- Synthesis and evaluation of oxindoles as promising inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1
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Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as an important therapeutic target for the treatment of cancer, chronic infections and other diseases that are associated with immune suppression. Recent developments in understanding the catalytic mechanism of the IDO1 enzyme revealed that conversion of l-tryptophan (l-Trp) to N-formylkynurenine proceeded through an epoxide intermediate state. Accordingly, we synthesized a series of 3-substituted oxindoles from l-Trp, tryptamine and isatin. Compounds with C3-substituted oxindole moieties showed moderate inhibitory activity against the purified human IDO1 enzyme. Their optimization led to the identification of potent compounds, 6, 22, 23 and 25 (IC50 = 0.19 to 0.62 μM), which are competitive inhibitors of IDO1 with respect to l-Trp. These potent compounds also showed IDO1 inhibition potencies in the low-micromolar range (IC50 = 0.33-0.49 μM) in MDA-MB-231 cells. The cytotoxicity of these potent compounds was trivial in different model cancer (MDA-MB-231, A549 and HeLa) cells and macrophage (J774A.1) cells. Stronger selectivity for the IDO1 enzyme (124 to 210-fold) over the tryptophan 2,3-dioxygenase (TDO) enzyme was also observed for these compounds. These results suggest that the oxindole moiety of the compounds could mimic the epoxide intermediate state of l-Trp. Therefore, the structural simplicity and low-micromolar inhibition potencies of these 3-substituted oxindoles make them quite attractive for further investigation of IDO1 function and immunotherapeutic applications.
- Paul, Saurav,Roy, Ashalata,Deka, Suman Jyoti,Panda, Subhankar,Srivastava, Gopal Narayan,Trivedi, Vishal,Manna, Debasis
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p. 1640 - 1654
(2017/08/22)
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- C ring may be dispensable for β-carboline: Design, synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of β-carboline alkaloids
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According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure-activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3 ± 2.1%, 67.1 ± 1.9%, 68.7 ± 1.3%, and 64.5 ± 3.1%, 500 μg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.
- Huang, Yuanqiong,Liu, Yongxian,Liu, Yuxiu,Song, Hongjian,Wang, Qingmin
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p. 462 - 473
(2016/01/25)
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- Tryptophan derivative, preparing method and application in preventing and treating plant viruses, killing bacteria and killing insects
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The invention relates to a tryptophan derivative (I), a preparing method of the tryptophan derivative (I), and application of the tryptophan derivative (I) in preventing and treating plant viruses, killing bacteria and killing insects. The formula of the tryptophan derivative (I) is shown in the description, and the meanings of all groups in the formula are shown in the description. The tryptophan derivative expresses especially excellent plant virus resisting activity, and also has broad-spectrum bactericidal activity and insecticidal activity.
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Paragraph 0085; 0086; 0087
(2017/06/02)
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- LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates
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Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood–brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure–activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.
- Zur, Arik A.,Chien, Huan-Chieh,Augustyn, Evan,Flint, Andrew,Heeren, Nathan,Finke, Karissa,Hernandez, Christopher,Hansen, Logan,Miller, Sydney,Lin, Lawrence,Giacomini, Kathleen M.,Colas, Claire,Schlessinger, Avner,Thomas, Allen A.
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supporting information
p. 5000 - 5006
(2016/10/05)
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- Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis
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Marine actinomycete-derived natural products continue to inspire chemical and biological investigations. Nocardioazines A and B (3 and 4), from Nocardiopsis sp. CMB-M0232, are structurally unique alkaloids featuring a 2,5-diketopiperazine (DKP) core functionalized with indole C3-prenyl as well as indole C3- and N-methyl groups. The logic of their assembly remains cryptic. Bioinformatics analyses of the Nocardiopsis sp. CMB-M0232 draft genome afforded the noz cluster, split across two regions of the genome, and encoding putative open reading frames with roles in nocardioazine biosynthesis, including cyclodipeptide synthase (CDPS), prenyltransferase, methyltransferase, and cytochrome P450 homologs. Heterologous expression of a twelve gene contig from the noz cluster in Streptomyces coelicolor resulted in accumulation of cyclo-l-Trp-l-Trp DKP (5). This experimentally connected the noz cluster to indole alkaloid natural product biosynthesis. Results from bioinformatics analyses of the noz pathway along with challenges in actinomycete genetics prompted us to use asymmetric synthesis and mass spectrometry to determine biosynthetic intermediates in the noz pathway. The structures of hypothesized biosynthetic intermediates 5 and 12-17 were firmly established through chemical synthesis. LC-MS and MS-MS comparison of these synthetic compounds with metabolites present in chemical extracts from Nocardiopsis sp. CMB-M0232 revealed which of these hypothesized intermediates were relevant in the nocardioazine biosynthetic pathway. This established the early and mid-stages of the biosynthetic pathway, demonstrating that Nocardiopsis performs indole C3-methylation prior to indole C3-normal prenylation and indole N1′-methylation in nocardioazine B assembly. These results highlight the utility of merging bioinformatics analyses, asymmetric synthetic approaches, and mass spectrometric metabolite profiling in probing natural product biosynthesis.
- Alqahtani, Norah,Porwal, Suheel K.,James, Elle D.,Bis, Dana M.,Karty, Jonathan A.,Lane, Amy L.,Viswanathan, Rajesh
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supporting information
p. 7177 - 7192
(2015/07/01)
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- Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist
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Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2-) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein. The Royal Society of Chemistry 2013.
- Hwang, Tsong-Long,Hung, Chih-Hao,Hsu, Ching-Yun,Huang, Yin-Ting,Tsai, Yu-Chi,Hsieh, Pei-Wen
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p. 3742 - 3755
(2013/06/27)
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- Orthogonal protecting groups in the synthesis of tryptophanyl- hexahydropyrroloindoles
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The synthesis of various polycyclic systems containing aC 3a-Ni bond between a hexahydropyrrolo[2,3-b]indole and an indole tryptophan is described here. A series of experiments were performed to determine the best combination of five orthogonal protecting groups and the best reaction conditions for formation of said bond, which is a common feature among many recently discovered marine natural products.
- Ruiz-Sanchis, Pau,Savina, Svetlana A.,Acosta, Gerardo A.,Albericio, Fernando,Alvarez, Mercedes
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- A concise preparation of the non-proteinogenic amino acid l-kynurenine
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A concise and practical preparation of the non-proteinogenic amino acid l-kynurenine is reported. The synthetic approach is scalable and provides ready access to this valuable amino acid in either l- or d-stereochemistry starting from l- or d-tryptophan, respectively. In the optimized procedure, two discreet oxidation steps are applied sequentially to convert the tryptophan indole ring into the keto-aniline moiety contained within the kynurenine side chain.
- Kleijn, Laurens H.J.,Müskens, Frederike M.,Oppedijk, Sabine F.,De Bruin, Gerjan,Martin, Nathaniel I.
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supporting information
p. 6430 - 6432
(2013/01/15)
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- PROCESS FOR PREPARING VAPREOTIDE
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A solution phase process for preparing vapreotide, having the formula:
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Page/Page column 21-22
(2010/11/27)
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- Aqueous phase mono-protection of amines and amino acids as N-benzyloxycarbonyl derivatives in the presence of β-cyclodextrin
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A simple and selective protection of amines/amino acids with Cbz-Cl has been achieved in aqueous phase with catalytic amounts of β-cyclodextrin in high yields at room temperature. This reaction proceeds without the formation of any by-products and has advantages over existing methods.
- Pavan Kumar,Somi Reddy,Narender,Surendra,Nageswar,Rama Rao
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p. 6393 - 6396
(2007/10/03)
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- Cyclodextrin-mediated deacylation of amino acid esters with marked stereoselectivity.
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With respect to the hydrolysis (deacylation) of Z-D(L)-amino acid esters (N-(benzyloxycarbonyl)-D(L)-amino acid p-nitrophenyl esters) mediated by alpha-, beta- and gamma-cyclodextrins (CyDs), a remarkably high enantioselectivity (L/D=9.0) was observed for the deacylation of Ala substrate with gamma-CyD. The kinetic results on the basis of the Michaelis-Menten principle indicate that the enantioselectivity should be mainly originated in the deacylation process of substrates following the formation of gamma-CyD-substrate (1 : 1) complexes. The computer modeling (molecular mechanics) studies on the inclusion complexes are also described.
- Goto, Koichi,Nakashima, Kentaro,Tanoue, Osamu,Nukushina, Satoshi,Toudo, Isao,Imamura, Chikara,Ihara, Yasuji,Matsumoto, Yoko,Ueoka, Ryuichi
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p. 1283 - 1285
(2007/10/03)
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- A facile and selective cleavage of prenyl esters catalyzed by CeCl3·7 H2O-NaI
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A highly selective cleavage of prenyl esters has been achieved in high yields using CeCl3·7 H2O-NaI in refluxing acetonitrile under neutral conditions. This method is mild and compatible with a wide variety of functional groups such
- Yadav,Subba Reddy,Venkateshwara Rao,Chand,Prasad
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p. 137 - 139
(2007/10/03)
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- Pd/C(en)-catalyzed chemoselective hydrogenation with retention of the N-Cbz protective group and its scope and limitations
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A chemoselective method for the hydrogenation of acetylene, olefin, azide, nitro and benzyl ester functionalities with retention of the aliphatic N-Cbz group was established. The chemoselectivity was accomplished by using a combination of 5% Pd/C-ethylenediamine [5% Pd/C(en)] and THF (or 1,4-dioxane) as a solvent, and the scope and limitations of this methodology were investigated. These results reinforce the utility of N-Cbz protective groups in synthetic chemistry, especially in peptide synthesis. (C) 2000 Elsevier Science Ltd.
- Hattori, Kazuyuki,Sajiki, Hironao,Hirota, Kosaku
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p. 8433 - 8441
(2007/10/03)
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- Chemoselective alkoxycarbonylation reagent having trifluoromethylsulfonyl-4-trifluoromethylanilide as a leaving group
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N-Benzyloxy- and N-tert-butoxycarbonyltrifluoromethylsulfonyl-4-trifluoromethylanilides were prepared and were found to be chemoselective and shelf-storable alkoxycarbonylation reagents.
- Yasuhara, Tomohisa,Nagaoka, Yasuo,Tomioka, Kiyoshi
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p. 2233 - 2234
(2007/10/03)
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- An Effective Water-Free Aprotic System for Dissolving Free Amino Acids
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An effective water-free system was proposed for dissolution and subsequent use in peptide synthesis of free amino acids and their derivatives. It consists of dimethylformamide, a tertiary base, and inorganic additives. Neutral salts (CF3COONa, Ba(ClO4)2, Ca(ClO4)2, NaClO4, BaI2, or Ca(NO3)2) serve as the inorganic additives that increase the solubility of free amino acids in dimethylformamide and provide true 0.2-3 M amino acid solutions. Triethylamine and N-methylmorpholine are most suitable as the tertiary bases. This system was used in reactions with acylating agents: Boc2O, ZOSu, FmocOSu, and activated derivatives of Nα-protected amino acids or peptides. The corresponding amino acid derivatives or Nα-protected di-, tri-, and tetrapeptides were obtained in yields of 80-99 percent at the reaction times of 30-240 min.
- Raydnov, M. G.,Klimenko, L. V.,Mitin, Yu. V.
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p. 283 - 287
(2007/10/03)
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- The role of the medium in solvent isotope effects on serine protease action
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The hydrolysis of N-carbobenzyloxyaminoacyl-O-p-nitrophenyl esters derived from L-leucine, L-phenylalanine, and L-tryptophan, with catalysis by bovine pancreatic α-chymotrypsin at pH 7.00 at 25.00°C in water containing acetonitrile from 15.0% to 60% (v/v)
- Tian, Jiaher,Tan, Jue,Schowen, K. Barbara,Schowen, Richard L.
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p. 781 - 786
(2007/10/03)
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- 3,5-substituted 4,5-dihydroisoxazoles as transglutaminase inhibitors
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The present invention is directed to certain 3,5 substituted, 4,5-dihydroisoxazoles, and methods for their use. These compounds are transgulatminase inhibitors, and are particularly effective in the inhibition of epidermal transglutaminase and the treatment of acne.
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- Direct Optical Resolution of Carboxylic Acids by Chyral HPLC on Tris(3,5-dimethylphenylcarbamate)s of Cellulose and Amylose
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A variety of racemic carboxylic acids have been for the first time directly resolved by normal-phase, high-performance liquid chromatography using a hexane-2-propanol eluting system containing a small amount (ca. 1percent) of a strong carboxylic acid, like formic acid, trichloroacetic acid, and trifluoroacetic acid.
- Okamoto, Yoshio,Aburatani, Ryo,Kaida, Yuriko,Hatada, Koichi
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p. 1125 - 1128
(2007/10/02)
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- Stereoselective Micellar Catalysis. Part V. Deacylation Behaviour in the Cleavage of Enantiomeric Esters by Optically Active Catalysts containing the Imidazolyl Group
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The rate constants of both acylation and deacylation in the cleavage of the enantiomers of amino acid p-nitrophenyl esters catalysed by optically active catalysts containing the imidazolyl group have been determined in the presence of surfactant micelles
- Ihara, Yasuji,Okamoto, Mari,Kawamura, Yoeko,Nakanishi, Eiji,Nango, Mamoru,Koga, Joichi
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p. 607 - 612
(2007/10/02)
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- On the Synthesis of Benzyloxycarbonyl Amino Acids
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Dibenzyl dicarbonate and 1-benzyloxycarbonyl-benzothiazole are proposed as efficient new acyl donors for the introduction of the benzyloxycarbonyl group into amines for the reversible protection of amino functions particularly in peptide synthesis.
- Wuensch, E.,Graf, W.,Keller, O.,Keller, W.,Wersin, G.
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p. 958 - 960
(2007/10/02)
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- New Amino-protective Reagents for t-Butoxycarbonylation and Benzyloxycarbonylation of Amines and Amino Acids
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New amino-protective reagents for t-butoxycarbonylation and benzyloxycarbonylation of amines and amino acids have been developed. t-Butyl 2-pyridyl carbonate and t-butyl S-(2-pyridyl) thiocarbonate react cleanly with various amines and amino acids to afford N-Boc amines and N-Boc amino acids in high yields.Benzyl 2-pyridyl carbonate and O-benzyl S-(2-pyridyl) thiocarbonate are also found to be very effective in the benzyloxycarbonylation of amino acids.
- Kim, Sunggak,Lee, Jae In,Yi, Kyu Yang
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p. 3570 - 3575
(2007/10/02)
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- 2(1H)-Pyridone as Leaving Group in Acylation Reactions - Applications in Peptide Synthesis
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Alkyl 2-pyridyl carbonates 3 or mixtures of 3 and the isomeric N-(alkoxycarbonyl)-2-pyridones 3' are useful for the introduction of urethane protective groups into amino acids.The N-protected amino acids 7 - 10 react with 2(1H)-pyridone (1a) using the carbodiimide method to yield 2-pyridyl active esters 11, which easily undergo coupling reactions with amino acid esters 12 with elimination of 1a to give peptides 13 in good yields as well as high optical purities.
- Effenberger, Franz,Brodt, Werner
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p. 468 - 482
(2007/10/02)
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- 3,6-Diisopropyl-2-hydroxypyrazine and 3,6-Diisopropyl-2-pyrazinethiol as Carriers of Some Alkoxycarbonyl Groups
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Some derivatives of benzyloxycarbonylated 3,6-diisopropyl-2-hydroxypyrazine and 3,6-diisopropyl-2-pyrazinethiol were prepared and shown to be versatile benzyloxycarbonylation reagents for amines and amino acids.It was also ascertained that 3,6-diisopropyl-2-hydroxypyrazine and 3,6-diisopropyl-2-pyrazinethiol serve effectively as carriers of the β,β,β-trichloroethoxycarbonyl group.
- Ohta, Akihiro,Inagawa, Yukiko,Mitsugi, Chie
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p. 1643 - 1646
(2007/10/02)
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- INTRAMOLECULAR CATALYTIC MECHANISMS INVOLVED IN THE ALKALINE HYDROLYSIS OF p-NITROPHENYL ESTERS OF α-CARBOBENZOXY AMINO ACIDS
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A study on the alkaline hydrolysis of p-nitrophenyl esters of α-carbobenzoxy amino acids, in the presence and absence of free amino acids as catalysts, are reported.The effect of free amino acids represents an interesting model for the study of the cataly
- Ascenzi, Paolo,Sleiter, Giancarlo,Antonini, Eraldo
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p. 307 - 318
(2007/10/02)
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- 3-ACYL- AND 3-ALKOXYCARBONYL-2-OXAZOLONES AND THEIR HOMOPOLYMERS AS AMINO-PROTECTING REAGENTS
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3-Acyl and 3-alkoxycarbonyl-2-oxazolones as well as their homopolymers serve as practically usefull N-protecting reagents of amines including α-amino acids.
- Kunieda, Takehisa,Higuchi, Tsunehiko,Abe, Yoshihiro,Hirobe, Masaaki
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p. 3065 - 3066
(2007/10/02)
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- Use of 2-pyrimidine thiol carbonates as acylating agents for amino or imino containing compounds
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Thiolcarbonates represented by the formula, SPC1 Wherein R1 and R2 are individually a hydrogen atom or a methyl group, and R3 is a straight chain or branched chain saturated or unsaturated alkyl group having 1 to 5 carbon atoms or is a benzyl or benzhydryl group which may be nuclear substituted, are quite useful for protecting the amino or imino groups of amines, hydrazines, amino acids and peptides with groups of the formula EQU1 The thiolcarbonates can be easily produced by reacting an alkali metal salt of 2-mercaptopyrimidine with phosgene, and reacting the resulting thiolchloroformate with an alcohol (R3 OH), or by reacting a 2-mercaptopyrimidine with a halocarbonic acid ester.
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