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-tetrahydr ochrysene-2,8-diol (THC, rac-2b) acts as an agonist on estrogen receptor al pha (ER alpha) and as a complete antagonist on estrogen receptor beta (ER b eta) (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 -dipropy l THCs 2a-c were prepared in a highly enantio- and diastereoselective manne r by the acyloin condensation of enantiomerically pure alpha-alkyl-beta-ary lpropionic esters, followed by a Lewis acid-mediated double cyclization und er conditions of minimal epimerization. ER alpha and ER beta binding affini ty of both cis and trans isomers of dimethyl, diethyl, and dipropyl THCs wa s determined in competitive binding assays, and their transcriptional activ ity was determined in reporter gene assays in mammalian cells. Nearly all T HCs examined were found to be affinity-selective for ER beta. All these THC s are agonists on ER alpha, and THCs with small substituents are agonists o n both ER alpha and ER beta. As substituent size was increased, ER beta-sel ective antagonism developed first in the (R,R)-cis enantiomer series and fi nally in the trans diastereomer and (S,S)-cis enantiomer series. The most p otent and selective ligand was identified as (R,R)-cis-diethyl THC 2b, whic h mimicked the ER beta-selective antagonist character of racemic cis-diethy l THC 2b. This study illustrates that the antagonist character in THC ligan ds for ER beta depends in a progressive way on the size and geometric dispo sition of substituent groups and suggests that the induction of an antagoni st conformation in ER beta can be achieved with these ligands with less ste ric perturbation than in ER alpha. Furthermore, antagonists that are select ively effective on ERP can have structures that are very different from the typical antiestrogens tamoxifen and raloxifene, which are antagonists on b oth ER alpha and ER beta.