Structure-toxicity relationships of the tetramethylated tetralin and indane analogs of retinoic acid.
The teratogenicity of retinoids containing either tetramethylated tetralin (Ro 13-6307 or Ro 13-2389) or tetramethylated indane (Ro 13-4306) ring system substitutions was compared to the teratogenic potency of all-trans-retinoic acid. Single oral doses, administered to Syrian Golden hamsters at 10:00 A.M. on day 8 of gestation, induced a syndrome of malformations identical to that induced by treatment with all-trans-retinoic acid. These retinoids failed to induce signs of maternal hypervitaminosis A at doses associated with a significant teratogenic response. The tetramethylated tetralin retinoids and indane retinoid were 18 and 2.4 times as embryotoxic on a molar basis, respectively, as all-trans-retinoic acid. Introduction of a supplementary ring in the side-chain restricted polyene chain flexibility and maintained the hydrophobic plane of the chain. The present results are consistent with previous studies showing that the presence of or biotransformation to a free acid congener was necessary for retinoid teratogenic activity in hamsters and that increasing conformational restriction of acidic retinoids increased teratogenic potency.
Howard
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Center for Environmental Toxicology, Utah State University, Logan 84322-5600.
Willhite
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Sharma
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D000014:Abnormalities, Drug-Induced; D000818:Animals; D006224:Cricetinae; D005260:Female; D007189:Indans / Q000633:toxicity*; D007192:Indenes / Q000633:toxicity*; D008647:Mesocricetus; D009281:Naphthalenes / Q000633:toxicity*; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013577:Syndrome; D013723:Teratogens; D013764:Tetrahydronaphthalenes / Q000633:toxicity*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000633:toxicity*
D007189:Indans; D007192:Indenes; D009281:Naphthalenes; D013723:Teratogens; D013764:Tetrahydronaphthalenes; D014212:Tretinoin