title: Structure-activity relationships of retinoids in developmental toxicology. IV. Planar Cisoid conformational restriction.
abstract: To evaluate the influence of the three-dimensional configuration of retinoids on teratogenic activity, 14 retinoids were studied in hamsters. Retinoids with a conformational restriction of the retinoic acid polyene chain adjacent to the beta-cyclogeranylidene ring showed increased teratogenic potency and retinoids with aromatic conformational restriction adjacent to the polar terminus showed potency equivalent to retinoic acid. Conformational restriction of the polyene chain that permits rotation of the bond adjacent to the beta-cyclogeranylidene ring abolished teratogenic activity. Incorporation of dimethyl substituents at positions corresponding to C1 and C4 positions of retinoic acid enhanced teratogenic potency. Elimination of the twist chair conformation of gem-dimethyl substituents via incorporation of a benzothiopyran or substituted planar aromatic ring decreased teratogenic potency. Planar cisoid conformational restriction alone was insufficient to confer teratogenic activity in that elimination of the polar terminus abolished teratogenic activity. That an acidic polar terminus, as contrasted to a carboxyl residue per se, was required for teratogenic activity was illustrated by administration of a retinoidal phenyl sulfone which was metabolized to the corresponding teratogenic sulfonic acid. Retinoid teratogenicity in hamsters depends upon the assumption of a 10,11 cisoid and/or 12,13 cisoid rotameric form by a conjugated spacer greater than five carbon atoms in length located between a hydrophobic ring system and an acidic terminus, ionized at physiologic pH. Comparison of the relative teratogenic potencies of this series of conformationally restricted retinoids with their activities in assays for chemoprevention activity showed that those analogs with high intrinsic control of epithelial or mesenchymal cell differentiation were also the more potent teratogens. The results suggest that those biochemical mechanisms responsible for retinoid control of normal adult or neoplastic cell differentiation also mediate retinoid-induced teratogenesis.
authors.affiliation: Department of Health Services, State of California, Toxic Substances Control Program, Berkeley 94710.
authors.forename: C C
authors.initials: CC
authors.lastname: Willhite
authors.forename: M I
authors.initials: MI
authors.lastname: Dawson
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005313:Fetal Death; D005315:Fetal Diseases / Q000139:chemically induced*; D005327:Fetal Resorption; D008968:Molecular Conformation; D011247:Pregnancy; D012176:Retinoids / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D012176:Retinoids