10-(3-hydroxyphenyl)-2,4-dioxo-2,3,4,10-tetrahydropyrimido[4,5-b]-quinoline-8-carbonitrile | 1448807-71-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 10-(3-hydroxyphenyl)-2,4-dioxo-2,3,4,10-tetrahydropyrimido[4,5-b]-quinoline-8-carbonitrile
• 英文别名: 10-(3-Hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile；10-(3-hydroxyphenyl)-2,4-dioxopyrimido[4,5-b]quinoline-8-carbonitrile
• CAS: 1448807-71-3
• 化学式: C₁₈H₁₀N₄O₃
• 分子量: 330.302
• InChiKey: ZGRZTJZRHOLFOO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  10-(3-hydroxyphenyl)-2,4-dioxo-2,3,4,10-tetrahydropyrimido[4,5-b]-quinoline-8-carbonitrile 、 3,4-二氯苯硼酸 在 copper diacetate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以48%的产率得到3-(3,4-dichlorophenyl)-10-(3-hydroxyphenyl)-2,4-dioxo-2,3,4,10-tetrahydropyrimido[4,5-b]quinoline-8-carbonitrile
  参考文献：
  名称：

  Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide

  摘要：

  Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.

  DOI：

  10.1021/acs.jmedchem.9b00274
• 作为产物：
  描述：

  3-氨基苯酚 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 10-(3-hydroxyphenyl)-2,4-dioxo-2,3,4,10-tetrahydropyrimido[4,5-b]-quinoline-8-carbonitrile
  参考文献：
  名称：

  Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide

  摘要：

  Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.

  DOI：

  10.1021/acs.jmedchem.9b00274

文献信息

• COMPOUNDS FOR CANCER CHEMOTHERAPEUTIC SENSITIZATION
  申请人：Regents of the University of Minnesota

  公开号：US20190240244A1

  公开（公告）日：2019-08-08

  The invention provides a compound of formula (I), (II) or (III): wherein R 1 , R 2 , R 3 , R 4 and R 5 have any of the values described in the specification, as well as compositions comprising a compound of formula (I), (II) or (III). The compounds and compositions are useful as chemotherapeutic sensitizing agents.

  本发明提供了一种公式(I)、(II)或(III)的化合物： 其中R1、R2、R3、R4和R5具有说明书中描述的任何值，以及包含公式(I)、(II)或(III)的化合物的组合物。这些化合物和组合物作为化学治疗增敏剂是有用的。
• Compounds for cancer chemotherapeutic sensitization
  申请人：Regents of the University of Minnesota

  公开号：US10617706B2

  公开（公告）日：2020-04-14

  The invention provides a compound of formula (I), (II) or (III): wherein R1, R2, R3, R4 and R5 have any of the values described in the specification, as well as compositions comprising a compound of formula (I), (II) or (III). The compounds and compositions are useful as chemotherapeutic sensitizing agents.

  本发明提供了一种式 (I)、(II) 或 (III) 的化合物： 其中 R1、R2、R3、R4 和 R5 具有说明书中描述的任一数值，以及包含式 (I)、(II) 或 (III) 化合物的组合物。这些化合物和组合物可用作化疗增敏剂。
• Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II
  作者：Ali Raoof、Paul Depledge、Niall M. Hamilton、Nicola S. Hamilton、James R. Hitchin、Gemma V. Hopkins、Allan M. Jordan、Laura A. Maguire、Alison E. McGonagle、Daniel P. Mould、Mathew Rushbrooke、Helen F. Small、Kate M. Smith、Graeme J. Thomson、Fabrice Turlais、Ian D. Waddell、Bohdan Waszkowycz、Amanda J. Watson、Donald J. Ogilvie

  DOI：10.1021/jm400568p

  日期：2013.8.22

  The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAP.) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
• Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide
  作者：Jayakanth Kankanala、Carlos J. A. Ribeiro、Evgeny Kiselev、Azhar Ravji、Jessica Williams、Jiashu Xie、Hideki Aihara、Yves Pommier、Zhengqiang Wang

  DOI：10.1021/acs.jmedchem.9b00274

  日期：2019.5.9

  Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.