Molecular Structures and Conformational Studies of Triarylcyclopropyl and Related Nonsteroidal Anti-Estrogens

Abstract

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 estrogen-receptor-positive MCF-7 human breast cancer cells in culture, are reported. In addition, structural and conformational features of the DTACs were compared to the first-known nonsteroidal antiestrogen, MER25, and the clinically useful antiestrogen Tamoxifen. The molecular structures of four DTAC compounds were determined by X-ray diffraction. Crystallographic structures show that the DTAC molecules have nearly the same relative conformation for the three aryl rings which is designated as a "nonpropeller" conformation in contrast to the observed "propeller" conformation for the three rings in all known triarylethylenes. Systematic conformational searches were performed to find the conformational 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 DTAC molecules have a common, single global minimum energy conformer for their central core containing the dichlorotriarylcyclopropyl system, which is similar to that found in their crystal structures. Conformational 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-isomer of Tamoxifen, while the lowest energy gauche conformer of MER25 resembles more closely the antiestrogenic Z-isomer of Tamoxifen. NMR spectroscopic analysis of MER25 showed that the molecule exists predominantly in the anti conformation in solution. A comparative review of the structural features and bioactivities of Tamoxifen, DTACs, and MER25 provides a possible explanation for their low estrogen receptor binding affinity which is common to these compounds together with their antiestrogenic activity.

Synthesis and Biological Evaluation of Cyclopropyl Analogs of the Antiestrogen MER 25

“…Earlier work (20) indicated that the presence of a 4-methoxy group in the ͱ ring, as in 11E and 11Z, might increase their antiestrogenic activity relative to analogs which are devoid of the methoxy moiety [7A(Z) and 7A(E)] (Fig. 2).…”

“…Crystal structure determination (19) and conformational studies of MER 25 (20) were performed to identify the preferred conformation of the molecule in various energy states. Molec- ular mechanics calculations and steric energy profile searches identified three lowenergy conformers: anti, gauche 1 , and gauche 2 ( Fig.…”

“…In addition to the stereochemistry of MER 25, the p-methoxy group was of interest to us in the development of more effective antiestrogens. Computer-aided molecular studies (20) revealed that the ͱ ring of MER 25 was directed toward the D ring in estradiol such that the p-methoxyphenyl group was in the vicinity of the 17-ͱ-hydroxy group when MER 25 was in the gauche 1 conformer, but not when in the anti conformer (Fig. 1).…”

“…A total of 150 mg (34%) of 18Z was collected, mp ϭ 38. 5 Z (20). Compound 13 (5 g, 14.32 mmol) was dissolved in 100 ml of dry THF, and 3.0 M phenylmagnesium bromide solution (in ether) (8.1 g, 44.46 mmol) in 100 ml THF was added dropwise over a 1-h period at 0ЊC.…”

Synthesis and Chiral Separation of Some Antitumor Agents

“…The fractional crystallization of the cyclopropanes (24, 25) and the subsequent dimethylamination of the individual diastereoisomers, followed by fractional crystallization, afforded the pure diastereoisomers 6 and 7. Single crystal X-ray analysis was used to determine the configuration of both the Z-and E-isomers (37,38).…”