10-phenyl-2H,3H,4H,10H-pyrimido[4,5-b]quinoline-2,4-dione | 84459-35-8

• 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-phenyl-2H,3H,4H,10H-pyrimido[4,5-b]quinoline-2,4-dione
• 英文别名: 10-phenylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione；10-phenylpyrimido[4,5-b]quinoline-2,4-dione
• CAS: 84459-35-8
• 化学式: C₁₇H₁₁N₃O₂
• 分子量: 289.293
• InChiKey: BBWFTVFLVHVBCD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  22
• 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：
  61.8
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  10-phenyl-2H,3H,4H,10H-pyrimido[4,5-b]quinoline-2,4-dione 、 碘甲烷 在 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 24.5h， 以33%的产率得到3-methyl-10-phenyl-5-deazaflavin
  参考文献：
  名称：

  5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2

  摘要：

  Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure-activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e. g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.038
• 作为产物：
  描述：

  2-氟苯甲醛 、 2,4-Dihydroxy-6-anilino-pyrimidin 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 以59%的产率得到10-phenyl-2H,3H,4H,10H-pyrimido[4,5-b]quinoline-2,4-dione
  参考文献：
  名称：

  5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2

  摘要：

  Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure-activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e. g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.038

文献信息

• A new, general, and convenient synthesis of 5-deazaflavins (5-deazaisoalloxazines)
  作者：Tomohisa Nagamatsu、Yuko Hashiguchi、Mastsugu Higuchi、Fumio Yoneda

  DOI：10.1039/c39820001085

  日期：——

  The condensation of 6-substituted-aminouracils with o-halogenobenzaldehydes in dimethylformamide led to the formation of the corresponding 5-deazaflavins in a single step.

  6-取代的氨基尿嘧啶与邻卤代苯甲醛在二甲基甲酰胺中的缩合导致一步形成相应的5-脱氮黄素。
• 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.
• Nagamatsu, Tomohisa; Hashiguchi, Yuko; Yoneda, Fumio, Journal of the Chemical Society. Perkin transactions I, 1984, # 3, p. 561 - 565
  作者：Nagamatsu, Tomohisa、Hashiguchi, Yuko、Yoneda, Fumio

  DOI：——

  日期：——
• NAGAMATSU, TOMOHISA;HASHIGUCHI, YUKO;YONEDA, FUMIO, J. CHEM. SOC. PERKIN TRANS., 1984, N 3, 561-565
  作者：NAGAMATSU, TOMOHISA、HASHIGUCHI, YUKO、YONEDA, FUMIO

  DOI：——

  日期：——
• 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2
  作者：Michael P. Dickens、Patricia Roxburgh、Andreas Hock、Mokdad Mezna、Barrie Kellam、Karen H. Vousden、Peter M. Fischer

  DOI：10.1016/j.bmc.2013.09.038

  日期：2013.11

  Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure-activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e. g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.