“thickness” of the molecule is important to its activity: the planes of the two phenyl
groups must have a 60° torsion angle, and four alkyl methyl groups will provide the
same steric hindrance as two ethyls; the dimethyl derivative is therefore inactive. In
addition to the geometric orientation of the two phenyl groups, the interatomic distance
between the two phenolic OH groups in DES is also important. Indeed, as long ago as
1946, Schuler suggested that the distance between the two OH groups in DES matched
the 3-OH to 17-OH distance in estradiol. Modern physical chemistry structural studies,
however, have shown that the OH–OH distances are 12.1 Å in DES but only 10.9 Å in
estradiol; this discrepancy can be eliminated by hydrogen bonding two water molecules
to the 17-OH moiety of estradiol and by considering the water -OH group rather than
the estradiol -OH group in the distance calculation. Recent quantum pharmacology
calculations by Wiese et al. support these observations and suggest that the estrogen
receptor can recognize as many as ten low-energy conformations of DES, provided the
OH–OH geometries are within an acceptable range. Further support of this conclusion
comes from the thousands of DES analogues that have been synthesized and biologically
evaluated.
In terms of toxicology, DES has been a fascinating drug. There have been a number
of reports of vaginal adenocarcinoma (vaginal cancer) in young women (so-called
“DES-babies”) whose mothers were treated with DES during pregnancy in the mistaken
belief that DES would reduce the possibility of miscarriage. Although the incidence of
cancer was low—less than 1 case per 1000 mothers exposed—it nonetheless quite
appropriately led to the discontinued use of DES in pregnancy. This agent should prob-
ably only be used for the treatment of cancer (e.g., of the prostate.)
HORMONES AND THEIR RECEPTORS 323