tert-butyl 1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-1,7-diazaspiro[3.5]nonane-7-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: tert-butyl 1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-1,7-diazaspiro[3.5]nonane-7-carboxylate
• 英文别名: tert-butyl 2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate；tert-butyl 2-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate
• 化学式: C₂₈H₃₁FN₄O₄
• 分子量: 506.577
• InChiKey: HTEJAQHUIZOZBK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  91.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-1,7-diazaspiro[3.5]nonane-7-carboxylate 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 15.0h， 生成 4-(3-(7-(cyclopropanecarbonyl)-1,7-diazaspiro[3.5]nonane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
  参考文献：
  名称：

  Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

  摘要：

  Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 +/- 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 +/- 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.

  DOI：

  10.1021/acs.jmedchem.8b00576
• 作为产物：
  描述：

  5-[(3,4-二氢-4-氧代-1-酞嗪基)甲基]-2-氟苯甲酸 、 2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以81%的产率得到tert-butyl 1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-1,7-diazaspiro[3.5]nonane-7-carboxylate
  参考文献：
  名称：

  Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

  摘要：

  Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 +/- 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 +/- 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.

  DOI：

  10.1021/acs.jmedchem.8b00576

文献信息

• LOW AFFINITY POLY(AD-RIBOSE) POLYMERASE 1 DEPENDENT CYTOTOXIC AGENTS
  申请人：THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

  公开号：US20200407374A1

  公开（公告）日：2020-12-31

  The present disclosure provides compounds of Formula (I) or (II), pharmaceutically acceptable salt, isotopic variant, stereoisomer, or a mixture thereof. Also provided are pharmaceutical compositions comprising a compound, methods of treating a poly(ADP-ribose)polymerase-1-mediated disease or disorder in a subject, methods of detecting a poly(ADP-ribose)polymerase-1-mediated neurodegenerative disease or disorder, or methods of monitoring cancer treatment in a subject. In some embodiments, the poly(ADP-ribose)polymerase-1-mediated disease or disorder is a neurodegenerative disease or cancer.
• Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity
  作者：Sean W. Reilly、Laura N. Puentes、Khadija Wilson、Chia-Ju Hsieh、Chi-Chang Weng、Mehran Makvandi、Robert H. Mach

  DOI：10.1021/acs.jmedchem.8b00576

  日期：2018.6.28

  Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 +/- 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 +/- 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.