- Discovery of a 1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity
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Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also rep
- Wittman, Mark,Carboni, Joan,Attar, Ricardo,Balasubramanian, Balu,Balimane, Praveen,Brassil, Patrick,Beaulieu, Francis,Chang, Chiehying,Clarke, Wendy,Dell, Janet,Eummer, Jeffrey,Frennesson, David,Gottardis, Marco,Greer, Ann,Hansel, Steven,Hurlburt, Warren,Jacobson, Bruce,Krishnananthan, Subramaniam,Lee, Francis Y.,Li, Aixin,Lin, Tai-An,Liu, Peiying,Ouellet, Carl,Sang, Xiaopeng,Saulnier, Mark G.,Stoffan, Karen,Sun, Yax,Velaparthi, Upender,Wong, Henry,Yang, Zheng,Zimmermann, Kurt,Zoeckler, Mary,Vyas, Dolatrai
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Read Online
- Purification and cloning of a ketoreductase used for the preparation of chiral alcohols
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The synthesis of the leading candidate compound in an anticancer program required (S)-2-chloro-1-(3-chlorophenyl)-ethanol as an intermediate. Other possible candidate compounds used analogues of the S-alcohol. Of 119 microbial cultures screened for reduction of the corresponding ketone to the S-alcohol, Hansenula polymorpha ATCC 58401 (73.8% ee) and Rhodococcus globerulus ATCC 21505 (71.8% ee) had the highest enantioselectivity for producing the desired alcohol. A ketoreductase from Hansenula polymorpha, after purification to homogeneity, gave the S-alcohol with 100% ee. Amino acid sequences from the purified enzyme were used to design PCR primers for cloning the ketoreductase. The cloned ketoreductase required NADP(H), had a subunit molecular weight of 29,220 and a native molecular weight of 88,000. The cloned ketoreductase was expressed in E. coli together with a cloned glucose 6-phosphate dehydrogenase from Saccharomyces cerevisiae to allow regeneration of the NADPH required by the ketoreductase. An extract of E. coli containing the two recombinant enzymes was used to reduce 2-chloro-1-(3-chloro-4-fluorophenyl)-ethanone and two related ketones to the corresponding S-alcohols. Intact E. coli cells provided with glucose were used to prepare (S)-2-chloro-1-(3-chloro-4-fluorophenyl)-ethanol in 89% yield with 100% ee.
- Hanson, Ronald L.,Goldberg, Steven,Goswami, Animesh,Tully, Thomas P.,Patel, Ramesh N.
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Read Online
- Unmasking the Hidden Carbonyl Group Using Gold(I) Catalysts and Alcohol Dehydrogenases: Design of a Thermodynamically-Driven Cascade toward Optically Active Halohydrins
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A concurrent cascade combining the use of a gold(I) N-heterocyclic carbene (NHC) and an alcohol dehydrogenase (ADH) is disclosed for the synthesis of highly valuable enantiopure halohydrins in an aqueous medium and under mild reaction conditions. The meth
- Escot, Lorena,González-Granda, Sergio,Gotor-Fernández, Vicente,Lavandera, Iván
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p. 2552 - 2560
(2022/02/16)
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- Characterization of a robust glucose 1-dehydrogenase, SyGDH, and its application in NADPH regeneration for the asymmetric reduction of haloketone by a carbonyl reductase in organic solvent/buffer system
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To realize coenzyme regeneration in the reduction of haloketones, a codon-optimized gene Sygdh encoding glucose 1-dehydrogenase (SyGDH) was synthesized based on the putative GDH gene sequence (Ta0897) in Thermoplasma acidophilum genomic DNA, and expressed in E. coli BL21(DE3). Recombinant SyGDH was purified to homogeneity by affinity chromatography with the specific activity of 86.3 U/mg protein towards D-glucose at the optimum pH and temperature of 7.5 and 40 °C. It was highly stable in a pH range of 4.5–8.0 and at 60 °C or below, and resistant to various organic solvents. The Km and catalytic efficiency (kcat/Km) of SyGDH towards NADP+ were 0.67 mM and 104.0 mM?1 s?1, respectively, while those towards NAD+ were 157.9 mM and 0.64 mM?1 s?1, suggesting that it preferred NADP+ as coenzyme to NAD+. Additionally, using whole cells of E. coli/Sygdh-Sys1, coexpressing SyGDH and carbonyl reductase (SyS1), as the biocatalyst, the asymmetric reduction of 60 mM m-chlorophenacyl chloride coupled with the regeneration of NADPH in situ was conducted in DMSO/phosphate buffer (2:8, v/v) system, producing (R)-2-chloro-1-(3-chlorophenyl)ethanol with over 99.9% eep and 99.2% yield. Similarly, the reduction of 40 mM α-bromoacetophenone in n-hexane/buffer (6:4, v/v) biphasic system produced (S)-2-bromo-1-phenylethanol with over 99.9% eep and 98.3% yield.
- Hu, Die,Wen, Zheng,Li, Chuang,Hu, Bochun,Zhang, Ting,Li, Jianfang,Wu, Minchen
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- Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR
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The rapid advancement of a series of noncovalent inhibitors of T790M mutants of EGFR is discussed. The optimization of pyridone 1, a nonselective high-throughput screening hit, to potent molecules with high levels of selectivity over wtEGFR and the broader kinome is described herein.
- Bryan, Marian C.,Burdick, Daniel J.,Chan, Bryan K.,Chen, Yuan,Clausen, Saundra,Dotson, Jennafer,Eigenbrot, Charles,Elliott, Richard,Hanan, Emily J.,Heald, Robert,Jackson, Philip,La, Hank,Lainchbury, Michael,Malek, Shiva,Mann, Sam E.,Purkey, Hans E.,Schaefer, Gabriele,Schmidt, Stephen,Seward, Eileen,Sideris, Steve,Wang, Shumei,Yen, Ivana,Yu, Christine,Heffron, Timothy P.
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supporting information
p. 100 - 104
(2016/02/03)
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- Preparation of (R)-2-chloro-1-(m-chlorophenyl)ethanol by Lipozyme TL IM-catalyzed second resolution
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(R)-2-Chloro-1-(m-chlorophenyl)ethanol, a precursor of (R)-3-chlorostyrene oxide which is the key chiral intermediate for the preparation of several β3-adrenergic receptor agonists was prepared in 40% yield and 99% ee by the Lipozyme TL IM-catalyzed second resolution of the corresponding racemate in the presence of vinyl acetate.
- Xia, Shi Wen,Lin, Hui,Chen, Yong Zheng
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experimental part
p. 289 - 292
(2012/05/05)
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- Purification and characterization of an NADH-dependent alcohol dehydrogenase from Candida maris for the synthesis of optically active 1-(pyridyl)ethanol derivatives
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A novel (R)-specific alcohol dehydrogenase (AFPDH) produced by Candida maris IFO10003 was purified to homogeneity by ammonium sulfate fractionation, DEAE-Toyopearl, and Phenyl-Toyopearl, and characterized. The relative molecular mass of the native enzyme was found to be 59,900 by gel filtration, and that of the subunit was estimated to be 28,900 on SDS-polyacrylamide gel electrophoresis. These results suggest that the enzyme is a homodimer. It required NADH as a cofactor and reduced various kinds of carbonyl compounds, including ketones and aldehydes. AFPDH reduced acetylpyridine derivatives, β-keto esters, and some ketone compounds with high enantioselectivity. This is the first report of an NADH-dependent, highly enantioselective (R)-specific alcohol dehydrogenase isolated from a yeast. AFPDH is a very useful enzyme for the preparation of various kinds of chiral alcohols.
- Kawano, Shigeru,Yano, Miho,Hasegawa, Junzo,Yasohara, Yoshihiko
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experimental part
p. 1055 - 1060
(2012/02/03)
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- Novel 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase
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A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.
- Wittman, Mark D.,Balasubramanian, Balu,Stoffan, Karen,Velaparthi, Upender,Liu, Pieying,Krishnanathan, Subramaniam,Carboni, Joan,Li, Aixin,Greer, Ann,Attar, Ricardo,Gottardis, Marco,Chang, Chiehying,Jacobson, Bruce,Sun, Yax,Hansel, Steven,Zoeckler, Mary,Vyas, Dolatrai M.
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p. 974 - 977
(2007/10/03)
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- Asymmetric hydrogenation of α-chloro aromatic ketones catalyzed by η6-arene/TsDPEN-ruthenium(II) complexes
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(Chemical Equation Presented) Asymmetric hydrogenation of various α-chloro aromatic ketones with Ru(OTf)(TsDPEN)(η6-arene) (TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) produces the chiral chlorohydrins in up to 98% ee. This reac
- Ohkuma, Takeshi,Tsutsumi, Kunihiko,Utsumi, Noriyuki,Arai, Noriyoshi,Noyori, Ryoji,Murata, Kunihiko
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p. 255 - 257
(2007/10/03)
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- Gene cloning and expression of Leifsonia alcohol dehydrogenase (LSADH) involved in asymmetric hydrogen-transfer bioreduction to produce (R)-form chiral alcohols
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The gene encoding Leifsonia alcohol dehydrogenase (LSADH), a useful biocatalyst for producing (R)-chiral alcohols, was cloned from the genomic DNA of Leifsonia sp. S749. The gene contained an opening reading frame consisting of 756 nucleotides corresponding to 251 amino acid residues. The subunit molecular weight was calculated to be 24,999, which was consistent with that determined by polyacrylamide gel electrophoresis. The enzyme was expressed in recombinant Escherichia coli cells and purified to homogeneity by three column chromatographies. The predicted amino acid sequence displayed 30-50% homology to known short chain alcohol dehydrogenase/reductases (SDRs); moreover, the NADH-binding site and the three catalytic residues in SDRs were conserved. The recombinant E. coli cells which overexpressed lsadh produced (R)-form chiral alcohols from ketones using 2-propanol as a hydrogen donor with the highest level of productivity ever reported and enantiomeric excess (e.e.).
- Inoue, Kousuke,Makino, Yoshihide,Dairi, Tohru,Itoh, Nobuya
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p. 418 - 426
(2008/02/10)
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- Production of (R)-chiral alcohols by a hydrogen-transfer bioreduction with NADH-dependent Leifsonia alcohol dehydrogenase (LSADH)
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Alcohol dehydrogenase (LSADH) isolated from Leifsonia sp. S749 was used to produce (R)-chiral alcohols. The enzyme with a broad substrate range reduced various prochiral ketones and keto esters to yield optically active secondary alcohols with a high enantiomeric excess. LSADH transferred the pro-S hydrogen of NADH to the carbonyl moiety of phenyl trifluoromethyl ketone 13 through its re face to give (S)-1-phenyl-2,2,2-trifluoroethanol 40. LSADH was able to efficiently reproduce NADH when 2-propanol was used as a hydrogen donor in the reaction mixture.
- Inoue, Kousuke,Makino, Yoshihide,Itoh, Nobuya
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p. 2539 - 2549
(2007/10/03)
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- 'Green' synthesis of important pharmaceutical building blocks: Enzymatic access to enantiomerically pure α-chloroalcohols
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Thirty one recombinant ketoreductase enzymes were screened for the reduction of six α-chloroketones, the precursors of pharmaceutically valuable α-chloroalcohols. Several highly active and enantioselective ketoreductases were found and their applications
- Zhu, Dunming,Mukherjee, Chandrani,Hua, Ling
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p. 3275 - 3278
(2007/10/03)
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- A practical synthesis of optically active aromatic epoxides via asymmetric transfer hydrogenation of α-chlorinated ketones with chiral rhodium-diamine catalyst
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A practical method for the synthesis of optically active aromatic epoxides has been developed via the formation of optically active α-chlorinated alcohols and intramolecular etherification. Optically active alcohols with up to 99% ee can be obtained from
- Hamada, Takayuki,Torii, Takayoshi,Izawa, Kunisuke,Ikariya, Takao
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p. 7411 - 7417
(2007/10/03)
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- Practical synthesis of optically active styrene oxides via reductive transformation of 2-chloroacetophenones with chiral rhodium catalysts
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(equation presented) A practical method for the synthesis of optically active styrene oxides has been developed via formation of optically active 2-chloro-1-phenylethanols generated by reductive transformation of ring-substituted 2-chloroacetophenones. Th
- Hamada, Takayuki,Torii, Takayoshi,Izawa, Kunisuke,Noyori, Ryoji,Ikariya, Takao
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p. 4373 - 4376
(2007/10/03)
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- Process for preparing optically active alcoholic compounds
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A process for preparing optically active alcoholic compounds wherein a carbonyl compound is assymmetrically reduced in an economical and practical manner. The process comprises treating a prochiral carbonyl compound represented by the general formula (1) with an optically active organoaluminum compound represented by the general formula (2) to conduct asymmetric reduction, thereby preparing an optically active alcoholic compound represented by the general formula (3).
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- A tandem enzyme reaction to produce optically active halohydrins, epoxides and diols
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The recombinant halohydrin dehalogenase from Agrobacterium radiobacter AD1 was used to obtain enantiomerically pure halohydrins and epoxides by kinetic resolution. By adding an excess of the recombinant epoxide hydrolase from the same organism the reversible conversion was drawn to completion. Halohydrins such as (S)-2,3-dichloro-1-propanol (E>100) and (S)-2-chloro-1-phenylethanol (E=73) were obtained with an enantiomeric excess of higher than 99%. This is a novel biocatalytic route for obtaining enantiomerically pure aromatic halohydrins and epoxides.
- Lutje Spelberg, Jeffrey H.,Van Hylckama Vlieg, Johan E. T.,Bosma, Tjibbe,Kellogg, Richard M.,Janssen, Dick B.
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p. 2863 - 2870
(2007/10/03)
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- Alternative synthesis of the chiral atypical β-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation
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We have developed an alternative synthesis of the atypical β-adrenergic phenylethanolaminotetraline agonist SR58611A. Two key intermediates have been synthesised involving enantioselective hydrogenation of an aminoketone and an enamide providing the corre
- Devocelle, Marc,Mortreux, Andre,Agbossou, Francine,Dormoy, Jean-Robert
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p. 4551 - 4554
(2007/10/03)
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