Estrogen receptor subtype-selective ligands:: Asymmetric synthesis and biological evaluation of cis- and trans-5,11-dialkyl-5,6,11,12-tetrahydrochrysenes

We have recently reported that racemic 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC, rac-2b) acts as an agonist on estrogen receptor alpha (ER alpha) and as a complete antagonist on estrogen receptor beta (ER beta) (Sun et al. Endocrinology 1999, 140, 800-804). To further investigate this novel ER subtype-selective estrogenic activity, we have synthesized a series of cis- and trans-dialkyl THCs. cis-Dimethyl, -diethyl, and -dipropyl THCs 2a-c were prepared in a highly enantio- and diastereoselective manner by the acyloin condensation of enantiomerically pure alpha-alkyl-beta-arylpropionic esters, followed by a Lewis acid-mediated double cyclization under conditions of minimal epimerization. ER alpha and ER beta binding affinity of both cis and trans isomers of dimethyl, diethyl, and dipropyl THCs was determined in competitive binding assays, and their transcriptional activity was determined in reporter gene assays in mammalian cells. Nearly all THCs examined were found to be affinity-selective for ER beta. All these THCs are agonists on ER alpha, and THCs with small substituents are agonists on both ER alpha and ER beta. As substituent size was increased, ER beta-selective antagonism developed first in the (R,R)-cis enantiomer series and finally in the trans diastereomer and (S,S)-cis enantiomer series. The most potent and selective ligand was identified as (R,R)-cis-diethyl THC 2b, which mimicked the ER beta-selective antagonist character of racemic cis-diethyl THC 2b. This study illustrates that the antagonist character in THC ligands for ER beta depends in a progressive way on the size and geometric disposition of substituent groups and suggests that the induction of an antagonist conformation in ER beta can be achieved with these ligands with less steric perturbation than in ER alpha. Furthermore, antagonists that are selectively effective on ERP can have structures that are very different from the typical antiestrogens tamoxifen and raloxifene, which are antagonists on both ER alpha and ER beta.