cas 32213-95-9, Dimethyl L-aspartate hydrochloride

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Antioxidant activity, synthesis and characterization of Schiff base ligand 'asasp' and metal complexes
In the present work, the synthesis and structural characterization of a novel Schiff base ligand derived from 2-acetyl pyridine and L-aspartic acid dimethyl ester and its metal complexes have been reported. All the synthesized compounds were characterized by using various spectral techniques like ESI-MS, FT-IR, 1H NMR, 13C NMR, UV-visible spectra, elemental analysis and ICP-OES analyses. The ligand and metal ions reacted to form in the 2:1 or 1:1 (M:L) ratio as found from the elemental analyses and the general stoichiometry was determined [L(Cu)2(AcO)4] and [LM(H2O)2]2Cl·nH2O where M = Co(II), Ni(II), Ni(II) and L = asasp and n = 1 or 2. On the basis of nalytical data, a possible structure for the copper(II) complex is tetrahedral and those for the Co(II), Ni(II) and Mn(II) complexes are ctahedral. The ligand and its metal complexes were tested for their possible antioxidant potentials. Comparison of antioxidant assays ere investigated by using two reference molecules, vitamin C and quercetin. The complexes showed significant activities in these in vitro ntioxidant assays compared to the reference (quercetin and vitamin C) and Ni(II)-complex exhibited a promising antioxidant activity.
Ozdemir, Mecit,Sonmez, Mehmet
p. 7009 - 7015
(2014)
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2-(2-Hydroxyethyl)piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity
Targeting Carbonic Anhydrases (CAs) represents a strategy to treat several diseases, from glaucoma to cancer. To widen the structure-activity relationships (SARs) of our series of piperazines endowed with potent human carbonic anhydrase (hCA) inhibition, a new series of chiral piperazines carrying a (2-hydroxyethyl) group was prepared. The Zn-binding function, the 4-sulfamoylbenzoyl moiety, was connected to one piperazine N-atom, while the other nitrogen was decorated with alkyl substituents. In analogy to the approach used for the synthesis of the previously reported series, the preparation of the new compounds started with (R)- and (S)-aspartic acid. A partial racemization occurred during the synthesis. In order to overcome this problem, other chemical strategies were investigated. The inhibitory activity of the new polar derivatives against four hCAs isoforms I, II, IV and IX using a stopped flow CO2 hydrase assay was determined. Some compounds showed potency in the nanomolar range and a preference for inhibiting hCA IX.
Chiaramonte, Niccolò,Angeli, Andrea,Sgambellone, Silvia,Bonardi, Alessandro,Nocentini, Alessio,Bartolucci, Gianluca,Braconi, Laura,Dei, Silvia,Lucarini, Laura,Teodori, Elisabetta,Gratteri, Paola,Wünsch, Bernhard,Supuran, Claudiu T.,Romanelli, Maria Novella
(2021/12/17)

Ribose conversion with amino acids into pyrraline platform chemicals-expeditious synthesis of diverse pyrrole-fused alkaloid compounds
One-pot conversion of sustainable d-ribose with l-amino acid, methyl esters produced pyrrole-2-carbaldehydes 5 in reasonable yields (32-63%) under pressurized conditions of 2.5 atm at 80 °C. The value-added pyrraline compounds 5 as platform chemicals were utilized for quick installation of poly-heterocyclic cores for the development of pyrrole-motif natural and artificial therapeutic agents. A pyrrole-fused piperazin-2-one scaffold 6 was prepared by reductive amination of pyrralines 5 with benzylamine. While further cyclization of pyrralines 5 with ethane-1,2-diamine produced pyrrolo-piperazin-2-ones 7 with an extra imidazolidine ring, the reaction with 2-amino alcohols derived from natural l-amino acids, alanine, valine, and phenylalanine, respectively provided pyrrolo-piperazin-2-ones 8, 9, and 10 with oxazolidine as the third structural core. Cell viability and an anti-inflammatory effect of the synthesized compounds were briefly tested by the MTT method and the Griess assay, among which 8h and 10g exhibited significant anti-inflammatory effects with negligible cell toxicity.
Cho, Soohyeon,Gu, Lina,In, Ik Joon,Kim, Hakwon,Koo, Sangho,Lee, Taehoon,Wu, Bo
p. 31511 - 31525
(2021/11/30)

Substrate Engineering in Lipase-Catalyzed Selective Polymerization of d -/ l -Aspartates and Diols to Prepare Helical Chiral Polyester
The synthesis of optically pure polymers is one of the most challenging tasks in polymer chemistry. Herein, Novozym 435 (Lipase B from Candida antarctica, immobilized on Lewatit VP OC 1600)-catalyzed polycondensation between d-/l-aspartic acid (Asp) diester and diols for the preparation of helical chiral polyesters was reported. Compared with d-Asp diesters, the fast-reacting l-Asp diesters easily reacted with diols to provide a series of chiral polyesters containing N-substitutional l-Asp repeating units. Besides amino acid configuration, N-substituent side chains and the chain length of diols were also investigated and optimized. It was found that bulky acyl N-substitutional groups like N-Boc and N-Cbz were more favorable for this polymerization than small ones probably due to competitively binding of these small acyl groups into the active site of Novozym 435. The highest molecular weight can reach up to 39.5 × 103 g/mol (Mw, D = 1.64). Moreover, the slow-reacting d-Asp diesters were also successfully polymerized by modifying the substrate structure to create a "nonchiral"condensation environment artificially. These enantiocomplementary chiral polyesters are thermally stable and have specific helical structures, which was confirmed by circular dichroism (CD) spectra, scanning electron microscope (SEM), and molecular calculation.
Zhang, Yu,Xia, Bo,Li, Yanyan,Lin, Xianfu,Wu, Qi
p. 918 - 926
(2021/02/01)

Conformationally rigid pyrazoloquinazoline α-amino acids: One- And two-photon induced fluorescence
The synthesis and photophysical properties of a new class of α-amino acid bearing a rigid pyrazoloquinazoline chromophore are described. Confromational constraint of the amino acid side-chains resulted in high emission quantum yields, while the demonstration of two-photon-induced fluorescence via near-IR excitation signifies their potential for sensitive bioimaging applications.
Bell, Jonathan D.,Harkiss, Alexander H.,Nobis, David,Malcolm, Eilidh,Knuhtsen, Astrid,Wellaway, Christopher R.,Jamieson, Andrew G.,Magennis, Steven W.,Sutherland, Andrew
supporting information
p. 1887 - 1890
(2020/02/22)

Synthesis of (+)- and (?)-Geissman-Waiss lactone from chiral sulfonium salts
A novel series of chiral cyclic zwitterionic pyrrolidinone type intermediates was prepared via regioselective 5-exo-trig-ring-closure of the corresponding chiral sulfonium salts. This synthetic strategy allowed the rapid non-racemic synthesis of the Geissman-Waiss lactone in six steps and 35% overall yield.
López-González, Ricardo,Gnecco, Dino,Juárez, Jorge R.,Orea, María L.,Gómez-Calvario, Victor,Bernès, Sylvain,Aparicio, David M.,Terán, Joel L.
supporting information

(2020/02/18)

Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics
Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.
Hillisch, Alexander,Gericke, Kersten M.,Allerheiligen, Swen,Roehrig, Susanne,Schaefer, Martina,Tersteegen, Adrian,Schulz, Simone,Lienau, Philip,Gnoth, Mark,Puetter, Vera,Hillig, Roman C.,Heitmeier, Stefan
p. 12574 - 12594
(2020/11/13)

Development of l-Amino-Acid-Based Hydroxyl Functionalized Biodegradable Amphiphilic Polyesters and Their Drug Delivery Capabilities to Cancer Cells
Hydroxyl-functionalized amphiphilic polyesters based on l-amino acid bioresources were designed and developed, and their nanoassemblies were explored as intracellular enzyme-biodegradable scaffolds for delivering anticancer drugs and fluorophores to cancer cells. To accomplish this task, acetal-masked multifunctional dicarboxylic ester monomer from l-aspartic acid was tailor-made, and it was subjected to solvent-free melt transesterification polycondensation with commercial diols to produce acetal-functionalized polyesters. Acid-catalyzed postpolymerization deprotection of these acetal-polyesters produced amphiphilic hydroxyl-functionalized polyesters. The amphiphilic polyesters were self-assembled in aqueous medium to produce nanoparticles of size 200 nm. Wide ranges of both water-soluble and water-insoluble anticancer drugs such as doxorubicin (DOX), camptothecin (CPT), and curcumin (CUR) and fluorophores such as Nile red (NR), Rose Bengal (RB), and Congo red (CR) were encapsulated in hydroxyl polyesters nanoparticles. In vitro drug release studies revealed that the aliphatic polyester backbone underwent lysosomal enzymatic-biodegradation to release the loaded cargoes at the intracellular compartments. Lysotracker-assisted live-cell confocal microscopy studies further confirmed the colocalization of the polymer nanoscaffolds in the lysosomes and supported their enzymatic-biodegradation for drug delivery. In vitro cytotoxicity studies showed that the nascent polymers were not toxic, whereas their anticancer drug-loaded nanoparticles exhibited excellent cell killing in cervical cancer (HeLa) cell lines. The drug-loaded (CPT, CUR, and DOX) and the fluorophore-loaded (NR, RB, and CR) polymer nanoparticles were highly luminescent; thus, the encapsulated polymer nanoparticles enabled the multiple color-tunable bioimaging in cancer cells in the entire visible region from blue to deep red. Time-dependent live-cell confocal microscopy studies established that the cellular uptake of drugs and fluorophores was 5 to 10-fold higher while they were delivered from the hydroxyl polyester platform. The hydroxyl polyester nanocarrier design strategy opens up new opportunities in drug delivery to cancer cells from a biodegradable polymer platform based on l-amino acids.
Saxena, Sonashree,Jayakannan, Manickam
p. 171 - 187
(2019/11/11)

Development of bisubstrate analog inhibitors of aspartate N-acetyltransferase, a critical brain enzyme
Canavan disease (CD) is a fatal leukodystrophy caused by mutations in the aspA gene coding for the enzyme aspartoacylase. Insufficient catalytic activity by this enzyme leads to the accumulation of its substrate, N-acetyl-l-aspartate (NAA), and diminished production of acetate in brain oligodendrocytes of patients with CD. There is growing evidence that this accumulation of NAA is the cause of many of the developmental defects observed in these patients. NAA is produced in the brain by a transacetylation reaction catalyzed by aspartate N-acetyltransferase (ANAT), and this membrane-associated enzyme has recently been purified as a soluble maltose binding protein fusion. Designing selective inhibitors against ANAT has the potential to slow the accumulation of NAA and moderate these developmental defects, and this is the goal of this project. Several bisubstrate analog inhibitors of ANAT have been synthesized that have achieved nanomolar level binding affinities against this enzyme. Truncated versions and fragments of these bisubstrate analog inhibitors have identified the essential structural elements needed for high binding affinity. More drug-like versions of these inhibitors can now be built, based on these essential core structures.
Mutthamsetty, Vinay,Dahal, Gopal P.,Wang, Qinzhe,Viola, Ronald E.
p. 48 - 57
(2019/11/25)

Unsaturation and Polar Head Effect on Gelation, Bioactive Release, and Cr/Cu Removal Ability of Glycolipids
Designing of multifunctional soft and smart materials from natural sources is a useful strategy for producing safer chemicals having potential applications in biomedical research and pharmaceutical industries. Herein, eight glycolipids with variation in unsaturation of hydrophobic tail and polar headgroup size were designed. The effect of unsaturation in the tail group and headgroup size on gelation ability, and mechanical and thermal stability of glycolipid hydro/organogels was studied to understand structure and property relationship. Glycolipids are functional amphiphilic molecules having potential applications in the field of drug delivery and metal removal. The encapsulation capacity and kinetic release behavior of hydrophobic/hydrophilic bioactives like curcumin/riboflavin from the hydrophobic/hydrophilic pockets of glycolipids hydro/organogels was examined. A significant observation was that the glucamine moiety of the glycolipid headgroup plays a vital role in removal of Cr and Cu from oil/water biphasic systems. Typical functions of the glycolipid hydrogels are metal chelation and enzyme-triggered release behavior, enabled them as promising material for Cr, Cu removal from edible oils and controlled release of water soluble/insoluble bioactives.
Bojja, Sreedhar,Holey, Snehal Ashokrao,Nayak, Rati Ranjan,Sekhar, Kanaparedu P. C.,Swain, Deepak Kumar
p. 3080 - 3088
(2020/08/06)

Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile
Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1H NMR and 13C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H+/K+-ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
Khan, Muhammad T.,Nadeem, Humaira,Khan, Arif-ullah,Abbas, Muzaffar,Arif, Muazzam,Malik, Nadia Shamshad,Malik, Zulkifal,Javed, Ibrahim
p. 1057 - 1072
(2020/08/13)

A Synthetic Route to the MT1-MMP Inhibitor Ancorinoside D
A methyl ester of ancorinoside D, a 3-acyltetramic acid metabolite of a sponge Penares sollasi, was synthesised in ten steps starting from a protected β- d -glucopyranosyl-(1→4)- d -galactopyranosyltrichloroacetimidate donor. Its attachment to the left half of the 3-acyl spacer by a Schmidt glycosylation, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation to the uronic acid, introduction of the Z -alkene via Wittig reaction, and functionalisation of the spacer terminus with Meldrum's acid gave a β-keto ester that reacted with dimethyl N -methyl- d -aspartate under neutral conditions to afford a fully protected ancorinoside D as the product of an unusual domino N -acylation-Dieckmann condensation. Global deprotection left a methyl ester of ancorinoside D, which resisted all saponification attempts.
Petermichl, Markus,Steinert, Christine,Schobert, Rainer
p. 730 - 738
(2019/01/23)

Preparation method of nitrogen-substituted aspartic acid
The invention discloses a preparation method of nitrogen-substituted aspartic acid, a nitrogen-substituted aspartic acid compound has the structural formula as shown in the specification, wherein R1 is alkyl, and R2 is an amino protecting group, and the preparation method can be used for preparation of the nitrogen-substituted aspartic acid from the nitrogen-substituted aspartic acid compound so as to reduce the cost of preparing the nitrogen-substituted aspartic acid and enables the nitrogen-substituted aspartic acid to be suitable for industrial production.
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Paragraph 0031; 0032; 0033; 0034

(2019/01/24)

Preparation method of nitrogen-substituted aspartic acid
The invention discloses a preparation method of nitrogen-substituted aspartic acid, the method comprises the following steps: providing a nitrogen-substituted aspartic acid compound with the structural formula as shown in the specification, wherein R1 is alkyl, and R2 is an amino protecting group; performing deprotection treatment on the nitrogen-substituted aspartic acid compound to obtain the nitrogen-substituted aspartic acid with the structural formula as shown in the specification, and the preparation method disclosed by the invention can be used for reducing the cost of preparing the nitrogen-substituted aspartic acid and enabling the nitrogen-substituted aspartic acid to be suitable for industrial production.
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Paragraph 0045; 0046; 0047; 0048

(2019/01/24)

Preparation method of sitagliptin intermediate
The invention discloses a preparation method of a sitagliptin intermediate and belongs to the field of medicine synthesis. The invention provides a preparation method of a compound 2; the compound 2 is prepared without the need of a catalyst and a resolving agent which have a high price and harsh low-temperature conditions, so that the cost is reduced to the great extent; the preparation method has the advantages of simple technology, high purity and high yield and is suitable for mass production.
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Paragraph 0035; 0064; 0065

(2018/04/01)

A novel aggregation-induced emission enhancement triggered by the assembly of a chiral gelator: from non-emissive nanofibers to emissive micro-loops
In this study, a novel aggregation-induced emission (AIE) enhancement triggered by the self-assembly of chiral gelator is described. Tuning of molecular chirality in situ triggers different assemblies of superstructures exhibiting fluorescence. This novel AIE material can constitute an emerging library of chiral supramolecules for turn-on fluorescent sensors. It will also help in better understanding the effects of chiral factors on the photophysical process.
Chen, Wenrui,Qing, Guangyan,Sun, Taolei
supporting information
p. 447 - 450
(2017/01/03)

Pig growth urges the medicinal preparation preparation method of gene expression (by machine translation)
The invention discloses a Pig growth gene expression urges the medicinal preparation preparation method, the present invention relates to a synthesis of amino acid derivatives, in particular to a Pig growth gene expression urges the medicinal preparation D - aspartic acid derivatives, N - methyl - D - aspartic acid of preparation method, through D - aspartic acid as the raw material, the D - aspartic acid with methanol and thionyl chloride reaction generating D - aspartic acid dimethyl ester hydrochloride, then with 40% formaldehyde of the woven fabric under the alkaline condition generating N - hydroxymethyl - D - aspartic acid, using pd/c as the catalyst under normal temperature and pressure hydrogenation to obtain N - methyl - D - aspartic acid; simple preparation method of the invention, the prepared product quality is stable, and in the preparation of environmental pollution, can promote the growth of livestock and at the same time, improve the utilization rate of the feed and the improvement of the quality of the carcass raising the Pig, popularization and application. (by machine translation)
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Paragraph 0019; 0026; 0033; 0040

(2017/08/30)

An azobenzene-based photoswitchable crystal growth modifier
An aspartic acid functionalised azobenzene derivative is found to be a light-switchable crystal growth modifier of calcite. UV irradiation of the molecule reversibly switches it to the cis isomer, which is a significantly less effective crystal growth inhibitor than the trans isomer. Visible light, or heat switches the inhibitor back “on”. Extended irradiation degrades the inhibitor such that it is irreversibly switched “off”. It was shown that the trans isomer is preferentially absorbed on to the crystal surface, which is consistent with its greater efficacy as an inhibitor.
Nealon, Gareth L.,Brown, David H.,Jones, Franca,Parkinson, Gordon,Ogden, Mark I.
p. 1286 - 1293
(2017/03/09)

Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease
Canavan disease is a fatal neurological disorder caused by defects in the metabolism of N-acetyl-L-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA observed in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-associated enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examined (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and soluble form of ANAT we can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compound libraries. Two core structures of these moderate binding compounds have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition constants (Kivalues) against ANAT. Slowing the production of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease.
Thangavelu, Bharani,Mutthamsetty, Vinay,Wang, Qinzhe,Viola, Ronald E.
p. 870 - 885
(2017/02/05)

POTENT INHIBITORS OF ASPARTATE N-ACETYL-TRANSFERASE FOR THE TREATMENT OF CANAVAN DISEASE
Compounds, compositions, and methods for the treatment of Canavan disease are described.
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Paragraph 00150; 00151

(2017/11/03)

Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity?
Stereoisomeric 2,5-diazabicyclo[2.2.2]octanes 14 and 15 were prepared in a chiral-pool synthesis starting from (S)- or (R)-aspartate. The key step in the synthesis was a Dieckmann-analogous cyclization of (dioxopiperazinyl)acetates 8, which involved trapping of the intermediate hemiketal anion with Me3SiCl. The σ1 affinity was tested using membrane preparations from animal (Guinea pig) and human origin. The binding of bicyclic compounds was analyzed by molecular dynamics simulations based on a 3D homology model of the σ1 receptor. The good correlation between Ki values observed in the σ1 assays and calculated free binding energy, coupled with the identification of four crucial ligand/receptor interactions, allowed the formulation of structure-affinity relationships. In an in vitro antitumor assay with seven human tumor cell lines, the bicyclic compounds inhibited selectively the growth of the cell line A427, which is due to induction of apoptosis. In this assay, the compounds behave like the known σ1 receptor antagonist haloperidol.
Weber, Frauke,Brune, Stefanie,B?rgel, Frederik,Lange, Carsten,Korpis, Katharina,Bednarski, Patrick J.,Laurini, Erik,Fermeglia, Maurizio,Pricl, Sabrina,Schepmann, Dirk,Wünsch, Bernhard
p. 5505 - 5519
(2016/07/06)

Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones
A synthetic approach for the preparation of a new class of highly conjugated unnatural α-amino acids bearing a 5-arylpyrazole side-chain has been developed. Horner-Wadsworth-Emmons reaction of an aspartic acid derived β-keto phosphonate ester with a range of aromatic aldehydes gave β-aryl α,β-unsaturated ketones. Treatment of these with phenyl hydrazine followed by oxidation allowed the regioselective synthesis of pyrazole derived α-amino acids. As well as evaluating the fluorescent properties of the α-amino acids, their synthetic utility was also explored with the preparation of a sulfonyl fluoride derivative, a potential probe for serine proteases.
Gilfillan, Lynne,Artschwager, Raik,Harkiss, Alexander H.,Liskamp, Rob M. J.,Sutherland, Andrew
supporting information
p. 4514 - 4523
(2015/04/14)

Synthesis, pharmacological evaluation, and σ1 receptor interaction analysis of hydroxyethyl substituted piperazines
Starting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. σ receptor affinity was recorded using receptor material from both animal and human o
Weber, Frauke,Brune, Stefanie,Korpis, Katharina,Bednarski, Patrick J.,Laurini, Erik,Dal Col, Valentina,Pricl, Sabrina,Schepmann, Dirk,Wünsch, Bernhard
p. 2884 - 2894
(2014/05/06)

Involvement of apoptosis and autophagy in the death of RPMI 8226 multiple myeloma cells by two enantiomeric sigma receptor ligands
Over-expression of σ receptors by many tumor cell lines makes ligands for these receptors attractive as potential chemotherapeutic drugs. Enantiomeric piperazines (S)-4 and (R)-4 were prepared as potential σ-receptor ligands in a chiral pool synthesis starting from (S)- and (R)-aspartate. Both compounds showed high affinities for the σ1 and σ2 receptors. In the human multiple myeloma cell line RPMI 8226, a line expressing high levels of σ receptors, both compounds inhibited cell proliferation with IC50 values in the low μM range. No chiral differentiation between either the σ receptor binding affinity or the cytotoxicity of the two enantiomers was observed. Both compounds induced apoptosis, which was evidenced by nuclear condensation, binding of annexin-V to phosphatidylserine in the outer leaf of the cell membrane, cleavage products of poly(ADP-ribose) polymerase-1 (PARP-1) and caspase-8 as well as the expression of bcl2 family members bax, bad and bid. However, apoptosis appeared to be caspase independent. Increased levels of the phosphorylated form of the microtubule associated protein light chain 3-II (LC3-II), an autophagosome marker, gave evidence that both compounds induced autophagy. However, further data (e.g., treatment with wortmannin) indicate that autophagy is incomplete and not cytoprotective. Lipid peroxidation (LPO) was observed in RPMI 8226 cells treated with the two compounds, and the lipid antioxidant α-tocopherol attenuated LPO. Interestingly, α-tocopherol reduced significantly both apoptosis and autophagy induced by the compounds. These results provide evidence that, by initiating LPO and changes in mitochondrial membrane potential, both compounds induce apoptosis and autophagy in RPMI 8226 cells.
Korpis, Katharina,Weber, Frauke,Brune, Stefanie,Wünsch, Bernhard,Bednarski, Patrick J.
p. 221 - 233
(2014/12/12)

Triple role of phenylselenonyl group enabled a one-pot synthesis of 1,3-oxazinan-2-ones from α-isocyanoacetates, phenyl vinyl selenones, and water
Reaction of α-substituted α-isocyanoacetates with phenyl vinyl selenones in the presence of a catalytic amount of base (DBU or Et3N, 0.05-0.1 equiv) followed by addition of p-toluenesulfonic acid (PTSA, 0.1-0.2 equiv) afforded 4,4,5-trisubstituted 1,3-oxazinan-2-ones in good to excellent yields. Enantiomerically enriched heterocycles can also be prepared using a Cinchona alkaloid-derived bifunctional organocatalyst for the Michael addition step. The phenylselenonyl group served as an activator for the Michael addition, a leaving group and a latent oxidant in this integrated reaction sequence.
Buyck, Thomas,Wang, Qian,Zhu, Jieping
supporting information
p. 11524 - 11528
(2014/10/15)

Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor
The Eph receptor-ephrin system is an emerging target for the development of novel antiangiogenetic agents. We recently identified lithocholic acid (LCA) as a small molecule able to block EphA2-dependent signals in cancer cells, suggesting that its (5β)-cholan-24-oic acid scaffold can be used as a template to design a new generation of improved EphA2 antagonists. Here, we report the design and synthesis of an extended set of LCA derivatives obtained by conjugation of its carboxyl group with different α-amino acids. Structure-activity relationships indicate that the presence of a lipophilic amino acid side chain is fundamental to achieve good potencies. The l-Trp derivative (20, PCM126) was the most potent antagonist of the series disrupting EphA2-ephrinA1 interaction and blocking EphA2 phosphorylation in prostate cancer cells at low μM concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small-molecule antagonists of the EphA2 receptor.
Incerti, Matteo,Tognolini, Massimiliano,Russo, Simonetta,Pala, Daniele,Giorgio, Carmine,Hassan-Mohamed, Iftiin,Noberini, Roberta,Pasquale, Elena B.,Vicini, Paola,Piersanti, Silvia,Rivara, Silvia,Barocelli, Elisabetta,Mor, Marco,Lodola, Alessio
supporting information
p. 2936 - 2947
(2013/05/22)

Synthesis and characterization of captopril derivatives
To develop more potential angiotensin converting enzyme (ACE) inhibitors, a series of captopril (Cap) derivatives were synthesized, including Cap-glycine methyl ester, Cap-l-alanine methyl ester, Cap-l-aspartic acid dimethyl ester, Cap-l-lysine methyl ester, Cap-O-acylisourea, acetyl captopril, and benzoyl captopril. The resulting products were characterized by IR and UV-visible spectroscopy and MS, which showed the desired products were successfully synthesized. This could serve as a guide for rational design of highly potent ACE inhibitors.
Li, He-Ping,Zhang, Juan-Juan,Qin, Long,Zhao, Ming-Dong
p. 621 - 629
(2013/07/27)

Expeditious novel routes to enantiopure 3-amino tetrahydrofuran hydrochloride
The synthesis of chemically and enantiomerically pure (S)-3-amino tetrahydrofuran hydrochloride starting from the natural amino acids, l-aspartic acid or l-methionine is described. The process involves no chromatography and can be easily carried out on a large scale. The enantiopurity of the final product was established by NMR and chiral HPLC methods.
Ramanujam, Rajendran,Ganjihal, Savita,Kalyanam, Nagabushanam,Majeed, Muhammed
p. 663 - 668
(2013/07/11)

BENZIIMIDAZOLE AND IMIDAZOPYRIDINE DERIVATIVES AS SODIUM CHANNEL MODULATORS
The invention relates to benzimidazole and imidazopyridine derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to new Nav1.8 modulators of formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7. X and Y are as defined in the description. Nav1.8 modulators are potentially useful in the treatment of a wide range of disorders, particularly pain.
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(2013/08/15)

NUCLEOSIDE DERIVATIVES, SYNTHESIS METHODS AND USES THEREOF FOR PREPARING ANTI-TUMOR AND ANTI-VIRUS MEDICAMENTS
The present invention relates to the field of pharmacochemistry. Disclosed are fluorinated and azido-substituted pyrimidine nucleoside derivatives, and preparation methods and uses thereof. The structural formula is as shown (I). These compounds can be used for preparing medicaments for treating diseases such as tumors and viral infections, and can be used separately or in combination with other medicaments. The compounds also have effective activity against diseases such as tumors and viral infections, while having few side effects, and thus have potential application value.
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Paragraph 0062

(2013/07/25)

PYRIMIDINE NUCLEOSIDE DERIVATIVES, SYNTHESIS METHODS AND USES THEREOF FOR PREPARING ANTI-TUMOR AND ANTI-VIRUS MEDICAMENTS
The present invention relates to the field of pharmacochemistry. Disclosed are fluorinated and azido-substituted pyrimidine nucleoside derivatives, and preparation methods and uses thereof. The structural formula is as shown (I). These compounds can be used for preparing medicaments for treating diseases such as tumors and viral infections, and can be used separately or in combination with other medicaments. The compounds also have effective activity against diseases such as tumors and viral infections, while having few side effects, and thus have potential application value.
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Paragraph 0068

(2013/11/19)

OxymaPure/DIC: An efficient reagent for the synthesis of a novel series of 4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino] benzoyl amino acid ester derivatives
OxymaPure (ethyl 2-cyano-2-(hydroxyimino)acetate) was tested as an additive for use in the carbodiimide (DIC) approach for the synthesis of a novel series of α-ketoamide derivatives (4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino] benzoyl amino acid ester derivatives). OxymaPure showed clear superiority to HOBt/DIC or carbodiimide alone in terms of purity and yield. The title compounds were synthesized via the ring opening of N-acylisatin. First, N-acetylisatin was reacted with 4-aminobenzoic acid under conventional heating as well as microwave irradiation to afford 4-(2-(2-acetamidophenyl)-2-oxoacetamido)benzoic acid. This α-ketoamide was coupled to different amino acid esters using OxymaPure/DIC as a coupling reagent to afford 4-[2-(2-acetylaminophenyl)-2- oxoacetylamino] benzoyl amino acid ester derivatives in excellent yield and purity. The synthesized compounds were characterized using FT-IR, NMR, and elemental analysis.
El-Faham, Ayman,Al Marhoon, Zainab,Abdel-Megeed, Ahmed,Albericio, Fernando
p. 14747 - 14759
(2014/01/17)

Iron-catalyzed oxidative C - H/C - H cross-coupling: An efficient route to α-quaternary α-amino acid derivatives
Fully loaded: A coordinating activation strategy has been developed to furnish α-quaternary α-amino acids through the iron(III)-catalyzed oxidative functionalization of α-C(sp3) - H bonds of α-tertiary α-amino acid esters. The reaction exhibits a broad substrate scope for both α-amino acids and nucleophiles (Nu) as well as good functional-group tolerance (see scheme, DTBP=di-tert-butyl peroxide, DCE=1,2-dichloroethane). Copyright
Li, Kaizhi,Tan, Guangying,Huang, Jingsheng,Song, Feijie,You, Jingsong
supporting information
p. 12942 - 12945
(2014/01/06)

Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αvβ3
A small library of integrin ligand-paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified αVβ3 integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin αVβ3, making them attractive to be tested in in vivo models. cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity compared with paclitaxel, despite the lower (about half) molar dosage used.
Colombo, Raffaele,Mingozzi, Michele,Belvisi, Laura,Arosio, Daniela,Piarulli, Umberto,Carenini, Nives,Perego, Paola,Zaffaroni, Nadia,De Cesare, Michelandrea,Castiglioni, Vittoria,Scanziani, Eugenio,Gennari, Cesare
supporting information
p. 10460 - 10474
(2013/02/22)

CRTH2 antagonist MK-7246: A synthetic evolution from discovery through development
In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure-activity relationships (SAR) and to procure the first milligrams of diverse target molecules for in vitro evaluation. The initial aziridine opening/cyclodehydration strategy was also directly amenable to the first GMP deliveries of MK-7246 (1), streamlining the transition from milligram to kilogram-scale production needed to support early preclinical and clinical evaluation of this compound. Subsequently a more scalable and cost-effective manufacturing route to MK-7246 (1) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N-H insertion of sulfoxonium ylide 41 and conversion of ketone 32 to amine 31 in a single step with excellent enantioselectivity through a transaminase process. Reactions such as these illustrate the enabling impact and efficiency gains that innovative developments in chemo- and biocatalysis can have on the synthesis of pharmaceutically relevant target molecules.
Molinaro, Carmela,Bulger, Paul G.,Lee, Ernest E.,Kosjek, Birgit,Lau, Stephen,Gauvreau, Danny,Howard, Melissa E.,Wallace, Debra J.,O'Shea, Paul D.
supporting information; experimental part
p. 2299 - 2309
(2012/05/20)

Chiral self-assembly of designed amphiphiles: Optimization for nanotube formation
Four amphiphiles with l-aspartic acid headgroups (Asp) and a diphenyldiazenyl group (Azo) contained within the hydrophobic tails were designed and synthesized for self-assembly into helically based nanotubes. The amphiphiles of the form R'-{4-[(4-alkylphenyl)diazenyl]phenoxy}alkanoyl-l- aspartic acid (where R' is 10 or 11) varied only in alkyl chain lengths either side of the azo group, having 4, 7, or 10 carbon distal chains and 10 or 11 carbon proximal chains (R-Azo-R'-Asp, where R denotes the number of carbons in the distal chain and R' denotes the number of carbons in the proximal chain). Despite the molecular similarities, distinct differences were identified in the chiral order of the structures self-assembled from hot methanolic aqueous solutions using microscopy and spectroscopic analyses. This was reflected in dominant thermodynamic aggregate morphologies that ranged from amorphous material for 10-Azo-10-Asp, through twisted ribbons (196 ± 49 nm pitch) for 7-Azo-11-Asp, to the desired helically based nanotubes for 4- and 7-Azo-10-Asp (81 ± 11 and 76 ± 6 nm diameters, respectively). Another key variable in the self-assembly of the amphiphiles was the use of a second method to precipitate aggregates from solution at room temperature. This method enabled the isolation of thermodynamically unstable and key transitional structures. Helical ribbons were precursor structures to the nanotubes formed from 4- and 7-Azo-10-Asp as well as the wide, flattened nanotube structures (587 ± 85 nm width) found for 4-Azo-10-Asp. Overall, the results highlighted the interplay of influence of the headgroup and the hydrophobic tail on self-assembly, providing a basis for future rational design of self-assembling amphiphiles.
Barclay, Thomas G.,Constantopoulos, Kristina,Matisons, Janis G.,Zhang, Wei,Fujiki, Michiya
p. 14172 - 14179,8
(2020/09/02)

Asymmetric michael additions of α-nitrocyclohexanone to aryl nitroalkenes catalyzed by natural amino acid-derived bifunctional thioureas
A series of new thiourea catalysts prepared from natural amino acids have been applied in organocatalytic asymmetric Michael additions of α-nitrocyclohexanone to nitroalkenes. The resulting addition products are formed with excellent enantioselectivities (up to an er of 98:2) in good yields (up to 90%).
J?rres, Manuel,Schiffers, Ingo,Atodiresei, Iuliana,Bolm, Carsten
supporting information
p. 4518 - 4521
(2012/10/29)

A one-pot, reductive amination/6-endo-trig cyclisation for the stereoselective synthesis of 6-substituted-4-oxopipecolic acids
The first stereoselective synthesis of 2,6-trans-6-substituted-4-oxo-l- pipecolic acids using a tandem reductive amination/6-endo-trig cyclisation process is described. The sequential reduction and cyclisation mediated by sodium cyanoborohydride allowed the preparation of a series of highly functionalised 6-alkyl and 6-aryl analogues.
Fowler, Lindsay S.,Thomas, Lynne H.,Ellis, David,Sutherland, Andrew
supporting information; experimental part
p. 6569 - 6571
(2011/06/26)

AZAINDOLE DERIVATIVES AS CRTH2 RECEPTOR ANTAGONISTS
Compounds of formula I are antagonists of the PGD2 receptor, CRTH2, and as such are useful in the treatment and/or prevention of CRTH2 -mediated diseases such as asthma.
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(2010/04/25)

Use of diphenyliodonium bromide in the synthesis of some N-phenyl-amino acids
The N-phenyl methyl esters 4 of glycine, alanine, valine, leucine, isoleucine, phenylalanine, methionine, proline, serine, threonine, tyrosine, aspartic acid, and glutamic acid have been synthesized in good to excellent yields using diphenyliodonium bromide, AgNO3, and a catalytic amount of CuBr starting from the relevant amino acid ester. The chiral integrity of the amino acids 5 was maintained during these reactions, which were confirmed by the synthesis of dipeptide for each N-phenyl amino acid. The structures of the new compounds were confirmed by the analysis of their IR, 1H, and 13C NMR spectra in addition to CHN microanalysis or high-resolution mass spectrometry for the new N-phenyl amino acids 5 and the esters 4.
McKerrow, Jason D.,Al-Rawi, Jasim M. A.,Brooks, Peter
experimental part
p. 1161 - 1179
(2010/04/28)

PROCESSES FOR PREPARING AMINO-SUBSTITUTED GAMMA-LACTAMS
The present application describes general process for the preparation of amino-substitued gamma-lactams involving the reaction of synthons of the general Formulae (I) and (VI): with amines. The processes are amenable to solid phase synthetic techniques and therefore allow the efficient incorporation of amino-substitued gamma-lactams into a wide variety of structural scaffolds, including, in particular peptides.
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Page/Page column 35; 36; 37

(2010/10/03)

COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
The present disclosure is directed to corn- pounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/ or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract
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Page/Page column 161

(2010/08/04)

Synthesis of fluorescent enone derived α-amino acids
The development of a facile and general method for the preparation of enone derived α-amino acids is described. The key step involves a Horner-Wadsworth-Emmons reaction between an aspartic acid derived β-keto phosphonate ester and a range of aldehydes resulting in the formation of highly functionalised α-amino acids in good yields. An efficient two-stage deprotection process using mild conditions was developed to give the parent α-amino acids. Application of this methodology has produced a novel fluorescent α-amino acid that has potential as a biological marker.
Fowler, Lindsay S.,Ellis, David,Sutherland, Andrew
supporting information; experimental part
p. 4309 - 4316
(2009/12/06)

Applications of the N-tert-butylsulfonyl (Bus) protecting group in amino acid and peptide chemistry
The utility of the tert-butylsulfonyl group (Bus) for the temporary protection of amino acids and peptides is reported. Compatibility and orthogonality in the presence of other N- and O-protecting groups were studied.
Hanessian, Stephen,Wang, Xiaotian
experimental part
p. 2803 - 2808
(2010/03/03)

Synthesis of 2,5-diazabicyclo[2.2.2]octanes by dieckmann analogous cyclization
Starting with (S)-aspartate, methyl (S)-2-[1-allyl-4-(4-methoxybenzyl)-3,6- dioxopiperazin-2-yl]acetate 10 was synthesized in a four-step synthesis. Deprotonation of 10 and subsequent trapping of the first cyclization product led to the bicyclic mixed acetal 13 in 15% yield. The low yield of 13, compared with the yield of the corresponding glutamate derivatives, is explained by the higher energy (strain) of the bicyclo[2.2.2]octane system and the lower conformational flexibility of the shorter acetate side chain. The formation of a six-membered Na+-chelate 12 as intermediate is responsible for the high diastereoselectivity of the cyclization step.
Holl, Ralph,Dykstra, Mareike,Schneiders, Martin,Froehlich, Roland,Kitamura, Masato,Wuerthwein, Ernst-Ulrich,Wuensch, Bernhard
experimental part
p. 914 - 919
(2009/04/11)

Toward the development of chemoprevention agents (III): Synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes
A new series of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes were designed and synthesized. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model. Sixteen of these new compounds exhibited comparable or better anti-inflammatory activities than aspirin suggesting that they can be further developed as potential anti-inflammatory drug leads. In addition, treatment with these anti-inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these compounds. Considering their good efficacy and safety profiles, some 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes are worthy to be explored further in assessing the possible link between anti-inflammation and cancer prevention.
Bi, Lanrong,Zhao, Ming,Gu, Keli,Wang, Chao,Ju, Jingfang,Peng, Shiqi
p. 1764 - 1774
(2008/09/20)

Synthesis and preliminary pharmacological evaluation of novel derivatives of l-β-threo-benzylaspartate as inhibitors of the neuronal glutamate transporter EAAT3
A series of β-benzylaspartate derivatives were prepared from N-trityl-l-aspartate dimethyl ester and evaluated as inhibitors of neuronal glutamate transporter EAAT3. The result of the structure-activity studies suggests that the position occupied by the aromatic ring of β-benzylaspartate within the binding site of EAAT3 may be different from that occupied by comparable groups in previously identified inhibitors, such as l-threo-benzyloxy aspartate (TBOA). Further, halogen substitutions at the 3-postition of the aromatic ring of β-benzylaspartate can increase the potency with which the analogues inhibit EAAT3.
Mavencamp, Terri L.,Rhoderick, Joseph F.,Bridges, Richard J.,Esslinger, C. Sean
p. 7740 - 7748
(2008/12/23)

A convenient synthesis of amino acid methyl esters
A series of amino acid methyl ester hydrochlorides were prepared in good to excellent yields by the room temperature reaction of amino acids with methanol in the presence of trimethylchlorosilane. This method is not only compatible with natural amino acids, but also with other aromatic and aliphatic amino acids.
Li, Jiabo,Sha, Yaowu
p. 1111 - 1119
(2008/09/21)

3-alkylaryl aspartate compounds and their use for selective enhancement of synaptic transmission
The present invention provides an L-aspartate derivative compound represented by the following structure wherein Ar represents an aromatic group; L represents a linking moiety; R represents hydrogen, alkyl, aryl, or heteroaryl; and indicates that the stereochemistry at the 3-position can be R or S. The compounds of the invention are useful for selectively inhibiting EAAT3 and for enhancing synaptic transmission. Additionally, the inventive compounds can be used to treat a patient suffering from Alzheimers disease or a neuropathy or a neurodegenerative disease in which L-glutamate transporter activity is involved in the onset of the disease.
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(2010/11/27)

Toward the development of chemoprevention agents. Part II: Chemo-enzymatic synthesis and anti-inflammatory activities of a new class of 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes
A new series of optically pure 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes were designed and synthesized via a chemo-enzymatic combined method to develop new chemoprevention agents. Twenty-four of newly synthesized compounds significantly inhibited xylene-induced rat ear edema and exhibited comparable or better anti-inflammatory activities than the reference drug aspirin. Treatment of these anti-inflammatory agents did not prolong the tail bleeding time in rat. In addition, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes exhibited good membrane permeability based on in vitro Caco-2 cell monolayer permeability assay. Furthermore, some preliminary structure-activity relationships were further analyzed among these compounds. Taken together, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes may represent a new class of anti-inflammatory drugs with safer pharmacological profile.
Gu, Keli,Bi, Lanrong,Zhao, Ming,Wang, Chao,Ju, Jingfang,Peng, Shiqi
p. 6273 - 6290
(2008/04/05)