- Inactivation of glutathione transferase zeta by dichloroacetic acid and other fluorine-lacking α-haloalkanoic acids
-
Dichloroacetic acid (DCA) is a contaminant of chlorinated drinking water supplies, is carcinogenic in rats and mice, and is a therapeutic agent used for the treatment of congenital lactic acidosis. The biotransformation of DCA to glyoxylic acid is catalyzed by glutathione transferase zeta (GSTZ). Treatment of rats and human subjects with DCA increases its plasma elimination half-life and reduces the extent of DCA biotransformation in rat hepatic cytosol. In the investigation presented here, the kinetics of the DCA-induced inactivation of GSTZ, the turnover of GSTZ, and the susceptibility of GSTZ to inactivation by a panel of α-haloacids were studied. DCA rapidly inactivated GSTZ in both rat hepatic cytosol and intact Fischer 344 rats. The time course of inactivation in vivo was mirrored by a concomitant loss of immunoreactive GSTZ protein. The turnover of GSTZ in rat liver was 0.21 day-1, which corresponded to a half-life of 3.3 days. The degree of GSTZ inactivation after daily administration of DCA could be predicted from the amount of inactivation after a single treatment. Other fluorine-lacking dihaloacetic acids also inactivated GSTZ, whereas α- monohaloacids and fluorine-containing dihaloacetic acids failed to inactivate GSTZ. These data show that the observed DCA-induced decrease in the level of DCA metabolism is caused by the inactivation of GSTZ.
- Anderson, Wayne B.,Board, Philip G.,Gargano, Bryan,Anders
-
-
Read Online
- Resolution and absolute configuration of bromofluoroacetic acid
-
The resolution of racemic bromofluoroacetic acid (BrFHCCO2H) 1 was effected by crystallisation of its diastereoisomeric α-methylbenzylamine salts. The crystal structure of the p salt (+)-3a {(+)-BrFHCCO2H·(R)-(+)-α-methylbenzylamine} was solved by X-ray crystallography and the (S)-(+)/(R)-(-) absolute configuration was established for 1. Diastereoisomeric esters 5a and 5b, obtained by addition of bromofluoroacetic acid to enantiomerically pure epoxychroman 4, were used to determine the enantiomeric excess of 1 by 19F NMR. Moreover, the diastereoisomerically pure ester 5a, resulting from addition of enantiomerically pure (+)-1 to 4, gave single crystals and its X-ray crystal structure corroborated the (S)-(+)/(R)-(-) absolute configuration of 1.
- Boussac, Helene,Crassous, Jeanne,Dutasta, Jean-Pierre,Grosvalet, Laurent,Thozet, Alain
-
-
Read Online
- BETA-LACTAMASE INHIBITOR COMPOUNDS
-
The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts are useful in combination with beta- lactam antibiotics, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3, R4, R5 and R6 are described herein.
- -
-
Page/Page column 192
(2018/04/13)
-
- Hydroxyquinazolines and their use as intermediates for pharmaceutical agents
-
6-Substituted-2-halofluoromethyl-1,2-dihydro-2-hydroxy-1-methyl-4-phenylquinazolines and their use as intermediates in the preparation of 3-fluorobenzodiazepines, which are useful as tranquilizers, muscle relaxants and sedatives.
- -
-
-
