SKELETAL CONFORMATIONS AND RECEPTOR-BINDING OF SOME 9,11-MODIFIED ESTRADIOLS

The effect of the modification of the 9-11 positions on the skeletal c onformation of estradiol (E(2)) has been analyzed by X-ray crystallogr aphy and MM2 molecular mechanics. The 11 beta-hydroxyl and 11-keto ana logs of E(2) maintained ring conformations which were similar to the n atural hormone (E(2)). Introduction of a double bond at position 9-11 induced a flattening of the entire steroid molecule. An 11 alpha-hydro xyl group brought about significant changes in the alicyclic rings of E(2). 9 beta-Estradiol and 11-keto-9 beta-estradiol formed ring confor mations which were significantly bent from E(2) (below the plane of th e A-ring). Examination of the affinity of these C-ring analogs of E(2) for the human estrogen receptor has shown extreme variations. A hydro xyl group placed either alpha or beta at the 11-position yielded ligan ds with vastly different and reduced affinities for the receptor. The low affinity of 11 alpha-hydroxyestradiol (1/300th of E(2)) may be due to the drastic structural change induced in the alicyclic portion of the molecule, as well as, to the steric or electrostatic effects of th e alpha-hydroxyl group upon the receptor protein. An 11 beta-hydroxyl group diminished the receptor binding to 1/60th that of E(2) without a licyclic ring distortions, whereas a 9-11 unsaturation reduced the bin ding to 1/5th although this steroid displayed a flattening of rings B, C, and D. The ll-keto function, which had little effect on the confor mation of the estrogen nucleus, reduced the affinity of this ligand to 1/1000th that of E(2). The negative bend at the C-ring of 11-keto-9 b eta-estradiol and 9 beta-estradiol prevented these ligands from bindin g receptor. Some of the observed receptor interactions were related to structural alterations in the estrogen ring system induced by modific ations on the 9-11 region.