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Development of Selective Estrogen Receptor Modulator (SERM)-Like Activity Through an Indirect Mechanism of Estrogen Receptor Antagonism: Defining the Binding Mode of 7-Oxabicyclo2.2.1hept-5-ene Scaffold Core Ligands

机译：通过雌激素受体拮抗作用间接机制的选择性雌激素受体调节剂（SERM） - 样活性的研制：定义7-氧基酰肼的结合模式2.2.1 Hept-5-Ene支架核心配体

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Earlier, we found estrogen receptor (ER) ligands having a novel three-dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity acted as partial agonists via small alkyl ester substitutions on the bicyclic core that indirectly modulate the critical switch helix in the ER ligand-binding domain, helix 12, by interactions with helix 11. This contrasts with the mechanism of action of tamoxifen, which directly pushes helix 12 out of the conformation required for gene activation. We now report that a much larger substitution can be tolerated at this position of the bicyclic core scaffold, namely a phenyl sulfonate group, which defines a novel binding epitope for the estrogen receptor. We prepared an array of 14 of these oxabicycloheptene sulfonates (OBHS), varying the phenyl sulfonate group. As with OBHS itself, these compounds showed preferential affinity for ERα, and the disposition and size of the phenyl substituents were important determinants of the binding affinity and selectivity of these compounds, with those having ortho substituents giving the highest, and para substituents the lowest affinities for ERα. A few analogs have ERα binding affinity that is comparable to or, in the case of the ortho chloro analog, higher than that of OBHS itself. In cell-based studies, we found several compounds with activity profiles comparable to tamoxifen, but acting entirely as indirect antagonists, allosterically interfering with recruitment of coactivator proteins to the receptor. Thus, the OBHS binding epitope represents a novel approach to the development of estrogen receptor antagonists via an indirect mechanism of antagonism.
机译：早些时候，我们发现雌激素受体（ER）配体具有新的三维恶双环[2.2.1]庚烯核心支架和良好的ER结合亲和力通过在间接调节关键开关螺旋的双环核上的小烷基酯取代作用为部分激动剂。通过与螺旋11的相互作用的ER配体结合结构域。这与Tamoxifen的作用机制相反，其直接将螺旋12推出基因活化所需的构象。我们现在报道，在双环芯支架的这种位置可以容忍更大的取代，即苯基磺酸盐基团，其定义了雌激素受体的新型结合表位。我们制备了其中14个这些氧化丙酸丁酸丁烯磺酸盐（OBHS）的阵列，改变苯基磺酸盐基团。与OBHS本身一样，这些化合物对ERα表示优先亲和力，并且苯基取代基的配置和尺寸是这些化合物的结合亲和力和选择性的重要决定因素，其中具有邻离取代基的邻级取代基和对取代基的最低亲和力对于ERα。少数类似物具有ERα结合亲和力，其与ORTHO氯类似物的情况相当，高于OBHS本身的情况。在基于细胞的研究中，我们发现几种具有与Tamoxifen相当的活性型材的化合物，但完全作为间接拮抗剂，并与受体的共同递蛋白的募集进行了模拟性干扰。因此，OBHS结合表位代表了通过拮抗拮抗机制的间接机制发展雌激素受体拮抗剂的新方法。

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