Hossain M B, van der Helm D, Schmitz F J, Pordesimo E O, Magarian R A, Meyer K L, Overacre L B, Day B W
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019.
J Med Chem. 1994 May 27;37(11):1670-83. doi: 10.1021/jm00037a018.
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.
据报道，一系列1,1 - 二氯 - 2,2,3 - 三芳基环丙烷（DTACs）具有明显的抗雌激素作用，且在培养中对雌激素受体阳性的MCF - 7人乳腺癌细胞具有抑制作用，本文报道了它们的分子结构和构象特征。此外，还将DTACs的结构和构象特征与首个已知的非甾体抗雌激素药物MER25以及临床上常用的抗雌激素药物他莫昔芬进行了比较。通过X射线衍射确定了四种DTAC化合物的分子结构。晶体结构表明，DTAC分子中三个芳基环的相对构象几乎相同，被指定为“非螺旋桨”构象，这与所有已知三芳基乙烯中三个环所观察到的“螺旋桨”构象形成对比。使用从各自晶体结构构建的理想化模型化合物进行了系统的构象搜索，以找出DTACs、MER25和他莫昔芬的构象偏好。能量最小化和构象搜索研究表明，所有DTAC分子的中心核心包含二氯三芳基环丙基系统，都有一个共同的、单一的全局最低能量构象异构体，这与它们晶体结构中发现的构象相似。对MER25的构象搜索表明，该分子可以呈现多种低能量构象异构体，其中两种，一种反式（A1）和一种gauche式（G1A），能量大致相同。反式构象与在其晶体结构中观察到的构象相似，类似于他莫昔芬的雌激素性E - 异构体，而MER25能量最低的gauche构象异构体更类似于他莫昔芬的抗雌激素性Z - 异构体。对MER25的核磁共振光谱分析表明，该分子在溶液中主要以反式构象存在。对他莫昔芬、DTACs和MER25的结构特征和生物活性的比较综述，为它们低雌激素受体结合亲和力以及共同的抗雌激素活性提供了一种可能的解释。
