Molecular structures of metabolites and analogues of diethylstilbestrol and their relationship to receptor binding and biological activity.

A series of indanyl derivatives of diethylstilbestrol (DES) have recently been identified as inv vivo metabolites of DES. These compounds are of interest because they possess effective uterine estrogen receptor-binding affinity but poor biological activity. The X-ray crystal structures of three of these derivatives were determined and their conformations were compared with those of estradiol and DES. The more active derivatives, indenestrol A (I) and indenestrol B (II) have nearly identical conformations, in which the overall molecule is highly planar, the phenyl ring is twisted out of the plane of the indene rings by approximately 30 degrees, and the distance between the hydroxyl groups is 11.6 A. In the least active derivative, idanestrol (III), the methyl, ethyl, and phenyl substituents were found to be in the same side of the indane ring so that the molecule is constrained to an L-shape. The crystallographically observed conformations of I, II, III, DES, and estradiol, their competative binding affinities, and their in vivo biological activities are consistent with the proposal that the steroid A-ring plays a dominant role in initiating receptor binding while the D-ring orientation relative to the A-ring has a more decisive influence upon activity. The reduction in estrogen receptor-binding affinity and associated reduced activity of III is almost certainly due to its L-shape conformation. The extended conformation of I and II in which both phenolic rings are exposed permitting ready access to both surfaces of either ring probably accounts for the ability of these derivatives to compete so successfully with estradiol for estrogen receptor binding. There are eight different ways in which the molecules of the racemic mixtures of I and II could initiate receptor binding. The reduced biological activity of I and II is probably due to the fact that not all eight binding orientations are compatible with eliciting estrogenic response. Comparison of the observed conformations of I, II, DES, and estradiol suggests that it is the alpha-ring of I and II that minics the steroid A-ring in receptor binding, and that two of the four possible alpha-ring/A-ring matches are most conducive to eliciting hormone activity.