- N-Pyrazinoyl substituted amino acids as potential antimycobacterial agents-the synthesis and biological evaluation of enantiomers
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Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 μM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing l-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-d/l-Pgl-Me, MIC 1.95 μg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the d- and l-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.
- Bárta, Pavel,Dole?al, Martin,Horá?ek, Ond?ej,Jand'Ourek, Ond?ej,Janou?ek, Ji?í,Juhás, Martin,Kone?ná, Klára,Ku?era, Radim,Ku?erová, Lucie,Kubí?ek, Vladimír,Kune?, Ji?í,Paterová, Pavla,Zitko, Jan
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- Exciton-Coupled Circular Dichroism Characterization of Monotopically Binding Guests in Host?Guest Complexes with a Bis(zinc porphyrin) Tweezer
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A stiff-stilbene-linked bisporphyrin tweezer with inherent helicity was used for exciton-coupled circular dichroism (ECCD) characterization of a series of monotopically binding amine guest molecules. CD signals were observed for a variety of monoamines at relatively low tweezer/amine (host/guest) ratios between 1 : 10 to 1 : 70. For the amines producing the most intense CD signals, a binding stoichiometry of 1 : 2 was found. A likely explanation is the presence of guest-guest interactions in the complexes. This is supported by the correlation observed between CD signal intensity and magnitude of possible noncovalent binding between the guests, which can be divided into three groups showing no, moderate and strong response, respectively. Further support for this rationalization comes from molecular modelling.
- Olsson, Sandra,Sch?fer, Clara,Blom, Magnus,Gogoll, Adolf
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p. 1169 - 1178
(2019/01/04)
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- Method for preparing amino ether compounds
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The invention belongs to the technical field of organic synthesis and relates to a method for preparing amino ether compounds. The method comprises the following steps: by taking amino alcohol as a raw material, protecting amino in the amino alcohol so as to obtain Schiff base; carrying out an etherification reaction on the hydroxyl group in the Schiff base; and finally, performing amino deprotection, thereby obtaining corresponding amino ethers. The method disclosed by the invention has high regio-selectivity, the substrates of higher than 99.9% are subjected to etherification reaction, the reaction conversion ratio of each step is higher than 99.8%, and the total yield is higher than 95%; when amino alcohol is chiral, the amino ethers with retention of configuration can be obtained; and moreover, each step of the method is a conventional operation, the process cost is low, and three wastes are few, the energy consumption is low, an environment-friendly effect is achieved, and large-scale industrial production is easily realized.
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Paragraph 0061; 0064; 0065
(2017/08/26)
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- STABILIZED POLYPEPTIDES AND USES THEREOF
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The present invention provides inventive stabilized STAT polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stabilized STAT polypeptides.
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- In situ deprotection and incorporation of unnatural amino acids during cell-free protein synthesis
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The S30 extract from E. coli BL21 Star (DE3) used for cell-free protein synthesis removes a wide range of α-amino acid protecting groups by cleaving α-carboxyl hydrazides; methyl, benzyl, tert-butyl, and adamantyl esters; tert-butyl and adamantyl carboxamides; α-amino form-, acet-, trifluoroacet-, and benzamides and sidechain hydrazides and esters. The free amino acids are produced and incorporated into a protein under standard conditions. This approach allows the deprotection of amino acids to be carried out in situ to avoid separate processing steps. The advantages of this approach are demonstrated by the efficient incorporation of the chemically intractable (S)-4-fluoroleucine, (S)-4,5- dehydroleucine, and (2S,3R)-4-chlorovaline into a protein through the direct use of their respective precursors, namely, (S)-4-fluoroleucine hydrazide, (S)-4,5-dehydroleucine hydrazide, and (2S,3R)-4-chlorovaline methyl ester. These results also show that the fluoroand dehydroleucine and the chlorovaline are incorporated into a protein by the normal biosynthetic machinery as substitutes for leucine and isoleucine, respectively. Copyright
- Arthur, Isaac N.,Hennessy, James E.,Padmakshan, Dharshana,Stigers, Dannon J.,Lesturgez, Stéphanie,Fraser, Samuel A.,Liutkus, Mantas,Otting, Gottfried,Oakeshott, John G.,Easton, Christopher J.
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supporting information
p. 6824 - 6830
(2013/06/26)
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- Enantioselective benzoylation of α-amino esters using (S)-1-benzoyl-2-(α-acetoxyethyl)benzimidazole, a chiral benzimidazolide
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(Chemical Equation Presented) A new chiral benzimidazolide is developed as a nonenzymatic acylating agent for enantioselective benzoylation of racemic α-amino esters. The process is highly efficient, which exhibits uniformly high enantioselectivity for α-amino esters with or without aryl substituents under mild reaction conditions. The chiral benzimidazolide is inexpensive and is easily accessible.
- Karnik, Anil V.,Kamath, Suchitra S.
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p. 7435 - 7438
(2008/02/11)
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- P38 inhibitors and methods of use thereof
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Inhibitors of p38 and methods for producing these inhibitors are provided. Also provided are pharmaceutical compositions comprising the inhibitors of the invention, methods of utilizing the inhibitors and pharmaceutical compositions comprising said inhibi
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Page/Page column 23
(2010/11/24)
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- Stereoselective synthesis of δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids
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Enantiomerically pure δ-heteroaryl substituted β-hydroxy-γ,δ-unsaturated α-amino acids were stereoselectively synthesized starting from (2R)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Schoellkopf's reagent) and suitable β-heteroaryl-α,β-unsaturate
- Cremonesi, Giuseppe,Croce, Piero Dalla,Fontana, Francesco,Rosa, Concetta La
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p. 2637 - 2641
(2007/10/03)
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- Compositions and methods for selectively binding amines or amino acid enantiomers over their counter-enantiomers
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Naphthyl crown ether ligand molecules containing at least two naphthyl groups that are covalently bonded to suitable solid supports and coated by hydrophobic organic solvents are disclosed. These compositions and associated methods are characterized by selectivity of desired amine or amino acid enantiomers over their counter-enantiomers and derivatives. The composition preferably has an α-value greater than or equal to 4. This allows for the separation of such enantiomers with nonchromatographic resin bed separations of three separation stages or less.
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Page column 17; 18
(2010/11/30)
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- Direct organo-catalytic asymmetric α-amination of aldehydes - A simple approach to optically active α-amino aldehydes, α-amino alcohols, and α-amino acids
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L-Proline as the catalyst: The first direct asymmetric α-amination of aldehydes using L-proline as the catalyst is presented (see scheme; Pg = protecting group). This new reaction gives easy access to optically active α-amino aldehydes, α-amino alcohols, and α-amino acids from simple and easily available starting materials and catalysts. The reactions proceed in high yields and excellent enantioselectivities with as little as 2 mol % of the catalyst.
- Bogevig, Anders,Juhl, Karsten,Kumaragurubaran, Nagaswamy,Zhuang, Wei,Jorgensen, Karl Anker
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p. 1790 - 1793
(2007/10/03)
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- Kinetic resolution of amines with enantiopure 3-N,N-diacylaminoquinazolin-4(3H)-ones
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The title compounds (DAQs) are chiral when the two N-acyl groups are different because of the absence of rotation around the N-N bond (a chiral axis). Enantiopure DAQs have been obtained by incorporation of a chiral centre in enantiopure form either into the substituent at the Q2-position or into one of the N-acyl groups, or into both, followed by separation of diastereoisomers. This separation is unnecessary in one case because conversion of the N-monoacylaminoquinazolinone (MAQ) into the DAQ is completely diastereoselective. Neither is separation of diastereoisomers necessary with 3-[N,N-di-(S)-2-acetoxypropanoylamino]-2-diphenylmethylquinazolin-4(3H)-one 37a: this DAQ 37a has its N-N bond rendered a chiral axis by the bias in its imide moiety wholly in favour of one exo/endo conformation. The high chemoselectivity exhibited by N,N-diacetyl- or N,N-dibenzoylaminoquinazolinones in reaction with the less hindered of two secondary amines (pyrrolidine in the presence of 1 eq. of piperidine) has a stereoselective counterpart: reaction of the above enantiopure DAQs enantioselectively with racemic amines leading to kinetic resolution. Using 1 eq. of DAQ and 2 eq. of amine, both the derivatised and unreacted amine enantiomers are recovered with high enantiomeric excess (ee) (better than 90% ee in some cases). Some of the higher ees are found in the recovered amides where non-chemoselective attack on both N-acyl groups of the DAQ has occurred: from the opposite configurations of the amine component in the two amides and from the low enantiopurity of the recovered unreacted amine, reaction of each of the N-acyl groups with complementary enantiomers of the amine is occurring (parallel kinetic resolution). Although higher ees are, in general, obtained using secondary amines, high ees are obtained in some cases using 1-phenylethylamine and, in particular, amino acid esters (valine and alanine). The sense of enantioselectivity in the reactions of these DAQs with amines is controlled by the configuration of the N-N axis: replacing the Q group in an N-(S)-2-acetoxypropanoyl-N-acetyl-bearing DAQ by phthalimide, thus eliminating the N-N chiral axis, drastically reduces the level of kinetic resolution.
- Al-Sehemi, Abdullah G.,Atkinson, Robert S.,Fawcett, John
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p. 257 - 274
(2007/10/03)
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- Efficient synthesis of differentially protected (S,S)-2,7- diaminooctanedioic acid, the dicarba analogue of cystine
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Convenient preparative syntheses of differentially protected forms of (S,S)-2,7-diaminooctanedioic acid (2), suitable for application in peptide chemistry, are described. The key compound, the di-Cbz-protected phenacyl monoester 7a (Cbz = [(benzyloxy)carb
- Lange, Meinolf,Fischer, Peter M.
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p. 2053 - 2061
(2007/10/03)
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- Stereoselective synthesis of α,α'-bridged bis(α-alanine) derivatives
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Stereoselective syntheses of α,α'-dimethylated C2-C4 alkylene- bridged bis(glycine) methyl esters are described. The products were further converted into N-Fmoc-protected bis(amino acids).
- Lange, Meinolf,Undheim, Kjell
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p. 5337 - 5344
(2007/10/03)
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- Stereoselective synthesis of meso-2,6-diaminopimelic acid and its selectively protected derivatives
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Four synthetic routes to selectively protected derivatives and isomers of meso-diaminopimelic acid (DAP) (1a), a key constituent of bacterial peptidoglycan, were investigated. N-(tert-butyloxycarbonyl)-D-allylglycine (2) and N-(benzyloxycarbonyl)-L-allylglycine (4) were esterified to ethylene glycol and cyclized via olefin metathesis to a protected derivative 7 of 2,7- diaminosuberic acid. Analogous linking of propane-1,3-diol with 2 and potential precursors of N-(benzyloxycarbonyl)-L-vinylglycine moieties, such as N-(benzyloxycarbonyl)-L-glutamate or N-(benzyloxycarbonyl)-L-methionine sulfoxide, gave 12 or 15, both of which produced the α,β-unsaturated ester 14 upon attempted generation of the vinylglycine precursor for olefin metathesis to DAP derivatives. An alternative route, based on SnCl4- catalyzed ene reaction of methyl N-(benzyloxycarbonyl)-L-allylglycinate (18) with glyoxylate esters of phenylcyclohexanol isomers as chiral auxiliaries, gave ca. 85:15 ratios of diastereomeric alcohols (19 or 20). These could be transformed to DAP derivatives in a series of steps employing azide displacement of corresponding mesylates to introduce the second nitrogen. A third method, involving reduction of pure dimethyl (6S)-2-keto-6-[N- (benzyloxycarbonyl)amino]pimelate (32) to the corresponding alcohol 33 with (S)-binaphthol-ruthenium catalyst as the key step, gives a 79:21 isomeric ratio. The fourth route employs the bis(oxazoline)-copper complex 41 as a chiral catalyst for the ene reaction of methyl (S)-4- (phenylthio)allylglycinate (39) and methyl glyoxylate to afford 42 and 94:6 isometric ratio. Nickel boride removal of sulfur and the double bond in the presence of the Cbz group gives the desired alcohol, dimethyl (2S,6S)-6-[N- (benzyloxycarbonyl)amino]-2-hydroxyheptane-1,7-dioate (33). The required selectively protected second nitrogen is introduced using Mitsunobu inversion with N-tert-butyl [[2-(trimethylsilyl)-ethyl]sulfonyl]carbomate (34) as a key step.
- Gao, Yong,Lane-Bell, Patricia,Vederas, John C.
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p. 2133 - 2143
(2007/10/03)
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- Ruthenium(II) in ring closing metathesis for the stereoselective preparation of cyclic 1-amino-1-carboxylic acids
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Stereoselective synthesis of α-amino acids where the α-carbon of the amino acid is incorporated into a five-, six- or seven-membered ring is described. The stereoselective control results from stepwise bisalkenylation of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine. Ring closing metathesis was effected by ruthenium(II)catalysis. The spiro-cycloalkene intermediates were further transformed into 1-aminocycloalkene-1-carboxylic acid derivatives by mild acid hydrolysis.
- Hammer, Kristin,Undheim, Kjell
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p. 2309 - 2322
(2007/10/03)
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- Stereospecific Synthesis of α-Deuteriated α-Amino Acids: Regiospecific Deuteriation of Chiral 3-Isopropyl-2,5-dimethoxy-3,6-dihydropyrazines
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Base-catalysed deuteriation of (3R)- or (3S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazines in refluxing CH3O2H-2H2O gives the -isotopomer in excellent yields without disturbing the stereogenic centre at C-3.These compounds provide convenient and efficient access to a range of (R)- and (S)-α-deuteriated α-amino acids, including serine, aspartic acid, allylglycine and phenylalanine, via alkylation of the butyllithium generated C-6 anion.
- Rose, Janet E.,Leeson, Paul D.,Gani, David
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p. 157 - 166
(2007/10/02)
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- Enantioselective synthesis of isotopically labelled L-α-amino acids preparation of 13C-, 18O- and 2H-labelled L-serines and L-threonines
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[3-18O]-L-serine, [3-13C]-L-serine, [3-18O]-L-threonine, [3,4-13C2]-L-threonine and [3-2H]-L-threonine are prepared from simple commercially available, isotopically enriched starting materials like H218O, [13C] paraformaldehyde, [13C2]-acetaldehyde and (1-2H]-acetaldehyde. The introduction of the side chain is based on the reaction of the anion of the bislactimether of cyclo-(D-Val-Gly) with a suitable reagent. For serine this is isotopically labelled benzylchloromethylether, whereas for threonine labelled acetaldehyde is used in combination with chlorotitaniumtris[diethylamide], introducing both stereocentres in one single step. The isotopomers of serine and threonine are obtained on the gram scale in good yields and high enantiomeric and diasteriomeric excesses. New syntheses for [18O]-benzylalcohol and isotopically enriched benzylchloromethylether are reported. Following the presented synthetic scheme these amino acids can be labelled at any position or at any combination of positions.
- Karstens,Berger,Van Haren,Lugtenburg,Raap
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p. 1077 - 1096
(2007/10/02)
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- Asymmetric total synthesis of the individual diastereoisomers of hypoglycin A
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The individual diastereoisomers that constitute the unusual methylenecyclopropane containing α-amino acid hypoglycin A have been synthesised utilising the Sharpless epoxidation to permit an asymmetric methylenecyclopropane synthesis.
- Baldwin, Jack E.,Adlington, Robert M.,Bebbington, David,Russell, Andrew T.
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p. 12015 - 12028
(2007/10/02)
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- Regiospecific Deuteriation of Chiral 3-Isopropyl-2,5-dimethoxy-3,6-dihydropyrazines in the Stereospecific Synthesis of α-Deuteriated α-Amino Acids
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Base-catalysed deuteriation of (3R)- or (3S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine in refluxing CH3O(2)H-(2)H2O gives the isotopomer in excellent yield without disturbing the stereogenic centre at C-3, and thus providing convenient and e
- Rose, Janet E.,Leeson, Paul D.,Gani, David
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p. 1563 - 1566
(2007/10/02)
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- 68. Stereoselective Synthesis of (2S,6S)-2,6-Diaminoheptanedioic Acid and of Unsymmetrical Derivatives of meso-2,6-Diaminoheptanedioic Acid
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Specific inhibition of enzymes of the diaminopimelate pathway (L-lysine biosynthesis) should, in principle, lead to selective antibacterial agents or herbicides.For this purpose, enantioselective syntheses were devised for (2S,6S)-2,6-diaminoheptanedioic acid (L,L-diaminopimelate, 1), (2R,6S)-2,6-diamino-2-methylhept-3-enedioic acid (10), (2R,6S)-2,6-diaminohept-3-enedioic acid (9),(2R,6S)-2,6-diamino-4-fluorohept-3-enedioic (42),and (2S,6S)-2,6-diamino-3-chloroheptanedioic acid (5).The Schoellkopf bislactim-ether methodology was applied to control the configuration of C(2) and C(6) of 1, C(2) of 10, as well as C(6) of 9 and 42.Semialdehyde derivatives of L-glutamate afforded C(6) of 10 and 5, while the (R)-configurated C(2) of 9 and 42 were derived from L-serine.For this purpose, the synthesis of the Garner aldehyde 32 has been improved.As chromatographic purifications and the low temperatures for the reduction of the carboxylic acid are eliminated, this valuable intermediate can now be prepared in bulk quantities.An enantio- and diastereoselective aldol addition of a glycine titanium-enolate was applied for the construction of 5(C(2) and C(3)).As all chiral building blocks and reagents used are available in both enantiomeric forms, these routes should also be suitable for the selective synthesis of the other stereoisomers of these bis(α-amino acids).
- Bold, Guido,Allmendinger, Thomas,Herold, Peter,Moesch, Luzia,Schaer, Hans-Peter,et al.
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p. 865 - 882
(2007/10/02)
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