• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

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.

DOI:10.1016/j.ejmech.2018.04.024
PMID:29677635
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5930004/
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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/f8038b239572/nihms961384f14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/5b3ca539d5a8/nihms961384f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/bb876343cbea/nihms961384f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/e74d1554d5c9/nihms961384f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/3e9ebb544743/nihms961384f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/6172928ed8de/nihms961384f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/79f75c788588/nihms961384f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/b609ada3a841/nihms961384f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/7748e6a94a7a/nihms961384f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/0d0b40fd178d/nihms961384f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/ca4e9454d177/nihms961384f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/ef2cf7014fa9/nihms961384f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/c306b8bf03f4/nihms961384f12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/c568adc255b1/nihms961384f13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/f8038b239572/nihms961384f14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/5b3ca539d5a8/nihms961384f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/bb876343cbea/nihms961384f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/e74d1554d5c9/nihms961384f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/3e9ebb544743/nihms961384f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/6172928ed8de/nihms961384f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/79f75c788588/nihms961384f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/b609ada3a841/nihms961384f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/7748e6a94a7a/nihms961384f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/0d0b40fd178d/nihms961384f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/ca4e9454d177/nihms961384f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/ef2cf7014fa9/nihms961384f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/c306b8bf03f4/nihms961384f12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/c568adc255b1/nihms961384f13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d64/5930004/f8038b239572/nihms961384f14.jpg

相似文献

1
Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2).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。
Eur J Med Chem. 2018 May 10;151:777-796. doi: 10.1016/j.ejmech.2018.04.024. Epub 2018 Apr 12.
2
Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft.通过靶向酪氨酰-DNA磷酸二酯酶2的酶DNA结合裂隙发现其选择性抑制剂。
Bioorg Med Chem Lett. 2016 Jul 15;26(14):3232-3236. doi: 10.1016/j.bmcl.2016.05.065. Epub 2016 May 24.
3
The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective Tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.呋喃并[2,3-d]嘧啶-4,6-二酮和异噁唑并[4,5-b]喹啉-6,8-二酮衍生物的合成及其作为选择性酪氨酰-DNA 磷酸二酯酶 2（TDP2）抑制剂的应用。
Bioorg Chem. 2021 Jun;111:104881. doi: 10.1016/j.bioorg.2021.104881. Epub 2021 Apr 1.
4
Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing.酪氨酰DNA磷酸二酯酶2活性的缺失增强了依托泊苷介导的双链断裂形成和细胞杀伤作用。
DNA Repair (Amst). 2016 Jul;43:38-47. doi: 10.1016/j.dnarep.2016.04.009. Epub 2016 May 7.
5
Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.新型去氮黄素酪氨酰-DNA 磷酸二酯酶 2（TDP2）抑制剂。
DNA Repair (Amst). 2020 Jan;85:102747. doi: 10.1016/j.dnarep.2019.102747. Epub 2019 Nov 6.
6
Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2).异喹啉-1,3-二酮作为酪氨酰DNA磷酸二酯酶II（TDP2）的选择性抑制剂。
J Med Chem. 2016 Mar 24;59(6):2734-46. doi: 10.1021/acs.jmedchem.5b01973. Epub 2016 Mar 7.
7
Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.针对人源酶且对细胞内TDP2具有活性的酪氨酰-DNA磷酸二酯酶2（TDP2）的脱氮黄素抑制剂
ACS Chem Biol. 2016 Jul 15;11(7):1925-33. doi: 10.1021/acschembio.5b01047. Epub 2016 May 11.
8
New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2).基于荧光的新型高通量筛选测定法，用于检测酪氨酰 DNA 磷酸二酯酶 2（TDP2）的小分子抑制剂。
Eur J Pharm Sci. 2018 Jun 15;118:67-79. doi: 10.1016/j.ejps.2018.03.021. Epub 2018 Mar 21.
9
TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1.在缺乏TDP1的情况下，TDP2促进拓扑异构酶I介导的DNA损伤修复。
Nucleic Acids Res. 2012 Sep 1;40(17):8371-80. doi: 10.1093/nar/gks622. Epub 2012 Jun 26.
10
New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2.新型去氧胆酸衍生酪氨酸-DNA 磷酸二酯酶 1 抑制剂也抑制酪氨酸-DNA 磷酸二酯酶 2。
Molecules. 2021 Dec 23;27(1):72. doi: 10.3390/molecules27010072.

引用本文的文献

1
Usnic Acid Derivatives Inhibit DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 and Act as Potential Anticancer Agents.松萝酸衍生物抑制 DNA 修复酶酪氨酰-DNA 磷酸二酯酶 1 和 2，并作为潜在的抗癌剂。
Genes (Basel). 2023 Oct 12;14(10):1931. doi: 10.3390/genes14101931.
2
Anticancer Properties of 3-Dietoxyphosphorylfuroquinoline-4,9-dione.3-二乙氧基磷酰基呋喃并[2,3-b]喹啉-4,9-二酮的抗癌特性。
Molecules. 2023 Mar 31;28(7):3128. doi: 10.3390/molecules28073128.
3
The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective Tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.

本文引用的文献

1
Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl-DNA Phosphodiesterase 2 (Tdp2).人类拓扑异构酶1、酪氨酰-DNA磷酸二酯酶1（Tdp1）和酪氨酰-DNA磷酸二酯酶2（Tdp2）的首个三联抑制剂的合成与生物学评价
J Med Chem. 2017 Apr 27;60(8):3275-3288. doi: 10.1021/acs.jmedchem.6b01565. Epub 2017 Apr 18.
2
Roles of eukaryotic topoisomerases in transcription, replication and genomic stability.真核生物拓扑异构酶在转录、复制和基因组稳定性中的作用。
Nat Rev Mol Cell Biol. 2016 Nov;17(11):703-721. doi: 10.1038/nrm.2016.111. Epub 2016 Sep 21.
3
呋喃并[2,3-d]嘧啶-4,6-二酮和异噁唑并[4,5-b]喹啉-6,8-二酮衍生物的合成及其作为选择性酪氨酰-DNA 磷酸二酯酶 2（TDP2）抑制剂的应用。
Bioorg Chem. 2021 Jun;111:104881. doi: 10.1016/j.bioorg.2021.104881. Epub 2021 Apr 1.
4
Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.新型去氮黄素酪氨酰-DNA 磷酸二酯酶 2（TDP2）抑制剂。
DNA Repair (Amst). 2020 Jan;85:102747. doi: 10.1016/j.dnarep.2019.102747. Epub 2019 Nov 6.
5
Molecular mechanisms of topoisomerase 2 DNA-protein crosslink resolution.拓扑异构酶 2 DNA-蛋白交联物的解析的分子机制。
Cell Mol Life Sci. 2020 Jan;77(1):81-91. doi: 10.1007/s00018-019-03367-z. Epub 2019 Nov 15.
6
Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide.新型去氮黄素类似物能有效抑制酪氨酰 DNA 磷酸二酯酶 2（TDP2），并能显著增强拓扑异构酶 II（TOP2）毒剂依托泊苷对癌细胞的敏感性。
J Med Chem. 2019 May 9;62(9):4669-4682. doi: 10.1021/acs.jmedchem.9b00274. Epub 2019 Apr 30.
Novel TDP2-ubiquitin interactions and their importance for the repair of topoisomerase II-mediated DNA damage.
新型TDP2-泛素相互作用及其对拓扑异构酶II介导的DNA损伤修复的重要性。
Nucleic Acids Res. 2016 Dec 1;44(21):10201-10215. doi: 10.1093/nar/gkw719. Epub 2016 Aug 19.
4
Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft.通过靶向酪氨酰-DNA磷酸二酯酶2的酶DNA结合裂隙发现其选择性抑制剂。
Bioorg Med Chem Lett. 2016 Jul 15;26(14):3232-3236. doi: 10.1016/j.bmcl.2016.05.065. Epub 2016 May 24.
5
Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing.酪氨酰DNA磷酸二酯酶2活性的缺失增强了依托泊苷介导的双链断裂形成和细胞杀伤作用。
DNA Repair (Amst). 2016 Jul;43:38-47. doi: 10.1016/j.dnarep.2016.04.009. Epub 2016 May 7.
6
Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.针对人源酶且对细胞内TDP2具有活性的酪氨酰-DNA磷酸二酯酶2（TDP2）的脱氮黄素抑制剂
ACS Chem Biol. 2016 Jul 15;11(7):1925-33. doi: 10.1021/acschembio.5b01047. Epub 2016 May 11.
7
Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2.酪氨酰DNA磷酸二酯酶2的DNA竞争性小分子抑制剂的作用模式
Biochem J. 2016 Jul 1;473(13):1869-79. doi: 10.1042/BCJ20160180. Epub 2016 Apr 20.
8
Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2.Tdp2对DNA损伤诱导的拓扑异构酶2 DNA-蛋白质交联的逆转作用
Nucleic Acids Res. 2016 May 5;44(8):3829-44. doi: 10.1093/nar/gkw228. Epub 2016 Apr 8.
9
Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2).异喹啉-1,3-二酮作为酪氨酰DNA磷酸二酯酶II（TDP2）的选择性抑制剂。
J Med Chem. 2016 Mar 24;59(6):2734-46. doi: 10.1021/acs.jmedchem.5b01973. Epub 2016 Mar 7.
10
Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections.肠道病毒感染期间对一种DNA修复酶的不同需求。
mBio. 2015 Dec 29;7(1):e01931-15. doi: 10.1128/mBio.01931-15.