- A simple synthesis of 6-hydroxynorleucine based on the rearrangement of an N-nitrosodichloroacetamide
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6-Hydroxynorleucine is a versatile chemical intermediate that has found broad use in target-oriented syntheses of numerous biologically active molecules. Despite its widespread use, and despite the various strategies that have been reported for its prepar
- McCarthy, Blaine G.,Macarthur, Nicholas S.,Jakobsche, Charles E.
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p. 502 - 504
(2016/01/12)
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- Nitrilases
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition, methods of designing new nitrilases and methods of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Paragraph 0265-0268
(2015/09/22)
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- Nitrilases, nucleic acids encoding them and methods for making and using them
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition methods of designing new nitrilases and method of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Page/Page column 52; 53
(2016/01/09)
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- KDM1A INHIBITORS FOR THE TREATMENT OF DISEASE
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Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDMIA, and methods of increasing gamma globin gene expression in a human or animal subject are also provided for the treatment diseases such as sickle cell disease.
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Paragraph 0288
(2014/10/18)
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- Asymmetric synthesis of l-6-hydroxynorleucine from 2-keto-6-hydroxyhexanoic acid using a branched-chain aminotransferase
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l-6-Hydroxynorleucine was synthesized from 2-keto-6-hydroxyhexanoic acid using branched-chain aminotransferase from Escherichia coli with l-glutamate as an amino donor. Since the branched-chain aminotransferase was severely inhibited by 2-ketoglutarate, the branched-chain aminotransferase reaction was coupled with aspartate aminotransferase and pyruvate decarboxylase. Aspartate aminotransferase converted the inhibitory 2-ketoglutarate back to l-glutamate by using l-aspartate as an amino donor. On the other hand, pyruvate decarboxylase further shifted the reaction equilibrium towards l-6-hydroxynorleucine through decarboxylation of pyruvate to acetaldehyde. The concerted action of the three enzymes significantly enhanced the yield compared to that of branched-chain aminotransferase alone. In the coupled reaction, 90.2 mM l-6-hydroxynorleucine (> 99% ee) was produced from 100 mM 2-keto-6-hydroxyhexanoic acid, whereas in a single branched-chain aminotransferase reaction only 22.5 mM l-6-hydroxynorleucine (> 99% ee) was produced.
- Seo, Young-Man,Kim, Aran,Bea, Han-Seop,Lee, Sang-Hyeup,Yun, Hyungdon
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scheme or table
p. 171 - 176
(2012/06/30)
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- An alternative total synthesis of pentosidine
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Pentosidine, a fluorescent advanced glycation endproduct that serves as a biomarker of diabetic complications, kidney dysfunction, oxidative stress, and aging and age-related diseases, was synthesized from 2,3-diaminopyridine and benzyloxycarbonyl (Cbz) p
- Liu, Yahua,Zhang, Weihan,Sayre, Lawrence M.
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p. 426 - 433
(2011/06/22)
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- Selective inhibitors of plasmepsin II of Plasmodium falciparum on the basis of pepstatin
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A number of new inhibitors of plasmepsin II (PlmII) Plasmodium falciparum, which was one of the key factors of survival of malarial parasite, was synthesized. The inhibitors were analogues of pepstatin with different substitutions for the alanine residue.
- Rumsh,Mikhailova,Mikhura,Prudchenko,Chikin,Mikhaleva,Kaliberda,Dergousova,Mel'Nikov,Formanovskii
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experimental part
p. 660 - 667
(2009/04/07)
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- Synthesis of 7,6-fused bicyclic lactams for use as beta-turn mimics
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An improved synthesis of the 7,6-fused bicyclic lactam is presented starting from readily available chiral starting materials. (S)-allylglycine is protected as the phthalimide derivative and coupled with (S)-2-amino-6- hydroxyhexanoic acid methyl ester. Oxidation of the hydroxyl group to the aldehyde followed by enamide synthesis and acyl iminium ion cyclization provide the bicyclic system as a single diastereomer in good overall yield. Copyright Taylor & Francis Group, LLC.
- Morales, Omar,Seide, Wesley,Watson, Samuel
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p. 965 - 973
(2007/10/03)
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- Process for producing hydroxyamino acid derivative
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Provided is a method of preparing a hydroxyamino acid derivative, particularly in an optically active form thereof with high efficiency. Specifically, provided is a method of preparing hydroxyamino acid derivatives represented by Formula (I) or salts ther
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- Process development in the synthesis of the ACE intermediate MDL 28,726
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MDL 28,726 is a key intermediate in the synthesis of the ACE inhibitors MDL 27,210A and MDL 100,240. An efficient nine-step synthesis of this tricyclic acid, which has three chiral centers, was developed beginning with 3,4-dihydro-2H-pyran. A key step in the synthesis features an enzyme-catalyzed resolution of the lithium salt of the W-trifluoroacetamide of (A,5)-6-hydroxynorleucine. All of the steps were optimized and completed in reactor equipment using environmentally acceptable processes. Process development of this route is described.
- Horgan, Stephen W.,Burkhouse, David W.,Cregge, Robert J.
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p. 241 - 247
(2013/09/08)
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- Enzymatic synthesis of L-6-hydroxynorleucine
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L-6-Hydroxynorleucine, a key chiral intermediate used for synthesis of a vasopeptidase inhibitor, was prepared in 89% yield and >99% optical purity by reductive amination of 2-keto-6-hydroxyhexanoic acid using glutamate dehydrogenase from beef liver. In an alternate process, racemic 6- hydroxynorleucine produced by hydrolysis of 5-(4-hydroxybutyl)hydantoin was treated with D-amino acid oxidase to prepare a mixture containing 2-keto-6- hydroxyhexanoic acid and L-6-hydroxynorleucine followed by the reductive amination procedure to convert the mixture entirely to L-6-hydroxynorleucine, with yields of 91 to 97% and optical purities of >99%.
- Hanson, Ronald L.,Schwinden, Mark D.,Banerjee, Amit,Brzozowski, David B.,Chen, Bang-Chi,Patel, Bharat P.,McNamee, Clyde G.,Kodersha, Gus A.,Kronenthal, David R.,Patel, Ramesh N.,Szarka, Laszlo J.
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p. 2247 - 2252
(2007/10/03)
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- Hydroxyoxazolidines as alpha-aminoacetaldehye equivalents: novel inhibitors of calpain.
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The synthesis of [1-[(5-hydroxy-4-(phenylmethyl)-3-oxazolidinyl)carbonyl]-2-ethylpropy lcarbamic acid phenylmethyl ester (2; MDL 104,903), a potent inhibitor of calpain, is described. Synthesis of related compounds, which offer insights into the mechanism of action for 2, are also described, as is an O-acetyl prodrug derivative of 2.
- Peet,Kim,Marquart,Angelastro,Nieduzak,White,Friedrich,Flynn,Webster,Vaz,Linnik,Koehl,Mehdi,Bey,Emary,Hwang
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p. 2365 - 2370
(2007/10/03)
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- Biocatalytic synthesis of chiral intermediates for antiviral and antihypertensive drugs
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The chiral intermediate (1S,2R) [3-chloro-2-hydroxy-1-(phenylmethyl)propyl] carbamic acid, 1,1-dimethyl-ethyl ester 2a was prepared for the total synthesis of a human immunodeficiency virus protease inhibitor, BMS-186318. The stereoselective reduction of (1S) [3-chloro-2-oxo-1(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester 1 was carried out using microbial cultures, among which Streptomyces nodosus SC 13149 efficiently reduced 1 to 2a. A reaction yield of 80%, enantiomeric excess (e.e.) of 99.8%, and diastereomeric purity of 99% were obtained for chiral alcohol 2a. Chiral L-6-hydroxy norleucine 3, an intermediate in the synthesis of antihypertensive drug, was prepared by reductive amination of 2-keto-6-hydroxyhexanoic acid 4 using beef liver glutamate dehydrogenase. The cofactor NADH required for this reaction was regenerated using glucose dehydrogenase from Bacillus sp. A reaction yield of 80% and e.e. of 99.5% were obtained for L-6-hydroxynorleucine 3. To avoid the lengthy chemical synthesis of the ketoacid, a second route was developed in which racemic 6-hydroxynorleucine [readily available from hydrolysis of 5-(4-hydroxybutyl) hydantoin 5] was treated with D-amino acid oxidase from Trigonopsis variabilis to selectively convert the D-isomer of racemic 6-hydroxynorleucine to 2-keto-6-hydroxyhexanoic acid 4 and L-6-hydroxynorleucine 3. Subsequently, the 2-keto-6-hydroxyhexanoic acid 4 was converted to L-6-hydroxynorleucine by reductive amination using glutamate dehydrogenase. A reaction yield of 98% and an e.e. of 99.5% were obtained.
- Patel, Ramesh N.
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p. 1275 - 1281
(2007/10/03)
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- A novel three-step hydroxy-deamination sequence: Conversion of lysine to 6-hydroxynorleucine derivatives
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Oxidation of carbamates with catalytic RuO4, generated from RuO2 and NaBrO3, provides the corresponding acyl carbamates, which can be reduced with NaBH4 to provide alcohols. Application of this methodology to L-lysine provides (S)-6-hydroxynorleucine derivatives.
- Nevill Jr., C. Richard,Angell, Paul T.
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p. 5671 - 5674
(2007/10/03)
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- Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase
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A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (
- Robl, Jeffrey A.,Sun, Chong-Qing,Stevenson, Jay,Ryono, Denis E.,Simpkins, Ligaya M.,Cimarusti, Maria P.,Dejneka, Tamara,Slusarchyk, William A.,Chao, Sam,Stratton, Leslie,Misra, Raj N.,Bednarz, Mark S.,Asaad, Magdi M.,Cheung, Hong Son,Abboa-Offei, Benoni E.,Smith, Patricia L.,Mathers, Parker D.,Fox, Maxine,Schaeffer, Thomas R.,Seymour, Andrea A.,Trippodo, Nick C.
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p. 1570 - 1577
(2007/10/03)
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- COMPOUNDS CONTAINING A FUSED BICYCLE RING AND PROCESSES THEREFOR
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Compounds of the formula STR1 wherein X is O or S--(O) t ; n is one or two; m is zero or one; Y is CH 2, O, or S--(O) t provided that Y is O or S--(O) t only when m is one; and A is STR2 are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective ACE inhibitors. Also disclosed are methods of preparation and intermediates.
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- A Novel Synthetic Route to Enantiomers of ε-Hydroxynorleucine and ε-Chloronorleucine from L- and D,L-Lysine
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Thermal rearrangement of (S)- or (R)-hexahydro-1-nitroso-3-phthalimido-2H-azepin-2-one to te corresponding lactone followed by nucleophilic ring opening of the latter gives ε-chloro- or ε-hydroxynorleucine.
- Belyaev, Alexander A.
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p. 439 - 440
(2007/10/02)
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- Reactivite du nitrite de sodium. V. Action sur les amino-acides, peptides et proteines
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The action of sodium nitrite on various amino-acids was re-examined in conditions approximating to a biological medium. 13C-NMR provides evidence of the existence of intramolecular ring closures and the formation of 5-membered rings with ornithine, citrulline and arginine.The reaction of cystine shows the opening of the sulphur bridges, whereas cysteine leads to the formation of carboxy-thiiran and 3-sulpho-lactic acid.The hydrolysis of the amide bonds of asparagine and glutamine is complete whereas the peptides studied - carnosine and aspartam - do not undergo hydrolysis of the peptide linkage.However, the first deamination of glutathion (γ-Glu-Cys-Gly) induces the peptide link to be broken and a cyclization with the formation of lactone to occur.A second deamination takes place on the cysteinyl residue released and allows the formation of a thiiran by intramolecular cyclization with the thiol group.The formation of thiiran was also observed with oxidized glutathion which has an S-S bridge.Finally, the formation of nitrosamines was detected by 15N-NMR during the reaction of sodium nitrite with two commercial products available to the general public.
- Gouesnard, Jean-Paul
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- Mycobactins: Synthesis of (-)-Cobactin T from ε-Hydroxynorleucine
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The synthesis of (-)-cobactin T is described, the key step being ring closure between C6 and the hydroxamate N of α-N-(tert-butoxycarbonyl)-ε-hydroxynorleucine O-benzylhydroxamate.
- Maurer, Peter J.,Miller, Marvin J.
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p. 2835 - 2836
(2007/10/02)
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- Obtention d'amino acides optiquement actifs a l'aide d'hydantoinases
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5-substituted hydantoines are intermediates in the Bucherer synthesis, the most widely used chemical synthesis of α-aminoacids.Enzymatic hydrolysis of these intermediates with hydantoinases leads to asymetric synthesis of optically active aminoacids.The enzymatic activities of two microbial strains are described: a Pseudomonas Sp. and an Arthrobacter globiformis, which catalyze the hydrolysis of a wide variety of hydantoines into D and L α-aminoacids respectively.In both cases, it was noticed that α-ureido (or 2-carbamoyl acids) are the reactive intermediates.Evidence is provided for the existence of a racemase.The experimental conditions for the culture of Arthrobacter are briefly described.
- Guivarch, Marcel,Gillonnier, Claude,Brunie, Jean-Claude
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