呋喃并喹啉二酮类化合物的合成及其作为酪氨酰 DNA 磷酸二酯酶 2（TDP2）抑制剂的构效关系。
Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2).
机构信息
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States.
出版信息
Eur J Med Chem. 2018 May 10;151:777-796. doi: 10.1016/j.ejmech.2018.04.024. Epub 2018 Apr 12.
Abstract
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered enzyme specifically repairing topoisomerase II (TOP2)-mediated DNA damage. It has been shown that inhibition of TDP2 synergize with TOP2 inhibitors. Herein, we report the discovery of the furoquinolinedione chemotype as a suitable skeleton for the development of selective TDP2 inhibitors. Compound 1 was identified as a TDP2 inhibitor as a result of screening our in-house compound library for compounds selective for TDP2 vs. TDP1. Further SAR studies provide several selective TDP2 inhibitors at low-micromolar range. The most potent compound 74 shows inhibitory activity with IC of 1.9 and 2.1 μM against recombinant TDP2 and TDP2 in whole cell extracts (WCE), respectively.
摘要
酪氨酰 DNA 磷酸二酯酶 2（TDP2）是一种最近发现的酶，专门修复拓扑异构酶 II（TOP2）介导的 DNA 损伤。已经表明，抑制 TDP2 与 TOP2 抑制剂协同作用。在此，我们报告了呋喃喹啉二酮化学型作为开发选择性 TDP2 抑制剂的合适骨架。由于筛选我们的内部化合物库以寻找对 TDP2 与 TDP1 具有选择性的化合物，化合物 1 被鉴定为 TDP2 抑制剂。进一步的 SAR 研究提供了几种在低微摩尔范围内具有选择性的 TDP2 抑制剂。最有效的化合物 74 对重组 TDP2 和 WCE 中的 TDP2 的抑制活性分别为 1.9 和 2.1 μM。
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