title: Enzymatic ring-opening reactions of the chiral cardioprotective agent (+) (S)-ICRF-187 and its (-) (R)-enantiomer ICRF-186 by dihydropyrimidine amidohydrolase.
abstract: The kinetics of the ring-opening reaction of the cardioprotective agent (+) (S)-ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane, dexrazoxane] and its (-) (R)-analog ICRF-186 by the enzyme dihydropyrimidine amidohydrolase (DHPase) has been studied by HLLC. Chromatographic separation of the two single-ring opened hydrolysis products allowed an estimation of the Michaelis parameters for the opening of each individual ring on the two optical isomers. Under nonsaturating conditions, DHPase acts on ICRF-187 4 times faster than it does on ICRF-186. However, the single-ring opened hydrolysis products of both ICRF-187 and ICRF-186 are not substrates of DHPase. Because the active form of ICRF-187 is thought to be its rings-opened metal ion chelating form, these results suggest that DHPase-catalyzed hydrolysis occurring in the liver and the kidney may lead to differences in the pharmacological action and effectiveness of these two optical isomers.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
authors.forename: B B
authors.initials: BB
authors.lastname: Hasinoff
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D011929:Razoxane / Q000378:metabolism* / Q000493:pharmacokinetics; D013237:Stereoisomerism
chemical_list: D011929:Razoxane; D000581:Amidohydrolases; C020047:dihydropyrimidinase