Development of benzophenone-alkyne bifunctional sigma receptor ligands.
Development of benzophenone-alkyne bifunctional sigma receptor ligands.
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二苯甲酮-炔双功能西格玛受体配体的开发。
DOI：
10.1002/cbic.201200427
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Ruoho,ArnoldE
中科院分区：
文献类型：
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作者：
Guo,Lian-Wang;Hajipour,AbdolR;Karaoglu,Kerim;Mavlyutov,TimurA;Ruoho,ArnoldE
西格玛 (σ) 受体是独特的非阿片类药物结合位点，与多种疾病状态相关。 Sigma-2 受体为诊断成像和药物干预提供了一个有希望的靶标，以抑制肿瘤进展。最近，黄体酮受体（PGRMC1，25 kDa）已被证明具有类似 σ2 受体的结合特性，因此强调需要了解具有类似 σ2 光亲和标记（此处表示为 σ2-18k）但其氨基酸序列未知的 18 kDa 蛋白质的生物学功能。为了为σ2-18k蛋白的研究提供新的工具，我们开发了双功能σ受体配体，每个配体都带有二苯甲酮光交联部分和炔基，光交联后可以通过点击化学将含叠氮化物的生物素亲和标签共价连接到炔基上。尽管几种化合物表现出良好的 σ2 结合特性，但化合物 22 表现出最高的亲和力 (2 nM) 和阻断放射性光亲和配体对 σ2-18k 光标记的最大效力。因此，这些二苯甲酮-炔 σ 受体配体可能适合通过化学生物学方法研究 σ2-18k 蛋白。据我们所知，这些化合物代表了第一个报道的含二苯甲酮的可点击σ受体配体，基于各种标签的“插入”，它们可能具有广泛的应用。
Sigma (σ) receptors are unique non‐opioid binding sites that are associated with a broad range of disease states. Sigma‐2 receptors provide a promising target for diagnostic imaging and pharmacological interventions to curb tumor progression. Most recently, the progesterone receptor (PGRMC1, 25 kDa) has been shown to have σ2 receptor‐like binding properties, thus highlighting the need to understand the biological function of an 18 kDa protein that exhibits σ2‐like photoaffinity labeling (denoted here as σ2‐18k) but the amino acid sequence of which is not known. In order to provide new tools for the study of the σ2‐18k protein, we have developed bifunctional σ receptor ligands each bearing a benzophenone photo‐crosslinking moiety and an alkyne group to which an azide‐containing biotin affinity tag can be covalently attached through click chemistry after photo‐crosslinking. Although several compounds showed favorable σ2 binding properties, the highest affinity (2 nM) and the greatest potency in blocking photolabeling of σ2‐18k by a radioactive photoaffinity ligand was shown by compound22. These benzophenone‐alkyne σ receptor ligands might therefore be amenable for studying the σ2‐18k protein through chemical biology approaches. To the best of our knowledge, these compounds represent the first reported benzophenone‐containing clickable σ receptor ligands, which might potentially have broad applications based on the “plugging in” of various tags.