Wiese T E, Polin L A, Palomino E, Brooks S C
Department of Biochemistry, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
J Med Chem. 1997 Oct 24;40(22):3659-69. doi: 10.1021/jm9703294.
Analogues of estradiol-17 beta (E2) have been evaluated for estrogen receptor (ER) binding affinity and mitogenic potential in the human breast cancer cell line MCF-7. These 42 compounds represent subtle modifications of the natural estrogen structure through the placement of hydroxyl, amino, nitro, or iodo groups around the ring system in addition to, or as replacement of, the 3- and 17 beta-hydroxyls of E2. The mitogenic activity of the analogues was found to be related to ER binding only to a limited extent. In order to elucidate structural features that are uniquely responsible for receptor binding affinity or mitogen potential of estrogens, the three-dimensional quantitative structure-activity (QSAR) method Comparative Molecular Field Analysis (CoMFA) was employed. Separate CoMFA models for receptor binding and cell growth stimulation were optimized through the use of various alignment rules and region step size. Whereas the CoMFA contour plots did outline the shared structural requirements for the two measured biological properties, specific topological features in this set of estrogens were delineated that distinguish mitogenic potential from ER binding ability. In particular, steric interference zones which affected growth extend in a band from above the A-ring to position 4 and below, whereas the ER binding steric interference zones are limited to isolated polyhedra in the 1, 2 and 4 positions and the alpha face of the B-ring. In addition, electronegative features located around the A-, B-, or C-rings contribute to receptor affinity. However, growth is dependent only on electronegative and electropositive properties near the 3-position. In a final QSAR model for the mitogenic response, the value of ER binding was included along with structural features as a descriptor in CoMFA. The resulting 3D-QSAR has the most predictive potential of the models in this study and can be considered a prototype model for the general evaluation of a steroidal estrogen's growth stimulating ability in MCF-7 cells. For example, the location of D-ring contours illustrate the model's preference for 17 beta-hydroxy steroids over the less mitogenic 17 alpha- and 16 alpha-hydroxy compounds. In addition, the enhanced mitogenic effect of steric bulk in the 11 alpha-position is also evident. The QSAR studies in this report illustrate the fact that while ER binding may be a required factor of the estrogen dependent growth response in MCF-7 cells, particular structural characteristics, in addition to those responsible for tight receptor binding, must be present to induce an optimal mitogenic response. Therefore, this report demonstrates that the CoMFA QSAR method can be utilized to characterize structural features of test compounds that account for different types of estrogenic responses.
已对雌二醇 - 17β（E2）类似物在人乳腺癌细胞系MCF - 7中的雌激素受体（ER）结合亲和力和促有丝分裂潜力进行了评估。这42种化合物通过在环系统周围引入羟基、氨基、硝基或碘基团，对天然雌激素结构进行了细微修饰，这些基团可取代E2的3 - 和17β - 羟基，或与之同时存在。结果发现，类似物的促有丝分裂活性仅在有限程度上与ER结合有关。为了阐明对雌激素受体结合亲和力或促有丝分裂潜力具有独特作用的结构特征，采用了三维定量构效关系（QSAR）方法——比较分子场分析（CoMFA）。通过使用各种比对规则和区域步长，分别对受体结合和细胞生长刺激的CoMFA模型进行了优化。尽管CoMFA等高线图确实勾勒出了这两种测量的生物学特性的共同结构要求，但在这组雌激素中确定了特定的拓扑特征，这些特征区分了促有丝分裂潜力和ER结合能力。特别是，影响生长的空间干扰区域在从A环上方到4位及其下方的一条带中延伸，而ER结合的空间干扰区域仅限于1、2和4位以及B环α面的孤立多面体。此外，位于A、B或C环周围的电负性特征有助于受体亲和力。然而，生长仅取决于3位附近的电负性和电正性性质。在促有丝分裂反应的最终QSAR模型中，ER结合值与结构特征一起作为CoMFA中的描述符。所得的三维QSAR在本研究的模型中具有最大的预测潜力，可被视为用于全面评估甾体雌激素在MCF - 7细胞中生长刺激能力的原型模型。例如，D环等高线的位置说明了该模型对17β - 羟基甾体的偏好超过促有丝分裂作用较弱的17α - 和16α - 羟基化合物。此外，11α位空间体积增加的促有丝分裂作用增强也很明显。本报告中的QSAR研究表明，虽然ER结合可能是MCF - 7细胞中雌激素依赖性生长反应的必要因素，但除了那些负责紧密受体结合的结构特征外，还必须存在特定的结构特征才能诱导最佳的促有丝分裂反应。因此，本报告表明CoMFA QSAR方法可用于表征测试化合物的结构特征，这些特征解释了不同类型的雌激素反应。
