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首页> 外文期刊>ChemMedChem >Development of Selective Estrogen Receptor Modulator (SERM)-Like Activity Through an Indirect Mechanism of Estrogen Receptor Antagonism: Defining the Binding Mode of 7-Oxabicyclo[2.2.1]hept-5-ene Scaffold Core Ligands
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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-Oxabicyclo[2.2.1]hept-5-ene Scaffold Core Ligands

机译：通过选择性的雌激素受体拮抗作用的间接选择性雌激素受体调节剂（SERM）的活动的发展：定义7-氧杂双环[2.2.1]庚-5-烯骨架核心配体的结合模式。

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Previously, we discovered estrogen receptor (ER) ligands with a novel three-dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity act 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 ox-abicycloheptene sulfonates, varying the phenyl sulfonate group. As with the parent compound, 5,6-bis-(4-hydroxyphen-yl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester (OBHS), 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 analogues exhibit ERα binding affinities that are comparable to or, in the case of the ortho-chloro analogue, 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：以前，我们发现具有新型三维氧杂双环[2.2.1]庚烯核心骨架和良好的ER结合亲和力的雌激素受体（ER）配体通过间接调节关键开关螺旋的双环核心上的小烷基酯取代作用作为部分激动剂ER配体结合域中的螺旋12与螺旋11相互作用。这与他莫昔芬的作用机理相反，后者将螺旋12直接推出基因激活所需的构象。我们现在报道，在双环核心支架的这个位置，即苯磺酸根基团，可以耐受更大的取代，该基团定义了雌激素受体的新型结合表位。我们制备了14个ox-双环庚烯磺酸盐阵列，改变了苯基磺酸盐基团。与母体化合物5,6-双-（4-羟基苯基）-7-氧杂双环[2.2.1]庚-5-烯-2-磺酸苯基酯（OBHS）一样，这些化合物对ERα，苯基取代基的位置和大小是这些化合物结合亲和力和选择性的重要决定因素，其中具有邻位取代基的化合物对ERα的亲和力最高，对位取代基的亲和力最低。一些类似物表现出的ERα结合亲和力与邻氯类似物相当或比OBHS本身更高。在基于细胞的研究中，我们发现了几种活性与他莫昔芬相当的化合物，但它们完全起间接拮抗剂的作用，以变构方式干扰共激活蛋白向受体的募集。因此，OBHS结合表位代表一种通过间接拮抗机制发展雌激素受体拮抗剂的新方法。

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