Skeletal conformations and receptor binding of some 9,11-modified estradiols

Abstract

The effect of the modification of the 9–11 positions on the skeletal confirmation of estradiol (E 2) has been analyzed by X-ray crystallography and MM2 molecular mechanics. The 11β-hydroxyl and 11-keto analogs of E 2 maintained ring conformations which were similar to the natural hormone (E 2). Introduction of a double bond at position 9–11 induced a flattening of the entire steroid molecule. An 11α-hydroxyl group brought about significant changes in the alicyclic rings of E 2. 9β-Estradiol and 11-keto-9β-estradiol formed ring conformations which were significantly bent from E 2 (below the plane of the A-ring). Examination of the affinity of these C-ring analogs of E 2 for the human estrogen receptor has shown extreme variations. A hydroxyl group placed either α or β at the 11-position yielded ligands with vastly different and reduced affinities for the receptor. The low affinity of 11α-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 the α-hydroxyl group upon the receptor protein. An 11β-hydroxyl group diminished the receptor binding to 1/60th that of E 2 without alicyclic ring distortions, whereas a 9–11 unsaturation reduced the binding to 1/5th although this steroid displayed a flattening of rings B, C, and D. The 11-keto function, which had little effect on the conformation 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-9β-estradiol and 9β-estradiol prevented these ligands from binding receptor. Some of the observed receptor interactions were related to structural alterations in the estrogen ring system induced by modifications on the 9–11 region.