- Diastereo- and enantioselective bioreduction of ethyl 2-(4-chlorophenoxy)- 3-oxobutanoate clofibrate analogues by Kluyveromyces marxianus and other whole cell biocatalysts
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Growing and resting cells of several yeasts, which catalyze the hydride transfer to a carbonyl, were screened and used in conditions to find out the suitable methodology to prepare clofibrate analogues. Clofibrate is an antilipidemic drug. In particular, the bioreduction of ethyl 2-(4-chlorophenoxy)-3-oxobutanoate 1 was investigated to separately prepare the four possible stereoisomers of the ethyl 2-(4-chlorophenoxy)-3-hydroxybutanoate 2. Compound (2R,3S)-2 was prepared with ee = 97% and 73% yield in the presence of Kluyveromyces marxianus; (2S,3S)-2 preparation with ee >99% in 9% and 33% yield was mediated by Saccharomyces cerevisiae CBS 7336 and Trigonopsis variabilis, respectively. Diastereomeric excess values of all the reactions investigated were up to >99%. Furthermore, enantiomeric excesses of the bioconversions varied between 2% and >99% using growing cells and, 12% and >99% using resting cells. The absolute configuration of (2R,3S)-2 was established by X-ray analysis of the corresponding acid 3.
- Perrone, Maria Grazia,Santandrea, Ernesto,Scilimati, Antonio,Syldatk, Christoph,Tortorella, Vincenzo,Capitelli, Francesco,Bertolasi, Valerio
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- Ion exchange resin catalyzed synthesis of substituted-4-methyl-3-(substituted phenoxy)coumarins
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Various substituted 2//-1-benzopyran-2-one-4-methyl-3-(substi-tuted phenoxy)compounds have been successfully synthesized by the reaction of ethyl-2-(substituted phenoxy)-3-oxobutanoates (Ia-Id) with re-sorcinol, 4-chloro resorcinol and α-naphthol using io
- Rathnam,Thatte, Chittaranjan S.,Pise, Abhinay C.
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p. 6092 - 6098
(2010/12/19)
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- Synthesis and biological evaluation of new clofibrate analogues as potential PPARα agonists
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Clofibrate is a lipid-profile modifying agent belonging to the fibrate class of drugs. Fibrates are known to exhibit their beneficial effects by activating peroxisome proliferator-activated receptor-α (PPARα) and used in the treatment of dyslipidemia and atherosclerosis and for the prevention of heart failure. Hereby, the preparation of two new sets of clofibrate analogues, ethyl 2-(4-chlorophenoxy)-3-oxoalkanoates and ethyl 2-(4-chlorophenoxy)-3-hydroxyalkanoates is described starting from commercially available 3-oxoalkanoates in fair to good yields. Treatment of 3-oxoalkanoates with SO2Cl2 yielded the corresponding 2-chloro-3- oxoalkanoates, that were then converted into 2-(4-chlorophenoxy)-3-oxoalkanoates by reacting with sodium or caesium 4-chlorophenate. Reduction of the keto group with NaBH4 afforded the corresponding 2-(4-chlorophenoxy)-3- hydroxyalkanoates in very high yields and with variable diastereoselectivity. Biological evaluation of the compounds was performed by a transactivation assay in a transiently transfected monkey kidney fibroblast cell line. The newly synthesised clofibrate analogues failed to show noticeable levels of PPAR activation at concentrations where clofibrate showed an evident activity, suggesting that the structural modifications caused the loss of PPAR activity.
- Perrone, Maria Grazia,Santandrea, Ernesto,Dell'Uomo, Natalina,Giannessi, Fabio,Milazzo, Ferdinando Maria,Sciarroni, Anna Floriana,Scilimati, Antonio,Tortorella, Vincenzo
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p. 143 - 154
(2007/10/03)
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- Alpha-adrenergic receptor antagonists
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Alpha-adrenoceptor antagonists having the formula: STR1 which are useful to produce α-adrenoceptor antagonism, pharmaceutical compositions including these antagonists, and methods of using these antagonists to produce α-adrenoceptor antagonism in mammals.
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- α-adrenergic receptor antagonists
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α-adrenoceptor antagonists having the formula: STR1 which are useful to produce α-adrenoceptor antagonism, pharmaceutical compositions including these antagonists, and methods of using these antagonists to produce α-adrenoceptor antagonism in mannals.
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- Selective Heteronuclear NOE Enhancements in Benzoheterocycles. Effect of Ring Size on Indirect Three-Spin Effects
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The 80 MHz 1H NMR and 20 MHz 13C NMR spectra of five 4-methylcoumarins, six 4-methyl-2(1H)-quinolones and nine 3-methylbenzofurans, including six new compounds, were fully assigned.Homonuclear 1H NOEs and selective heteronuclear 13C NOEs were measured after low-power pre-saturation of the methyl protons.Indirect, negative heteronuclear NOE enhancements were found in suitable three-spin systems of the 13C-1H- type, and their magnitude was found to be dependent on ring size.The first examples of indirect, heteronuclear NOE enhancements on non-protonated carbons are described.KEY WORDS Heteronuclear NOE Selective heteronuclear 13C NOE Indirect negative NOE 13C-1H- three-spin effects Coumarins 2(1H)-Quinolones Benzofurans.
- Redondo, Jordi,Sanchez-Ferrando, Francisco,Valls, Montserrat,Virgili, Albert
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p. 511 - 517
(2007/10/02)
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