MOLECULAR-STRUCTURES AND CONFORMATIONAL STUDIES OF TRIARYLCYCLOPROPYLAND RELATED NONSTEROIDAL ANTIESTROGENS

Molecular structures and conformational characteristics of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), which were reported previously to be distinctly antiestrogenic and inhibitors of the estro gen-receptor-positive MCF-7 human breast cancer cells in culture, are reported. In addition, structural and conformational features of the D TACs were compared to the first-known nonsteroidal antiestrogen, MER25 , and the clinically useful antiestrogen Tamoxifen. The molecular stru ctures of four DTAC compounds were determined by X-ray diffraction. Cr ystallographic structures show that the DTAC molecules have nearly the same relative conformation for the three aryl rings which is designat ed as a ''nonpropeller'' conformation in contrast to the observed ''pr opeller'' conformation for the three rings in all known triarylethylen es. Systematic conformational searches were performed to find the conf ormational preferences of DTACs, MER25, and Tamoxifen using idealized model compounds built from their respective crystal structure. Energy- minimization and conformational-search studies demonstrated that all D TAC molecules have a common, single global minimum energy conformer fo r their central core containing the dichlorotriarylcyclopropyl system, which is similar to that found in their crystal structures. Conformat ional search of MER25 showed that the molecule can assume a number of low-energy conformers of which two, one anti (A1) and one gauche (G1A) , have about the same energy. The anti conformation is similar to the one observed in its crystal structure and resembles the estrogenic E-i somer of Tamoxifen, while the lowest energy gauche conformer of MER25 resembles more closely the antiestrogenic Z-isomer of Tamoxifen. NMR s pectroscopic analysis of MER25 showed that the molecule exists predomi nantly in the anti conformation in solution. A comparative review of t he structural features and bioactivities of Tamoxifen, DTACs, and MER2 5 provides a possible explanation for their low estrogen receptor bind ing affinity which is common to these compounds together with their an tiestrogenic activity.