SYNTHESIS, BINDING AFFINITIES AND UTEROTROPHIC ACTIVITY OF SOME 2-SUBSTITUTED ESTRADIOL AND RING-A-FUSED PYRONE DERIVATIVES

A series of estradiol analogs has been synthesized and examined as pot ential estrogens. Nuclear modifications included a variety of substitu ents at the 2 position of estradiol, which was previously thought to b e inhibitory for activity, and inclusion of the 3-phenolic hydroxyl gr oup in a gamma-pyrone and 3'-formylchromone rings fused to ring A of e stradiol. The estrogen relative binding affinities and in vivo assays for uterotrophic activity in rats showed that all the tested compounds were capable of displacing [H-3]E(2) from the estrogen receptor sites by different degrees. The highest inhibition of [H-3]E(2) binding (78 %) to the estrogen receptor was displayed by 2-acetylestradiol which w as also a potent uterotrophic agent. Omission of the free 3-hydroxyl f unctionality by inclusion in a gamma-pyrone ring produced a chromone d erivative that was capable of inhibiting [3H]E(2), binding by 60% and displayed a uterotrophic response of 97%. Further nuclear modification by introduction of thiosemicarbazone moieties decreased the uterotrop hic activity, the highest activity being elicited by the p-bromophenyl thiosemicarbazone derivative. The diketone 2-benzoylacetylestradiol 1 7 beta-acetate, 2-(3'-benzylideneacetyl)estradiol and 2-[3'-(3-anisyli dene)acetyl]estradiol exhibited high inhibition of binding affinity wh ile eliciting approximate to 50% the uterotrophic activity of estradio l.