CRYSTAL-STRUCTURE, RECEPTOR-BINDING, AND GENE-REGULATION OF 2-NITROESTRADIOL AND 4-NITROESTRADIOL

Crystal structures of 2-nitroestradiol and 4-nitroestradiol showed two different molecular conformations for each compound. The crystal stru cture of 3-nitroestradiol, as well as that of 4-nitroestrane-3-methyl ether, displayed a nitro group in, which the oxygens were perpendicula r to the aromatic ring and were thus nonconjugating. On the other hand , the nitro-oxygens in 2-nitroestradiol were periplanar, with the arom atic ring permitting conjugation. This latter structure bound to estro gen receptor with 1/1000th the affinity of estradiol and was inefficie nt in gene stimulation. 4-Nitroestradiol possessed a relative binding affinity 40-fold greater than that of the 2-nitro derivative and activ ely induced responsive genes at a concentration of 10(-8) M. Whereas b inding affinity can be explained primarily by polar groups and skeleta l structure, gene induction may be linked to electronic induction in r ing A that causes a requisite electronegative isopotential around the molecule. This electronegative characteristic also produces conformati onal changes in the alicyclic backbone of the estrogen, specially ring B, which could interfere with the molecular fit of the nitroestradiol s with estrogen receptor, (C) 1996 by Elsevier Science Inc.