Elemental isomerism: A boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands
Elemental isomerism: A boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands
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DOI：
10.1016/j.chembiol.2007.04.009
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发表时间：
2007-06-01
影响因子：
--
通讯作者：
Katzenellenbogen, John A.
中科院分区：
文献类型：
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作者：
Zhou, Hai-Bing;Nettles, Kendall W.;Katzenellenbogen, John A.
为了通过掺入不寻常元素来增加生物活性分子的化学多样性，我们研究了在非甾体雌激素受体 (ER) 配体中用等电子、同结构 B-N 键替换 C=C 双键。虽然 B-N 键在无阻碍的环芬尼系统中水解不稳定，但受阻较多的苯胺基二甲硼烷（三芳基乙烯雌激素的类似物）很容易制备，具有水解稳定性，并且对 ER 具有显着的亲和力。对一种 ER α-配体复合物的 X 射线分析揭示了与扭曲受体的对甲基的空间冲突；去除这些基团导致亲和力、效力和转录功效的增加。这些研究定义了非甾体雌激素中 B-N 取代 C=C 的稳定性和细胞生物活性的结构决定因素，并为进一步探索药物样分子多样化的“基本异构现象”提供了框架。
To increase the chemical diversity of bioactive molecules by incorporating unusual elements, we have examined the replacement of a C=C double bond with the isoelectronic, isostructural B-N bond in the context of nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was hydrolytically labile in the unhindered cyclofenil system, the more hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial affinity for ERs. X-ray analysis of one ER alpha-ligand complex revealed steric clashes with the para methyl groups distorting the receptor; removal of these groups resulted in an increase in affinity, potency, and transcriptional efficacy. These studies define the structural determinants of stability and cellular bioactivity of a B-N for C=C substitution in nonsteroidal estrogens and provide a framework for further exploration of "elemental isomerism" for diversification of drug-like molecules.