Flavonoids. 8. Synthesis and antifertility and estrogen receptor binding activities of coumarins and delta3-isoflavenes.
A series of coumarins and delta3-isoflavenes was prepared. Although antifertility activity was shown by all of these compounds, the required dosage in mice varied from 13.5 mug/kg/day to 50 mg/kg/day. The most potent compounds were the 2-methyl-4-ethylisoflavenes, two of which (2a and 2b) were about equipotent with DES on a molar basis. They were followed by the 2,2-dimethylisoflavenes, the 2-unsubstituted isoflavene, and the coumarins. The most active compounds possessed an acetoxy group at C-7 and an oxygen function at C-4'. Presence of fluorine at C-4' or diethylaminoethoxy at C-M decreased the antifertility activity. The uterotropic activity followed the same trends as the antifertility activity with some evidence for the separation of the two effects in the 2,2-dimethylisoflavene series. Based on a limited study it appears that two phenolic hydroxyl groups are required for the presence of good estrogen receptor binding activity. An apparent lack of correlation between the estrogen binding activity and uterotropic or antifertility effects is probably explained by in vivo metabolism.
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D003283:Contraceptives, Postcoital, Synthetic / Q000138:chemical synthesis; D003374:Coumarins / Q000138:chemical synthesis*; D003600:Cytosol / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D045166:Estradiol Congeners / Q000138:chemical synthesis*; D004968:Estrogens, Non-Steroidal / Q000138:chemical synthesis*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D003283:Contraceptives, Postcoital, Synthetic; D003374:Coumarins; D045166:Estradiol Congeners; D004968:Estrogens, Non-Steroidal; D005419:Flavonoids; D011956:Receptors, Cell Surface; D004958:Estradiol