title: The enantiomers of the valproic acid analogue 2-n-propyl-4-pentynoic acid (4-yn-VPA): asymmetric synthesis and highly stereoselective teratogenicity in mice.
abstract: The teratogenic activities of R(+)- and S(-)-2-n-propyl-4-pentynoic acid (R and S-4-yn-VPA), the enantiomers of the highly teratogenic valproic acid (VPA) analogues (+/-)-4-yn-VPA, were investigated in mice. The enantiomers were prepared via asymmetric synthesis, each in three steps employing the chiral auxiliaries (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and S-4-benzyl-2-oxazolidinone. The determination of the absolute configurations and the optical purities is described. R(+)-4-yn-VPA contained 7%, and S(-)-4-yn-VPA 8%, of the respective antipodes. The aqueous solutions of the sodium salts of R- and S-4-yn-VPA were administered as single i.p. injections during early organogenesis in the mouse (day 8 of gestation) using the induction of exencephaly as the teratological end point. Dose/exencephaly curves indicated that S-4-yn-VPA is 7.5 times more teratogenic than its antipode, 1.9 times more teratogenic than (+/-)-4-yn-VPA and 3.9 times more teratogenic than the parent drug VPA. In contrast, the neurotoxicity (maternal toxicity) of the 4-yn-VPA enantiomers was found to be independent of the stereo-chemical configuration and lower than achieved after VPA administration. Due to its low neurotoxicity and highly stereoselective neural tube-inducing activity, S-4-yn-VPA should prove an important tool for the investigation of molecular mechanism of the teratogenic action in this class of compounds; R-4-yn-VPA could act as the negative control in these studies.
authors.affiliation: Institute of Toxicology and Embryopharmacology, Free University Berlin, Germany.
authors.forename: R S
authors.initials: RS
authors.lastname: Hauck
authors.forename: H
authors.initials: H
authors.lastname: Nau
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis* / Q000633:toxicity; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009422:Nervous System Diseases / Q000139:chemically induced; D011247:Pregnancy; D012886:Skull / Q000002:abnormalities*; D013237:Stereoisomerism
chemical_list: D005229:Fatty Acids, Monounsaturated; C045022:2-propyl-4-pentenoic acid