janssen, Dick B.
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supporting information; experimental part
p. 9152 - 9157
(2010/03/01)
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- Use of whole cell culture of Aeromonas sp. as enantioselective scavenger: A facile preparation of l-amino acid derivatives in high enantiomeric excess
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The bacterium Aeromonas sp. (CGMCC 2226) can enantioselectively scavenge d-isomer, making l-amino acid derivatives (AADs) in high ee. The enantioselective scavenger (ES) has shown a broad substrate scope. Eleven l-AADs, Phe derivatives substituted with methyl-, mono- and dichloro-, bromo-, and nitro-group, were produced in high ee from corresponding racemates.
- Zhang, Zizhang
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experimental part
p. 1129 - 1131
(2009/09/04)
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- Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy
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An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of 212Bi, 213Bi, and 177Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. 177Lu-C-NETA and 205/6Bi-C-NETA possess an excellent or acceptable in vivo biodistribution profile.
- Chong, Hyun-Soon,Ma, Xiang,Le, Thien,Kwamena, Baidoo,Milenic, Diane E.,Brady, Erik D.,Song, Hyun A.,Brechbiel, Martin W.
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p. 118 - 125
(2008/09/18)
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- HYDROXAMIC ACID DERIVATIVE AND AGE GENERATION INHIBITOR CONTAINING THE DERIVATIVE
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To provide a novel compound which inhibits the generation of AGE and an AGE generation inhibitor containing the compound. A compound represented by the following formula or a pharmaceutically acceptable salt thereof, a medicinal composition containing the compound or such a salt thereof, and an additive composition containing the compound.
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Page/Page column 42
(2010/11/24)
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- Engineered phenylalanine dehydrogenase in organic solvents: Homogeneous and biphasic enzymatic reactions
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The use of engineered phenylalanine dehydrogenase N145A supported on Celite for the reductive amination of phenylpyruvic acid in homogeneous and biphasic aqueous-organic solvents is reported. The results indicate that the immobilised biocatalyst is remarkably robust, even in the presence of high concentrations of polar or non-polar organic solvents such as acetone, methanol, n-hexane, toluene and methylene chloride. Cofactor regeneration with alcohol dehydrogenase from Saccharomyces cerevisiae and ethanol was successfully explored. Application to the non-natural poorly water-soluble 2-oxo acid p-NO 2-phenylpyruvic acid was successfully performed, resulting in the biocatalytic synthesis of p-NO2-phenylalanine. In all cases 100% stereoselectivity for the production of the amino acid was retained. The Royal Society of Chemistry 2005.
- Cainelli, Gianfranco,Engel, Paul C.,Galletti, Paola,Giacomini, Daria,Gualandi, Andrea,Paradisi, Francesca
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p. 4316 - 4320
(2007/10/03)
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- A convenient synthesis of 4-nitrophenethylamine hydrochloride
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A short, convenient, and efficient synthesis of 4-nitrophenethylamine hydrochloride is described. The key step involved removal of water from 4-nitrophenylalanine monohydrate followed by decarboxylation.
- Joshi, Uday M.,Kobal, Balu S.,Joshi, Hemant V.
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p. 1829 - 1832
(2007/10/03)
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- Synthesis of novel bifunctional Schiff-base ligands derived from condensation of 1-(p-nitrobenzyl)ethylenediamine and 2-(p-nitrobenzyl)-3-monooxo-1,4,7-triazaheptane with salicylaldehyde
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Two potentially tetradentate (N2O2) and pentadentate (N3O3) bifunctional Schiff-base ligands, N,N′-bis(2-hydroxybenzyl)-1-(p-aminobenzyl)ethylenediamine (7) and N,N′-bis(2-hydroxybenzyl)-2-(p-aminobenzyl)-3-monooxo-1,4,7- triazaheptane (5′) have been prepared and characterized by various spectroscopic methods (IR, FAB-MS, NMR). They are derived from the condensation reactions of the C-functionalized diamines 1-(p-nitrobenzyl)ethylenediamine and 2-(p-nitrobenzyl)-3-monooxo-1,4,7-triazaheptane with 2.1 equiv. of salicylaldehyde. The first complexation trials with 99mTc are reported.
- Mishra, Anil Kumar,Panwar, Puja,Chopra, Madhu,Sharma, Rakesh Kumar,Chatal, Jean-Francois
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p. 1054 - 1058
(2007/10/03)
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- Solid phase reduction of oxazolones using BER-Ni2B-A simple synthesis of N-benzoylphenylalanines
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Borohydride exchange resin (BER)-Ni2B is successfully used as a reagent for the solid phase reduction of the C-4 exocyclic double bond of oxazolones to give the N-benzoylphenylalanines and hence the corresponding amino acids.
- Sikdar, Atul P.,Chetri, Ajoy B.,Das, Pranab J.
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p. 2878 - 2881
(2007/10/03)
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- Highly efficient catalytic synthesis of α-amino acids under phase-transfer conditions with a novel catalyst/substrate pair
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A facile and fast enantioselective synthesis of α-amino acids with high ee values was achieved by the asymmetric alkylation of the glycine derivative 1 under phase-transfer conditions with (R)-2-amino-2′-hydrozy-1,1′-binaphthyl (NOBIN; see sceme). The ee value of the amino acid products. This occures as a results of a significant positive nonlinear effect in the alkylation reaction.
- Belokon, Yuri N.,Kochetkov, Konstantin A.,Churkina, Tatiana D.,Ikonnikov, Nikolai S.,Larionov, Oleg V.,Harutyunyan, Syuzanna R.,Vyskocil, Stepan,North, Michael,Kagan, Henri B.
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p. 1948 - 1951
(2007/10/03)
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- Asymmetric synthesis of conformationally restricted L-arginine analogues as active site probes of nitric oxide synthase
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Using the catalytic asymmetric sharpless carbamate aminohydroxylation, conformationally restricted L-arginine and L-homoarginine derivatives (5-8) were prepared in good enantiomeric excess to investigate the binding requirements of L-arginine-based compounds with nitric oxide synthase. The L- arginine derivatives (5 and 6) inhibited both the inducible and neuronal isoforms of nitric oxide synthase with little isoform selectivity (5, IC50 = 42 and 144 μM, 6, 8 and 12 μM, respectively). The guanidine-containing compound (5) did not act as a nitric oxide producing substrate for nitric oxide synthase. The ability of these compounds to interact with the enzyme supports the idea that L-arginine-based inhibitors bind to the enzyme in a folded conformation. The L-homoarginine derivatives (7 and 8) did not interact with the enzyme as either substrates or inhibitors. The two-carbon L-arginine homologue (9), prepared from L-phenylalanine, demonstrated the greatest isoform selective inhibition of the compounds examined (IC50(iNOS) = 19 and IC50(nNOS) = 147 μM, IC50(nNOS)/IC50i(NOS) = 7.7). These results suggest isoform selective inhibition may be related to the folded conformations required for binding of these higher L-arginine homologues.
- Atkinson,Moore,Tobin,King
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p. 3467 - 3475
(2007/10/03)
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- Method for preparing enantiomeric forms of amino alkylaminophenyl propanoic acid
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A process for preparing an enantiomeric form of 2-amino-3-(4-alkylaminophenyl)-propanoic acid of formula (I) or a salt thereof: STR1 in which Alk represents an alkyl radical containing 1 to 2 carbon atoms, from (L)-phenylalanine to obtain the (S)-enantiomer of 2-amino-3-(4-alkylaminophenyl)-propanoic acid, or from (D)-phenylalanine to obtain the (R)-enantiomer of 2-amino-3-(4-alkylaminophenyl)propanoic acid.
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- Acylase I catalysed hydrolysis of para-substituted (S)-phenylalanine derivatives from mixtures of the racemic ortho- and para-substituted isomers
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para-Substituted (S)-phenylalanines may be obtained by treatment of the corresponding mixtures of ortho- and para-substituted N-acetyl-(RS)- phenylalanines with Acylase I from porcine kidney. The selectivity of the enzyme may be attributed to its evolution to digest peptide derivatives of (S)-phenylalanine and (S)-tyrosine.
- Easton, Christopher J.,Harper, Jason B.
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p. 5269 - 5272
(2007/10/03)
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- Two novel amino acid derivatives containing side-chain thioamides for the synthesis of photoactivatable peptides
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The highly efficient preparation of two optically pure phenylalanine analogues containing p-N-aryl thiobenzamide moieties are described. These amino acids are readily incorporated into peptides via standard solid-phase strategies.
- Singh, Preeti,Hurrell, Craig R.,Findlay, John B. C.,Fishwick, Colin W. G.
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p. 715 - 718
(2007/10/03)
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