Relationship among structure, cytotoxicity, and Michael acceptor reactivity of quinocidin
Relationship among structure, cytotoxicity, and Michael acceptor reactivity of quinocidin
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奎尼西丁的结构、细胞毒性和迈克尔受体反应性之间的关系
DOI：
10.1016/j.bmc.2020.115308
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
M.
中科院分区：
文献类型：
--
作者：
Nakagawa;Y.; Sawaki;Y.; Miyanishi;W.; Shimomura;S.; Shibata;T.; Ojika;M.
奎诺杀菌素（Quinocidin，QCD）是一种具有3，4-二氢喹嗪骨架的细胞毒性抗生素。我们以前发现QCD在中性水介质中通过Michael加成反应捕获硫醇。然而，目前还不清楚QCD的迈克尔受体反应性是否是其细胞毒性的原因。在这项研究中，我们合成了13个类似物的QCD，以研究其结构，细胞毒性和对硫醇的反应性之间的关系。巯基捕获实验和细胞毒性试验共同表明，迈克尔受体功能的QCD是独立的其细胞毒性活性，并与疏水性侧链的吡啶部分是一个关键的结构因素的细胞毒性。这些发现进一步使我们证明，将酰胺基团并入QCD的侧链中显着降低其毒性，但几乎不影响迈克尔受体功能。本研究奠定了基于QCD的药物设计的基础，并强调了QCD作为一种独特的亲电试剂用于开发共价抑制剂和蛋白质标记探针的潜力。
Quinocidin (QCD) is a cytotoxic antibiotic with an unusual 3,4-dihydroquinolizinium skeleton. We previously found that QCD captures thiols in neutral aqueous mediaviaa Michael addition-type reaction. However, it remains unclear whether the Michael acceptor reactivity of QCD is responsible for its cytotoxicity. In this study, we synthesized thirteen analogs of QCD to examine the relationship among its structure, cytotoxicity, and reactivity toward thiols. Thiol-trapping experiments and cytotoxicity tests collectively suggested that the Michael acceptor function of QCD is independent of its cytotoxic activity, and that the pyridinium moiety with the hydrophobic side chain is a key structural factor for cytotoxicity. These findings further led us to demonstrate that incorporation of an amide group into the side chain of QCD significantly reduced its toxicity but hardly affected the Michael acceptor function. The present study lays the foundation for QCD-based drug design and highlights the potential of QCD as a unique electrophile for use in the development of covalent inhibitors and protein-labeling probes.