Induction of the estrogen specific mitogenic response of MCF-7 cells by selected analogues of estradiol-17 beta: A 3D QSAR study
Induction of the estrogen specific mitogenic response of MCF-7 cells by selected analogues of estradiol-17 beta: A 3D QSAR study
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DOI：
10.1021/jm9703294
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发表时间：
1997-10-24
影响因子：
7.3
通讯作者：
Brooks, SC
中科院分区：
文献类型：
--
作者：
Wiese, TE;Polin, LA;Brooks, SC
雌二醇-17β(E-2)类似物在人乳腺癌细胞株MCF-7中对雌激素受体(ER)结合亲和力和有丝分裂潜能进行了评估。这42个化合物通过在环系周围放置羟基、氨基、硝基或碘基，或作为E-2的3-和17个β-羟基的替代，对天然雌激素结构进行了微妙的修饰。研究发现，类似物的促有丝分裂活性与内质网结合只有一定程度的关系。为了阐明雌激素受体结合亲和力或有丝分裂原潜能的独特结构特征，采用三维定量结构-活性(QSAR)方法比较分子场分析(CoMFA)。通过使用不同的比对规则和区域步长，分别优化了受体结合和细胞生长刺激的CoMFA模型。虽然CoMFA等高线图确实概述了这两个测量的生物属性的共同结构要求，但这组雌激素中的特定拓扑特征被描绘出来，以区分有丝分裂潜能和ER结合能力。特别是，影响生长的立体干扰区在一个带内从A环上方延伸到位置4及以下，而ER结合的立体干扰区仅限于1，2和4位以及B环的a面上的孤立多面体。此外，位于A-、B-或C-环周围的电负性特征有助于受体的亲和力。然而，生长只依赖于3位附近的电负性和电正性。在一个最终的有丝分裂反应的QSAR模型中，ER结合值与结构特征一起被包括在CoMFA中作为描述符。由此得到的3D-QSAR具有本研究中最具预测潜力的模型，可被视为一般评估类固醇雌激素在MCF-7细胞中的生长刺激能力的原型模型。例如，D环轮廓的位置说明了该模型对17β-羟基类固醇的偏好，而不是促分裂活性较低的17α和16α-羟基化合物。此外，立体块体在11α位的促有丝分裂作用也很明显。本报告中的QSAR研究表明，虽然ER结合可能是MCF-7细胞雌激素依赖性生长反应的必需因素，但除了那些负责紧密受体结合的结构特征外，还必须存在特殊的结构特征，以诱导最佳的有丝分裂反应。因此，这份报告表明，CoMFA QSAR方法可以用来表征测试化合物的结构特征，这些结构特征解释了不同类型的雌激素反应。
Analogues of estradiol-17 beta (E-2) 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 E-2. 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 a 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.