198561-27-2Relevant academic research and scientific papers
Design, synthesis and biological evaluation of novel inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors
Dunkern, Torsten,Chavan, Sunil,Bankar, Digambar,Patil, Anuja,Kulkarni, Pritee,Kharkar, Prashant S.,Prabhu, Arati,Goebel, Heike,Rolser, Edith,Burckhard-Boer, Waltraud,Arumugam, Premkumar,Makhija, Mahindra T.
, p. 408 - 419 (2014/06/09)
This study is based on our attempts to further explore the structure-activity relationship (SAR) of VX-148 (3) in an attempt to identify inosine 5′-mono-phosphate dehydrogenase (IMPDH) inhibitors superior to mycophenolic acid. A five-point pharmacophore developed using structurally diverse, known IMPDH inhibitors guided further design of novel analogs of 3. Several conventional as well as novel medicinal chemistry strategies were tried. The combined structure- and ligand-based approaches culminated in a few analogs with either retained or slightly higher potency. The compounds which retained the potency were also checked for their ability to inhibit human peripheral blood mononuclear cells proliferation. This study illuminates the stringent structural requirements and strict SAR for IMPDH II inhibition.
Biocatalytic and Structural Properties of a Highly Engineered Halohydrin Dehalogenase
Schallmey, Marcus,Floor, Robert J.,Hauer, Bernhard,Breuer, Michael,Jekel, Peter A.,Wijma, Hein J.,Dijkstra, Bauke W.,Janssen, Dick B.
, p. 870 - 881 (2013/07/25)
Two highly engineered halohydrin dehalogenase variants were characterized in terms of their performance in dehalogenation and epoxide cyanolysis reactions. Both enzyme variants outperformed the wild-type enzyme in the cyanolysis of ethyl (S)-3,4-epoxybutyrate, a conversion yielding ethyl (R)-4-cyano-3-hydroxybutyrate, an important chiral building block for statin synthesis. One of the enzyme variants, HheC2360, displayed catalytic rates for this cyanolysis reaction enhanced up to tenfold. Furthermore, the enantioselectivity of this variant was the opposite of that of the wild-type enzyme, both for dehalogenation and for cyanolysis reactions. The 37-fold mutant HheC2360 showed an increase in thermal stability of 8°C relative to the wild-type enzyme. Crystal structures of this enzyme were elucidated with chloride and ethyl (S)-3,4-epoxybutyrate or with ethyl (R)-4-cyano-3-hydroxybutyrate bound in the active site. The observed increase in temperature stability was explained in terms of a substantial increase in buried surface area relative to the wild-type HheC, together with enhanced interfacial interactions between the subunits that form the tetramer. The structures also revealed that the substrate binding pocket was modified both by substitutions and by backbone movements in loops surrounding the active site. The observed changes in the mutant structures are partly governed by coupled mutations, some of which are necessary to remove steric clashes or to allow backbone movements to occur. The importance of interactions between substitutions suggests that efficient directed evolution strategies should allow for compensating and synergistic mutations during library design.
Efficient preparation of (R)-3-hydroxypentanenitrile with high enantiomeric excess by enzymatic reduction with subsequent enhancement of the optical purity by lipase-catalyzed ester hydrolysis
Kawano, Shigeru,Hasegawa, Junzo,Yasohara, Yoshihiko
, p. 1796 - 1798,3 (2012/12/11)
An efficient chemo-enzymatic procedure for the synthesis of (R)-3-hydroxypentanenitrile (1) with over 99% enantiomeric excess using two enzymatic reactions was successfully established. Initial enantioselective enzymatic reduction of 3-oxopentanenitrile with reductase S1 gave (R)-1 with an 81.5% ee which was then converted to (R)-1-(cyanomethyl) propyl n-butyrate (3b). Subsequent lipase-catalyzed enantioselective hydrolysis of 3b gave (R)-1 in a high yield with over 99% ee.
Efficient preparation of (R)-3-hydroxypentanenitrile with high enantiomeric excess by enzymatic reduction with subsequent enhancement of the optical purity by lipase-catalyzed ester hydrolysis
Kawano, Shigeru,Hasegawa, Junzo,Yasohara, Yoshihiko
, p. 1796 - 1798 (2013/01/14)
An efficient chemo-enzymatic procedure for the synthesis of (R)-3-hydroxypentanenitrile (1) with over 99% enantiomeric excess using two enzymatic reactions was successfully established. Initial enantioselective enzymatic reduction of 3-oxopentanenitrile with reductase S1 gave (R)-1 with an 81.5% ee which was then converted to (R)-1-(cyanomethyl) propyl n-butyrate (3b). Subsequent lipase-catalyzed enantioselective hydrolysis of 3b gave (R)-1 in a high yield with over 99% ee.
A rational design of phosphonium salt type ionic liquids for ionic liquid coated-lipase catalyzed reaction
Abe, Yoshikazu,Yoshiyama, Kazuhide,Yagi, Yusuke,Hayase, Shuichi,Kawatsura, Motoi,Itoh, Toshiyuki
experimental part, p. 1976 - 1980 (2011/02/23)
A rational design of phosphonium ionic liquid for ionic liquid coated-lipase (IL1-PS)-catalyzed reaction has been investigated, and very rapid transesterification of secondary alcohols accomplished when IL1-PS was used as catalyst in 2-methoxyethoxymethyl(tri-n-butyl)phosphonium bis(trifluoromethanesulfonyl)amide ([P444MEM][NTf2]) as solvent while perfect enantioselectivity was maintaining. Increased K cat value was suggested to be the most important factor in IL1-PS working the best in [P444MEM][NTf2] solvent. The Royal Society of Chemistry 2010.
Preparation of novel hydrophobic fluorine-substituted-alkyl sulfate ionic liquids and application as an efficient reaction medium for lipase-catalyzed reaction
Tsukada, Yasuhiro,Iwamoto, Kazuhisa,Furutani, Hiroyuki,Matsushita, Yuichi,Abe, Yoshikazu,Matsumoto, Kei,Monda, Keishi,Hayase, Shuichi,Kawatsura, Motoi,Itoh, Toshiyuki
, p. 1801 - 1804 (2007/10/03)
Various types of differently fluorinated-alkyl sulfate ionic liquids have been prepared; the hydrophobicity was dependent on the content ratio of the fluorine on the alkyl sulfate anion and 2,2,3,3,4,4,5,5-octafluoropentyl sulfate salts showed hydrophobic properties. Melting point and viscosity were also dependent on the fluorine contents of the anionic part, while conductivity was determined by the cationic part and not influenced by the fluorine contents. Efficient lipase-catalyzed transesterification was demonstrated using hydrophobic 1-butyl-3-methylimidazolim 2,2,3,3,4,4,5,5-octafluoropentyl sulfate ([bmim][C5F8]) as solvent.
Increased enantioselectivity and remarkable acceleration of lipase-catalyzed transesterification by using an imidazolium PEG-Alkyl sulfate ionic liquid
Itoh, Toshiyuki,Matsushita, Yuichi,Abe, Yoshikazu,Han, Shi-Hui,Wada, Shohei,Hayase, Shuichi,Kawatsura, Motoi,Takai, Shigeomi,Morimoto, Minoru,Hirose, Yoshihiko
, p. 9228 - 9237 (2007/10/03)
Several types of imidazolium salt ionic liquids were prepared derived from poly(oxyethylene)alkyl sulfate and used as an additive or coating material for lipase-catalyzed transesterification in an organic solvent. A remarkably increased enantioselectivity was obtained when the salt was added at 3-10 mol % versus substrate in the Burkholderia cepacia lipase (lipase PS-C)-catalyzed transesterification of 1-phe nylethanol by using vinyl acetate in diisopropyl ether or a hexane solvent system. In particular, a remarkable acceleration was accomplished by the ionic liquid coating with lipase PS in an iPr2O solvent system while maintaining excellent enantioselectivity; it reached approximately 500- to 1000-fold acceleration for some substrates with excellent enantioselectivity. A similar acceleration was also observed for IL1-coated Candida rugosa lipase. MALDITOF mass spectrometry experiments of the ionic-liquid-coated lipase PS suggest that ionic liquid binds with lipase protein.
Enantioselective ring opening of epoxides with cyanide catalysed by halohydrin dehalogenases: A new approach to non-racemic β-hydroxy nitriles
Elenkov, Maja Majeric,Hauer, Bernhard,Janssen, Dick B.
, p. 579 - 585 (2007/10/03)
Halohydrin dehalogenases (HheA, HheB and HheC) were found to efficiently catalyse a carbon-carbon bond forming reaction between terminal aliphatic epoxides and cyanide, yielding β-hydroxy nitriles. With all three enzymes nucleophilic ring opening of epoxi
Manufacture of water-soluble beta-hydroxynitriles
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Page 3, (2008/06/13)
A process for making a water-soluble beta-hydroxynitrile. A 1,2-epoxide and an inorganic cyanide salt are reacted in a solvent having aqueous methanol and a buffer therein to form betahydroxynitrile. The buffer substantially inhibits the formation of reaction products other than betahydroxynitrile. Optionally, water may be removed from the betahydroxynitrile by azeotropic distillation with acetonitrile and subsequently purified via vacuum distillation and filtration.
Thiocrown ether additive effects on diastereoselectivity of the lipase- catalyzed reaction: Preparation of optically active 3-hydroxy-2- methylalkanenitriles through a double enzymatic reaction strategy
Mitsukura, Koichi,Choraku, Hiroko,Da, San Thi,Itoh, Toshiyuki
, p. 1589 - 1595 (2007/10/03)
The additive effect on diastereoselectivity towards the lipase-catalyzed hydrolysis of acetates of 3-hydroxy-2-methyl-or 3-hydroxy-2- ethylalkanenitriles has been investigated. Diastereoselectivity was not influenced by thiocrown ether additives, although a significant modification of enantioselectivity was observed. Origin of the diastereoselectivity of the lipase-catalyzed reaction was thus evidently different from that of enantioselectivity. Based on these results, an easy preparation of optically active 3-hydroxy-2-methylpentanenitrile and 3-hydroxy-2-methylbutanenitrile have been demonstrated through lipase-catalyzed reaction by a double enzymatic reaction strategy.
