- Identification of novel metabolites of butadiene monoepoxide in rats and mice
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Differences in the metabolism of 1,3-butadiene (Bd) in rats and mice may account for the observed species difference in carcinogenicity. Previous studies of the metabolic fate of Bd have identified epoxide formation as a key metabolic transformation which gives 1,2-epoxy-3-butene (BMO), although some evidence of aldehyde metabolites is reported. In this study, male Sprague-Dawley rats and male B6C3F1 mice received single doses of [4- 14C]BMO at 1, 5, 20, and 50 mg/kg of body weight (0.014, 0.071, 0.286, and 0.714 mmol/kg of body weight). Analysis of urinary metabolites indicated that both species preferentially metabolize BMO by direct reaction with GSH when given by ip administration. The excretion of (R)-2-(N-acetyl-L-cystein-S- yl)-1-hydroxybut-3-ene (IIa), 1-(N-acetyl-L-cystein-S-yl)-2-(S)-hydroxybut- 3-ene (IIb), 1-(N-acetyl-L-cystein-S-yl)-2-(R)-hydroxybut-3-ene (IIc), and (S)-2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene (IId) accounted for 48- 64% of urinary radioactivity in rats and 46-54% in mice. The metabolites originating from the R-stereoisomer of BMO (IIc and IId) predominated over those arising from the S-stereoisomer (IIa and IIb) in both species. IIc was formed preferentially in mice and IId in rats. The corresponding mercaptoacetic acids, S-(1-hydroxybut-3-en-2-yl)mercaptoacetic acid (IIf) and S-(2-hydroxybut-3-en-1-yl)mercaptoacetic acid (IIg), were identified only in mouse urine (ca. 20% of the recovered radioactivity). 4-(N-Acetyl-L-cystein- S-yl)-1,2-dihydroxybutane (Ia), a metabolite derived from hydrolysis of BMO, accounted for 10-17% of the radioactivity in rat and 6-10% in mouse urine. 4- (N-Acetyl-L-cystein-S-yl)-2-hydroxybutanoic acid (Ib), 3-(N-acetyl-L-cystein- S-yl)propan-1-ol (Ic), and 3-(N-acetyl-L-cystein-S-yl)propanoic acid (Id), also derived from the hydrolysis of BMO, were only present in the rat. Metabolites of 1,2,3,4-diepoxybutane (DEB) were not detected after administration of BMO in rat or mouse urine. This study showed both quantitative and qualitative differences in the metabolism of BMO with varying doses and between species. The data aid in the safety evaluation of Bd and contribute to the interpretation of mathematical models developed for quantitative risk assessment and extrapolation of animals to humans.
- Richardson, Kevan A.,Peters, Melanie M. C. G.,Megens, Rene H. J. J. J.,Van Elburg, Paul A.,Golding, Bernard T.,Boogaard, Peter J.,Watson, William P.,Van Sittert, Nico J.
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- Enzyme-mediated enantioselective hydrolysis of 1,2-diol monotosylate derivatives bearing an unsaturated substituent
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We have succeeded in the easy preparation of optically active 1,2-diol monotosylates bearing an unsaturated substituent via enzymatic hydrolysis. Lipase PS quickly catalyzes the hydrolyses of 2-acetoxybut-3-enyl tosylate, which has a double bond, and 2-acetoxybut-3-ynyl tosylate, which has a triple bond, with excellent enantioselectivity to afford the corresponding optically active compounds. The reaction is also applicable to acetates with a longer chain, which has a double bond at the terminus. To demonstrate the applicability of this method, enantiomerically pure (R)-massoialactone, a natural coconut flavor, has been synthesized from racemic 2-acetoxypent-4-enyl tosylate in several steps. Furthermore, the enzyme can recognize the stereochemistry of olefins, and the (Z)-alkenyl structure is more suitable for the enantioselective hydrolysis than the (E)-isomer.
- Matsumoto,Oohana,Hashimoto,Usuda,Shimoda,Ohshima,Suzuki,Togawa
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p. 3981 - 3988
(2018/06/15)
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- Expedient synthesis of epigoitrin from L-ascorbic acid
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Epigoitrin is the main bioactive constituent of an important traditional Chinese herbal medicine, Radix isatidis. Reported pharmacological effects of epigoitrin include antiviral, anticancer, and antithyroid activities. Extensive biological exploration of
- Yang, Jing-Jing,Wu, Jian-Zhong,Qiao, Chunhua
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supporting information
p. 1240 - 1244
(2014/04/17)
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- Stereoselective preparation of a key intermediate toward the synthesis of nelfinavir
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A stereoselective synthesis of an intermediate that can be elaborated into the potent HTV-protease inhibitor, nelfinavir, is described. The key step of the reaction sequence is the stereoselective preparation of a bromosulfonamide from an olefin using the
- Raghavan, Sadagopan,Kumar, Ch. Naveen
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experimental part
p. 821 - 828
(2011/08/09)
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- New synthesis of sn-1,2- and sn-2,3-O-diacylglycerols application to the synthesis of enantiopure phosphonates analogous to triglycerides: A new class of inhibitors of lipases
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Phosphonate compounds mimic the first transition state occurring during enzymatic carboxyester hydrolysis of natural substrates by forming a covalent bond with the catalytic serine. However, until now the organophosphorus compounds used in the inhibition studies more or less resembled a natural triglyceride substrate. In order to elucidate the interfacial activation and the mechanism of action of lipases, specific inhibitors need to be prepared. To achieve this goal, enantiomerically pure sn-1,2- and sn-2,3O- didecanoylglycerol compounds were prepared - starting from a C-4 chiral synthon, 3-buten-1,2-diol - and treated with n-pentylphosphonic dichloride and p-nitrophenol to afford the corresponding diastereomeric phosphonates, which were acylglycerol analogs. Subsequent separation of each of the phosphonate diastereomers A/B or ent-A/ent-B, performed by HPLC, led to four enantiopure stereoisomers that will be investigated as inhibitors of Human Pancreatic Lipase (HPL) and Human Gastric Lipase (HGL) using the monomolecular film technique.
- Marguet, Frank,Cavalier, Jean-Francois,Verger, Robert,Buono, Gerard
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p. 1671 - 1678
(2007/10/03)
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- Chemoenzymatic synthesis of enantiomerically pure alkene 1,2-diols and glycosides thereof
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The kinetic resolution of racemic 2-O-acylated 3-butene-1,2-diol and 1- O-acylated 3-butene-1,2-diol derivatives by enzymatic saponification and enzymatic esterification, respectively, is investigated with several lipases and esterases. The resulting part
- Ziegler, Thomas,Bien, Frank,Jurisch, Claus
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p. 765 - 780
(2007/10/03)
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- Synthesis of enantiomerically pure 3-butene-1,2-diol derivatives via a Sharpless asymmetric epoxidation route
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A short enantiospecific synthesis of the butenediol monotosylates (1,2), the epoxybutanediol monotosylates (3,4) and the epoxybutenes (5,6) is described.
- Neagu,Hase
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p. 1629 - 1630
(2007/10/02)
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