title: Structure-activity relationships of retinoids in developmental toxicology. I. Studies on the nature of the polar terminus of the vitamin A molecule.
abstract: The teratogenic activities of all-trans-retinoyl fluoride, all-trans-3-retinylidene-2,4-pentanedione, all-trans-2-retinylidene-1,3-cyclopentanedione, all-trans-2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione, all-trans-2-retinylidene-5-p-methoxyphenyl-1,3-cyclohexanedione, all-trans-2-retinylidene-1,3-cyclooctanedione, all-trans-5-[2,6-dimethyl-8-(2,6,6-trimethylcyclohexen-1-yl)-1,3, 5,7-octatetrae n-1-yl]tetrazole, ethyl all-trans-9-(exo-2-bicyclo[2.2.1.]heptyl)-3,7-dimethyl-2,4,6,8- nonatetraenoate, ethyl all-trans-4-[2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3- butadien-1-yl]benzoate, 13-cis-N-(4-hydroxyphenyl)retinamide, and 13-cis-N-(2-hydroxyethyl)retinamide were determined in the hamster and compared with that of all-trans-retinoic acid. Administration of a single oral dose of the retinoids failed to induce signs of the hypervitaminosis A intoxication syndrome in any of the dams, and the maternal weight gain was not significantly different from the vehicle control value, except following intubation of the retinamides where maternal weight gain was significantly depressed. All of the retinylidene 1,3-diketones studied here were devoid of significant teratogenic activity. The retinamides failed to induce either an elevated mean litter frequency of malformed fetuses or a syndrome of anomalies similar to that induced by administration of an equimolar dose of all-trans-retinoic acid. All of the other retinoids induced a syndrome of malformations similar to that induced by administration of all-trans-retinoic acid and were associated with a significant increase in the number of litters containing one or more malformed fetuses and an elevated mean litter frequency of malformed fetuses. The teratogenic activity in the hamster of this series of retinoids was independent of structural modifications in either the beta-cyclogeranylidene ring or the polyene chain of the molecule. The results of the present study suggest that the changes in teratogenic activity associated with structural modification of vitamin A at C15 were primarily dependent upon the presence of or biotransformation to a free carboxyl or a moiety with an equivalent pKa at C15, not upon the molecular size of the substituent or the stereochemical position about C13. Since major structural modifications of vitamin A were made without the substantial loss of teratogenic activity, the structural requirements of retinoids for induction of terata were not extraordinarily exacting.
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006224:Cricetinae; D005260:Female; D005327:Fetal Resorption; D005333:Fetus / Q000187:drug effects*; D011247:Pregnancy; D012176:Retinoids / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013723:Teratogens
chemical_list: D012176:Retinoids; D013723:Teratogens