Comparison of estramustine with its dihydroxy analogue,estradiol 3-bis(2-hydroxyethyl)carbamate

Estramustine is an antimicrotubule agent that is effective against prostate cancer when used in combination with other microtubule-binding drugs. It is a derivative of estradiol and has a nitrogen mustard group attached via an intervening carbamate group. The molecular dimensions published for estramustine from crystal structure analyses (Mol. Pharmacol. 41∶569, 1992) indicate that the carbamate group modifies the mustard group by giving considerable double-bond character to the C-N bond. As a result the mustard group cannot form an active aziridine ring and therefore does not show the expected alkylating function. The substitution at O(3) of the aromatic A ring of the steroid moiety has also modified its activity as a steroid. Geometric data are presented here on a compound in which the two chlorine atoms of the mustard group of estramustine are replaced by hydroxyl groups. The question was, why does the dihydroxy derivative not show biological activity when chlorine atoms do not appear to be activated in estramustine itself? A comparison of the molecular geometries of the two compounds shows that the dimensions of the carbamate group are similar in both compounds. Therefore it appears that it is the extensive hydrogen-bonding capability of the dihydroxy compound that destroys its estramustine-like activity. In crystals of both compounds there is a hydrogen bond between O(17) -H and O(19) of another molecule, but the dihydroxy compound can form two more hydrogen bonds. This may possibly prevent it from reaching the site of action of estramustine or, if it does reach that site, cause it to behave differently.