- Hybrid catalysis of 8-quinolinecarboxaldehyde and br?nsted acid for efficient racemization of α-amino amides and its application in chemoenzymatic dynamic kinetic resolution
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The combination of 8-quinolinecarboxaldehyde and benzoic acid proved to be an effective catalyst system for the racemization of N-unprotected α-aryl- or α-alkyl-substituted α-amino amides. Application of this system to chemoenzymatic dynamic kinetic resolution provided an efficient access to enantiomerically pure N-acetyl-α-amino amides in good to high yields.
- Kiyokawa, Mari,Nagato, Yuya,Ohmatsu, Kohsuke,Ooi, Takashi,Shirai, Yuto
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- Mapping the s1 and s1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents
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The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1′ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.
- Cianni, Lorenzo,Lemke, Carina,Gilberg, Erik,Feldmann, Christian,Rosini, Fabiana,Rocho, Fernanda Dos Reis,Ribeiro, Jean F. R.,Tezuka, Daiane Y.,Lopes, Carla D.,de Albuquerque, Sérgio,Bajorath, Jürgen,Laufer, Stefan,Leit?o, Andrei,Gütschow, Michael,Montanariid, Carlos A.
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- Synthetic method for chiral alpha-aminoamide compounds
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The invention provides a synthetic method for chiral alpha-aminoamide compounds, belongs to the technical field of organic synthetic methodology, and concretely relates to a synthetic method for chiral alpha-aminoamide compounds, wherein the method has a simple process, low costs and good economy. The method comprises the following steps: 1, performing ammonolysis: adding substituted chiral alpha-aminocarboxylate hydrochloride into concentrated ammonia water, performing stirring for 4-12h under a room temperature, wherein each 1mmol substituted chiral alpha-aminocarboxylate hydrochloride is corresponding to 2-8mL the concentrated ammonia water; 2, after a reaction is finished, performing distillation for removing ammonia water after the reaction to obtain crude products chiral alpha-aminoamide compounds; and 3, performing filtration on the obtained crude products chiral alpha-aminoamide compounds by adopting a manner of adding a solvent or performing purification on the obtained crude products chiral alpha-aminoamide compounds through a manner of column chromatography which uses ammonia water as a mobile phase to obtain the products chiral alpha-aminoamide compounds. Compared with the prior art, a large number of an ammonia gas for ammonolysis is not needed in the method, the process and post-treatment are simple, costs are low and reaction time is short.
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Paragraph 0042; 0043; 0044
(2018/01/11)
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- Characterization of an enantioselective amidase from Cupriavidus sp. KNK-J915 (FERM BP-10739) useful for enzymatic resolution of racemic 3-piperidinecarboxamide
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A novel amidase (CsAM) acting on (R,S)-N-benzyl-3-piperidinecarboxamide was purified from Cupriavidus sp. KNK-J915 (FERM BP-10739) and characterized. The enzyme acts on (R,S)-N-benzyl-3-piperidinecarboxamide S-selectively to yield (R)-N-benzyl-3-piperidinecarboxamide. Analytical gel filtration column chromatography and SDS-PAGE revealed that the enzyme is a tetramer with a subunit of approximately 47 kDa. It has a broad substrate spectrum against nitrogen-containing heterocyclic amides. Its optimal pH and temperature are 8.0-9.0 and 50 °C, respectively. The CsAM gene was cloned and sequenced, and it was found to comprise 1341 bp and encode a polypeptide of 46,388 Da. The deduced amino acid sequence exhibited 78% identity to that of a putative amidase (CnAM) from Cupriavidus necator JMP134. The cultured cells of recombinant Escherichia coli producing CnAM could be used for the S-selective hydrolysis of (R,S)-N-benzyl-3-piperidinecarboxamide but could not be used for the S-selective hydrolysis of (R,S)-3-piperidinecarboxamide because of its very low level of selectivity. In contrast, the cultured cells of recombinant E. coli producing CsAM could hydrolyze both (R,S)-N-benzyl-3-piperidinecarboxamide and (R,S)-3-piperidinecarboxamide with high S-selectivity.
- Nojiri, Masutoshi,Taoka, Naoaki,Yasohara, Yoshihiko
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p. 136 - 142
(2014/12/10)
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- 2-(N-Benzyl-N-phenylsulfonamido)alkyl amide derivatives as γ-secretase inhibitors
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A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
- Parker, Michael F.,Barten, Donna M.,Bergstrom, Carl P.,Bronson, Joanne J.,Corsa, Jason A.,Dee, Michael F.,Gai, Yonghua,Guss, Valerie L.,Higgins, Mendi A.,Keavy, Daniel J.,Loo, Alice,Mate, Robert A.,Marcin, Larry R.,McElhone, Katharine E.,Polson, Craig T.,Roberts, Susan B.,MacOr, John E.
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p. 6828 - 6831,4
(2020/09/02)
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- Carbamates of 4′-demethyl-4-deoxypodophyllotoxin: Synthesis, cytotoxicity and cell cycle effects
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In an attempt to generate compounds with superior bioactivity and reduced toxicity, 12 carbamates of 4′-demethyl-4-deoxypodophyllotoxin, N-(1-oxyl-4′-demethyl- 4-deoxypodophyllic)-α-amino acids amides, were synthesized and evaluated for antiproliferative activity and cell cycle effects. These synthesized compounds proved to be more hydrophilic, as well as improved or comparable in vitro cytotoxicities against four cell lines (A-549, HeLa, SiHa, and HL-60) compared with either parent DPT or anti-cancer drug VP-16. Furthermore, flow cytometric analysis exhibited that N-(1-oxyl-4′- demethyl-4-deoxypodophyllic)-d-α-methine amide (15f) induced cell cycle arrest in the G2/M phase in A-549 cells.
- Chen, Shi-Wu,Gao, Yuan-Yu,Zhou, Ni-Ni,Liu, Jie,Huang, Wen-Ting,Hui, Ling,Jin, Yan,Jin, Yong-Xin
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supporting information; experimental part
p. 7355 - 7358
(2012/02/04)
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- Enantiopure trans -3-arylaziridine-2-carboxamides: Preparation by bacterial hydrolysis and ring-openings toward enantiopure, unnatural D -α-amino acids
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Several racemic trans-3-arylaziridine-2-carboxamides were prepared and then resolved by Rhodococcus rhodochrous IFO 15564-catalyzed hydrolysis. The resulting enantiopure (2R,3S)-3-arylaziridine-2-carboxamides are adequate substrates to undergo fully stereoselective nucleophilic ring-openings at the C-3 ring position to finally yield enantiopure, unnatural d-α- aminocarboxylic acids. Experimental evidence is provided that suggests the fate of the (2S,3R)-3-arylaziridine-2-carboxylic acids concomitantly formed during the resolution processes. In this context, the similar bacterial resolution of racemic 1-arylaziridine-2-carboxamides and -carbonitriles, previously investigated by our research group, has been partially re-examined.
- Moran-Ramallal, Roberto,Liz, Ramon,Gotor, Vicente
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experimental part
p. 6614 - 6624
(2010/11/17)
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- Structure-based design of novel human Pin1 inhibitors (II)
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Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge-charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand-protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.
- Dong, Liming,Marakovits, Joseph,Hou, Xinjun,Guo, Chuangxing,Greasley, Samantha,Dagostino, Eleanor,Ferre, RoseAnn,Johnson, M. Catherine,Kraynov, Eugenia,Thomson, James,Pathak, Ved,Murray, Brion W.
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supporting information; experimental part
p. 2210 - 2214
(2010/06/15)
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- Induced-fit in the gas phase: Conformational effects on the enantioselectivity of chiral tetra-amide macrocycles
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The structure, stability, and reactivity of proton-bound diastereomeric [M?H?A]+ complexes between some amino acid derivatives (A) and several chiral tetra-amide macrocycles (M) have been investigated in the gas phase by ESI-FT-ICR and ESI-ITMS-CID mass spectrometry. The displacement of the A guest from the diastereomeric [M?H?A]+ complexes by reaction with the 2-aminobutane enantiomers (B) exhibits a distinct enantioselectivity with regards to the leaving amino acid A and, to a minor extent, to the amine reactant B. The emerging selectivity picture, discussed in the light of molecular mechanics calculations, provides compelling evidence that the most stable conformers of the selected chiral tetraamide macrocycles M may acquire in the gas phase a different conformation by induced fit on complexation with some representative amino acid derivatives A. This leads to the coexistence in the gas phase of stable diastereomeric [M?H?A] + eq-eq and ax-ax structures, in proportions depending on the configuration of A and M and characterized by different stability and reactivity toward the 2-aminobutane enantiomers. The enantioselectivity of the gas-phase A-to-B displacement in the diastereomeric [M?H?A]+ complexes essentially reflects the free energy gap between the homo- and heterochiral [M?H?A]+ complexes, except when the tetra-amidic host presents an additional macrocycle generated by a decamethylene chain. In this case, the measured enantioselectivity mostly reflects the stability difference between the relevant diastereomeric transition structures.
- Gasparrini, Francesco,Pierini, Marco,Villani, Claudio,Filippi, Antonello,Speranza, Maurizio
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p. 522 - 534
(2008/10/09)
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- Nitrile and amide biotransformations for the synthesis of enantiomerically pure 3-arylaziridine-2-carboxamide derivatives and their stereospecific ring-opening reactions
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(Chemical Equation Presented) Catalyzed by Rhodococcus erythropolis AJ270 (whole cell catalyst) under very mild conditions, a number of racemic trans-3-arylaziridine-2-carbonitriles and amides were efficiently transformed into enantiopure 2R,3S-3-arylazir
- Wang, Jin-Yuan,Wang, De-Xian,Pan, Jie,Huang, Zhi-Tang,Wang, Mei-Xiang
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p. 9391 - 9394
(2008/03/14)
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- Methods and compositions for treating amyloid-related diseases
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Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid-related disease.
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Page/Page column 139
(2010/11/24)
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- Process for producing optically active alpha-amino acid and optically active alpha-amino acid amine
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The present invention provides a process for efficiently producing an optically active α-amino acid and an optically active α-amino acid amide. After contacting with cells or processed cells thereof having an ability to asymmetrically hydrolyse, a water solvent is substituted with at least one solvent selected from the group consisting of linear, branched, or cyclic alcohol having 3 or more carbon atoms and the optically active α-amino acid is preferentially precipitated from the alcohol solution. The addition of basic compounds, particularly potassium compounds to the alcohol solution containing the optically active α-amino acid amide, which is obtained after the separation of the optically active α-amino acid, enables the purification of the amide without the inclusion of amino acid into amino acid amide. Thus, the amide is subjected to the step of racemization and then recycled.
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- Practical and convenient enzymatic synthesis of enantiopure α-amino acids and amides
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Catalyzed by the nitrile hydratase and the amidease in Rhodococcus sp. AJ270 cells under very mild conditions, a number of α-aryl- and α-alkyl-substituted DL-glycine nitriles 1 rapidly underwent a highly enantioselective hydrolysis to afford D-(-)-α-amino acid amides 2 and L-(+)-α-amino acids 3 in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of a high L-enantioselective amidase and a low enantioselective nitrile hydratase. The influence of the substrates on both reaction efficiency and enantioselectivity was also discussed in terms of steric and electronic effects. Coupled with chemical hydrolysis of D-(-)-α-phenylglycine amide, biotransformation of DL-phenylglycine nitrile was applied in practical scale to produce both D- and L-phenylglycines in high optical purity.
- Wang, Mei-Xiang,Lin, Shuang-Jun
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p. 6542 - 6545
(2007/10/03)
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- Enantioselective enzyme catalysed ammoniolysis of amino acid derivatives. Effect of temperature
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The lipases from Candida antarctica (B type), Thermomyces lanuginosus and Pseudomonas alcaligenes catalysed the enantioselective ammoniolysis of free amino acid esters. In the ammoniolysis of phenylalanine methyl ester catalysed by T. lanuginosus lipase a
- Lopez-Serrano, Paloma,Wegman, Margreth A.,Van Rantwijk, Fred,Sheldon, Roger A.
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p. 235 - 240
(2007/10/03)
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- La pronase immobilisee sur poly(N-acryloylpiperidin-4-one): un catalyseur d'hydrolyse L-enantiospecifique des α-aminonitriles
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Pronase immobilized on poly(N-acryloylpiperidin-4-one) : a L-enantiospecific hydrolysis of α-aminonitriles with immobilized amidase. α-Aminonitriles are not substrates for pronase (an amidase) in the homogeneous phase but become substrates for pronase when it is immobilized on polymer matrix with ketonic sites (piperidin-4-one).In this paper we show that under low basic aqueous conditions (pH 10-11), the hydration of α-aminonitriles can be efficiently catalyzed by poly(N-acryloylpiperidin-4-one) crosslinked with 1,4-bis acryloylpiperazine (A(80:20)) in the presence of phosphate or borate buffers.These conditions comply with the hydrolysis of α-aminoamides by pronase immobilized on poly(N-acryloylpiperidin-4-one)crosslinked with 1,4-bis(acryloyl)piperazine (A(80:20/p).Thus, in a buffered borate solution at pH 10.5, α(DL)-aminonitrile is enantiospecifically hydrolyzed into α(D)-aminoamide and α(L)-amino acid. Key words: α-aminonitriles / α amino acids / L-enantiospecific hydrolysis / polymer-supported catalysis / nitrilasic activity
- Taillades, Jacques,Garrel, Laurence,Guillen, Franck,Collet, Helene,Commeyras, Auguste
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p. 119 - 127
(2007/10/02)
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- Auxiliary chiral ketones in the asymmetric synthesis of α-amino acids by Strecker reaction
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The asymmetric synthesis of α-aminoamides 1 R1CH(CONH2)NH2 1 = Ph-CH2, 1b: R1 = Pri, 1c: R1 = Ph> that leads to the corresponding α-amino acids is achieved by a classical Strecker reaction 1CHO, HCN, NH3> using an auxiliary chiral ketone (R2R'2CO) as a catalyst.In the presence of an aqueous solution of HCN and NH3, the (-)-5R-(methylethenyl)-3R-cyano-2R-methylcyclohexanone 2(-) leads to the 5R-(methylethenyl)-3R-cyano-2R-methyl-1R-cyano-cyclohexylamine 3 with 80percent stereoselectivity.Following condensation with R1CHO, this α-aminonitrile R2R'2C(CN)NH2 3 yields the corresponding iminonitrile which undergoes a second asymmetric addition of HCN yielding an asymmetric α-aminodinitrile 4 R2R'2C(CN)-NH-CHR1(CN) with stereoselectivity that varies betweeen 62percent (R1 = Ph) and 79percent (R1 = Ph-CH2).The α-aminodinitrile obtained as the major product undergoes regioselective hydration of the secondary aminonitrile moiety followed by the decomposition ("retro-Strecker") of the tertiary aminonitrile moiety yielding an optically active α-aminoamide (eg 78percent optical purity for 1a) and the auxiliary chiral ketone 2 and ketonic derivatives.Keywords - α-aminonitrile / α-amino acid / asymmetric synthesis
- Bousquet, C.,Tadros, Z.,Tonnel, J.,Mion, J.,Taillades, J.
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p. 513 - 520
(2007/10/02)
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- Optically Active Derivatives of Imidazolines. α-Adrenergic Blocking Properties
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The synthesis and α-adrenergic blocking activity of a series of optically active 2,4-disubstituted imidazolines are presented.The substituted analogues of naphazoline, tolazoline, and clonidine possess moderate α-adrenergic blocking activity with -logKsu
- Hsu, Fu-Lian,Hamada, Akihiko,Booher, Mark E.,Fuder, H.,Patil, P. N.,Miller, Duane D.
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p. 1232 - 1235
(2007/10/02)
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