title: Enantioselective synthesis and preliminary metabolic studies of the optical isomers of 2-n-propyl-4-pentenoic acid, a hepatotoxic metabolite of valproic acid.
abstract: The enantiomers of 2-n-propyl-4-pentenoic acid (delta 4-VPA), a known hepatotoxic metabolite of 2-n-propylpentanoic acid (valproix acid, VPA), were synthesized with the aid of the chiral auxiliaries (4S)-4-(2-propyl)-2-oxazolidone and (4R,5S)-4-methyl-5-phenyloxazolidone. Alkylation of the n-valeryl derivatives of these oxazolidones with allyl bromide, followed by reductive cleavage and chromic acid oxidation of the product, afforded the desired acids, (R)- and (S)-delta 4-VPA. Greater than 93% enantiomeric excess was achieved in the preparation of both enantiomers. Preliminary studies on the metabolic fate of (R)- and (S)-delta 4-VPA in freshly isolated rat hepatocytes revealed striking differences in the biotransformation of the two enantiomers. Quantification of two major metabolites of delta 4-VPA, viz., 4,5-diOH-VPA gamma-lactone and 2-n-propyl-2(E),4-pentadienoic acid (delta 2E,4-VPA), indicated that larger amounts of the gamma-lactone were formed in incubations utilizing (R)-delta 4-VPA as substrate, whereas production of the diene was greater in incubations with (S)-delta 4-VPA. On the basis of the premise that delta 4-VPA serves as a mechanism-based irreversible inhibitor of enzymes of the fatty acid beta-oxidation complex, these differences in metabolism suggest that the two enantiomers of delta 4-VPA may differ in their hepatotoxic potential.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: D J
authors.initials: DJ
authors.lastname: Porubek
authors.forename: H
authors.initials: H
authors.lastname: Barnes
authors.forename: L J
authors.initials: LJ
authors.lastname: Theodore
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie
mesh_terms: D000818:Animals; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis* / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
chemical_list: D005229:Fatty Acids, Monounsaturated; C045022:2-propyl-4-pentenoic acid