2-methoxyestradiol and analogs as novel antiproliferative agents: Analysis of three-dimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding
2-methoxyestradiol and analogs as novel antiproliferative agents: Analysis of three-dimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding
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DOI：
10.1124/mol.61.5.1053
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发表时间：
2002-05-01
影响因子：
3.6
通讯作者：
Stewart, AG
中科院分区：
文献类型：
--
作者：
Hughes, RA;Harris, T;Stewart, AG
2-甲氧基雌二醇（2-MEO）是雌激素的代谢物，因其具有抗肿瘤和抗血管生成活性而成为开发新型抗肿瘤和抗炎药的先导化合物。然而，2-MEO对雌激素受体的亲和力会导致不良的副作用。作为设计具有最佳活性谱的2-MEO样化合物的前导，我们分析了2-MEO和一系列类似物引起G(1)细胞周期阻滞（通过测量人培养气道平滑肌中DNA合成的抑制）和抑制[H-3]雌二醇与雌激素受体（ER；来自大鼠子宫平滑肌）结合的能力。其中一个二乙酰氧基烯二醇衍生物对DNA合成具有合理的效价（pIC(50) = 5.97），但对ER的亲和力可忽略不计（pIC(50) < 5）。利用比较分子场分析（CoMFA）技术建立了这些活性的三维定量构效关系。比较优化后的CoMFA模型，发现DNA合成抑制和ER结合的结构要求不同。例如，在甾体a环平面以下的2位上电正取代可以增强DNA合成抑制，而在这个位置上电负取代则有利于内质网结合。同样，DNA合成抑制与聚集在A环和B环周围区域的空间体积增加呈负相关；这些区域的空间体积变化与内质网结合关系不大。这些观察结果将指导设计新的类似物，这些类似物具有更高的效力，具有所需的特性（例如，DNA合成抑制），并且具有最小的不必要的活性（例如，内质网结合）。
2-Methoxyestradiol (2-MEO), a metabolite of estrogen, is an attractive lead compound for the development of novel antitumor and anti-inflammatory agents, because it embodies anti-proliferative and antiangiogenic activities in one molecule. However, the affinity of 2-MEO for the estrogen receptor would lead to undesirable side effects. As a prelude to the design of 2-MEO-like compounds with an optimal activity profile, we assayed 2-MEO and a series of analogs for their ability to cause G(1) cell-cycle arrest (by measuring inhibition of DNA synthesis in human cultured airway smooth muscle) and to inhibit binding of [H-3] estradiol at the estrogen receptor (ER; from rat uterine smooth muscle). One compound, a diacetoxy enediol derivative, was identified with reasonable potency for DNA synthesis (pIC(50) = 5.97) but showed negligible affinity for the ER (pIC(50) < 5). Three-dimensional quantitative structure-activity relationships were developed for these activities using comparative molecular field analysis (CoMFA) techniques. Comparison of optimized CoMFA models revealed distinct structural requirements for DNA synthesis inhibition and ER binding. For example, DNA synthesis inhibition is enhanced by electropositive substitutions in the 2-position below the plane of the steroid A-ring, whereas ER binding is favored by electronegative substitution in this position. Similarly, DNA synthesis inhibition correlates negatively with increased steric bulk in regions clustered around the A and B rings; changes in steric bulk in these regions has little correlation with ER binding. These observations will guide the design of new analogs with improved potency for desired characteristics (e. g., DNA synthesis inhibition) with minimal unwanted activities (e. g., ER binding).