Asymmetric synthesis and enantioselective teratogenicity of 2-n-propyl-4-pentenoic acid (4-en-VPA), an active metabolite of the anticonvulsant drug, valproic acid.
Previous studies indicated that the enantiomers of thalidomide and its analogue EM12 exhibit differing teratogenic potencies. Unfortunately, these substances proved to be unstable and racemised considerably, so that the intrinsic teratogenic potencies of the pure enantiomers were difficult to elucidate. We have therefore studied the teratogenicity of the enantiomers of 2-n-propyl-4-pentenoic acid (4-en-VPA), a metabolite of the human and animal teratogen valproic acid (VPA). Both enantiomers were prepared via asymmetric synthesis using (R)- and (S)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP: SAMP). The determination of the absolute configuration and of the optical purities is described. They were administered as single intraperitoneal injections during early organogenesis in the mouse (day 8 of gestation), a period shown to be highly susceptible to interference with neural tube closure by VPA. S-(-)-4-en-VPA was significantly more teratogenic (formation of exencephaly) and embryotoxic (incidence of embryolethality and fetal growth retardation) than R-(+)-4-en-VPA. The rate of neural tube defects (exencephaly) produced by the S-enantiomer was about 4 times higher than that produced by the R-enantiomer. The S-enantiomer of 4-en-VPA is the first analogue of VPA with higher teratogenic potency than the parent drug. Our results show that racemic mixtures may consist of enantiomers with greatly differing teratogenic potencies. These findings may lead to the development of clinically useful drug enantiomers with low teratogenic potencies, and assist in studies of molecular mechanisms in drug and chemical teratogenesis.
Hauck
R S
RS
Institute for Toxicology and Embryopharmacology, Free University of Berlin, Germany.
Nau
H
H
D000014:Abnormalities, Drug-Induced; D000818:Animals; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced*; D013237:Stereoisomerism; D014635:Valproic Acid / Q000378:metabolism / Q000633:toxicity*
D005229:Fatty Acids, Monounsaturated; C045022:2-propyl-4-pentenoic acid; D014635:Valproic Acid