64508-87-8Relevant articles and documents
Structure activity studies with xenobiotic substrates using carboxylesterases isolated from Arabidopsis thaliana
Cummins, Ian,Landrum, Marie,Steel, Patrick G.,Edwards, Robert
, p. 811 - 818 (2008/03/13)
Carboxylesterases (CXEs) catalyse the hydrolysis of xenobiotics and natural products radically altering their biological activities. Whereas the substrate selectivity of animal CXEs, such as porcine liver esterase (PLE) have been well studied, the respective enzymes in plants have yet to be defined and their activities determined. Using Arabidopsis thaliana (At) as a source, five representative members of the α/β hydrolase AtCXE family of proteins have been cloned, expressed and the purified recombinant proteins assayed for esterase activity with xenobiotic substrates. Two members, AtCXE5 and AtCXE18 were found to be active carboxylesterases, though AtCXE5 proved to be highly unstable as a soluble protein. AtCXE18 and the previously characterised S-formylglutathione hydrolase from Arabidopsis (AtSFGH) were assayed against a series of esters based on methylumbelliferone in which the acyl moiety was varied with respect to size and conformation. The same series was used to assay crude esterase preparation from Arabidopsis plants and the results compared with those obtained with the commonly used PLE. With straight chain esters, AtCXE18 behaved like PLE, but the Arabidopsis hydrolases proved less tolerant of branched chain acyl components than the mammalian enzyme. While none of the enzyme preparations accurately reflected all the activities determined with crude Arabidopsis protein extracts, the plant enzymes proved more useful than PLE in predicting the hydrolysis of the more sterically constrained esters.
Asymmetric synthesis of 2-substituted chroman-4-ones using lipase-catalyzed kinetic resolutions
Kawasaki, Masashi,Kakuda, Hiroko,Goto, Michimasa,Kawabata, Shigeki,Kometani, Tadashi
, p. 1529 - 1534 (2007/10/03)
2-Methylchroman-4-one and 2-phenylchroman-4-one were synthesized in optically active form. Their chiral intermediates were obtained via lipase-catalyzed enantioselective reactions.
Hydantoin Bioisosteres. In Vivo Active Hydroxy Acetic Acid Aldose Reductase Inhibitors
Lipinski, Christopher A.,Aldinger, Charles E.,Beyer, Thomas A.,Bordner, Jon,Burdi, Douglas F.,et al.
, p. 2169 - 2177 (2007/10/02)
The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin ring led to a bioisosteric analysis and replacement of the hydantoin by a spiro hydroxy acetic acid moiety as in 40.These hydroxy acids, compared to hydantoins, showed a similar potency increase on chroman 2-methyl substitution, a similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioselectivity.In this series the six-membered spiro hydroxy acetic acid anion array is a bioisostere for a spiro hydantoin anion and leads to ARIs with excellent in vivo activity.In vitro and in vivo activity was improved over 40 by chroman cis 2-methylation as in 4 and by aromatic 6,7-halogen substitution.Compounds with the best acute in vivo activity in rats were compared for chronic in vivo activity.The highest tissue levels and best chronic in vivo activities were found in the racemic 6,7-dichloro and 6-fluoro-7-chloro analogues 18 and 23.ARI activity was enantioselective for 58 and 60, the 2R,4R-enantiomers of 18 and 23. 7-Chloro-6-fluoro-cis-4-hydroxy-2(R)-methyl-chroman-4-acetic acid (60) was selected for phase 1 clinical trials and did not exhibit sorbinil-like hypersensitivity side effects.
