5-bromo-2-((1-methyl-2-nitro-1H-imidazol-5-yl)methyl)isoquinolin-1(2H)-one | 245677-37-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 5-bromo-2-((1-methyl-2-nitro-1H-imidazol-5-yl)methyl)isoquinolin-1(2H)-one
• 英文别名: 5-Bromo-2-[(3-methyl-2-nitroimidazol-4-yl)methyl]isoquinolin-1-one
• CAS: 245677-37-6
• 化学式: C₁₄H₁₁BrN₄O₃
• 分子量: 363.17
• InChiKey: BXYIPHCVHMOLDZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  84
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-bromo-2-((1-methyl-2-nitro-1H-imidazol-5-yl)methyl)isoquinolin-1(2H)-one 在 tin(ll) chloride 作用下， 以 甲醇 为溶剂， 生成 、
  参考文献：
  名称：

  2-Nitroimidazol-5-ylmethyl as a potential bioreductively activated prodrug system: reductively triggered release of the parp inhibitor 5-bromoisoquinolinone

  摘要：

  5-Chloromethyl-1-methyl-2-nitroimidazole reacted efficiently with the anion derived from 5-bromo-isoquinolin-1-one to give 5-bromo-2-((1-methyl-2-nitroimidazol-5-yl)methyl)isoquinolin-1-one. Biomimetic reduction effected release of the 5-bromoisoquinolin-1-one. The 2-nitroimidazol-5-ylmethyl unit thus has potential for development as a general prodrug system for selective drug delivery to hypoxic tissues. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00306-6
• 作为产物：
  描述：

  (3-甲基-2-硝基-3H-咪唑-4-基)-甲醇 在 甲基磺酰氯 、 N,N-二异丙基乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 5-bromo-2-((1-methyl-2-nitro-1H-imidazol-5-yl)methyl)isoquinolin-1(2H)-one
  参考文献：
  名称：

  Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors

  摘要：

  聚(ADP-核糖)聚合酶(PARP)抑制剂(PARPi)最近被批准用于治疗同源重组修复(HRR)缺陷的乳腺癌和卵巢肿瘤。尽管已证明PARPi也能使HRR功能正常的肿瘤对细胞毒性化疗或放疗敏感，但正常细胞毒性一直是其在该领域应用的障碍。缺氧激活的前药(HAPs)提供了一种限制正常细胞接触活性药物的方法，从而增加了肿瘤选择性的一层。我们研究了模型PARPi的潜在HAPs，在其中我们将一个生物可还原的“触发器”连接到酰胺氮上，从而阻断了关键的结合相互作用。一个代表性的例子在生物化学测定中显示出抑制PARPi酶活性的前景，其中苄基酞嗪酮4的效力大约是相应的模型HAP 5的160倍，但这些N-烷基化化合物在通过放射分解进行单电子还原后并未释放PARPi。因此，我们将研究范围扩展到包含NU1025，一种含有远离核心结合基序的酚的PARPi。由此产生的2-硝基咪唑基醚适度抑制了PARPi活性，其效力降低了大约七倍，但在还原后有效地释放了PARPi。这项对PARPi潜在前药方法的调查确定了一种有用的前药策略，供未来探索。

  DOI：

  10.3390/molecules24081559

文献信息

• Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors
  作者：Benjamin D. Dickson、Way Wua Wong、William R. Wilson、Michael P. Hay

  DOI：10.3390/molecules24081559

  日期：——

  Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.

  聚(ADP-核糖)聚合酶(PARP)抑制剂(PARPi)最近被批准用于治疗同源重组修复(HRR)缺陷的乳腺癌和卵巢肿瘤。尽管已证明PARPi也能使HRR功能正常的肿瘤对细胞毒性化疗或放疗敏感，但正常细胞毒性一直是其在该领域应用的障碍。缺氧激活的前药(HAPs)提供了一种限制正常细胞接触活性药物的方法，从而增加了肿瘤选择性的一层。我们研究了模型PARPi的潜在HAPs，在其中我们将一个生物可还原的“触发器”连接到酰胺氮上，从而阻断了关键的结合相互作用。一个代表性的例子在生物化学测定中显示出抑制PARPi酶活性的前景，其中苄基酞嗪酮4的效力大约是相应的模型HAP 5的160倍，但这些N-烷基化化合物在通过放射分解进行单电子还原后并未释放PARPi。因此，我们将研究范围扩展到包含NU1025，一种含有远离核心结合基序的酚的PARPi。由此产生的2-硝基咪唑基醚适度抑制了PARPi活性，其效力降低了大约七倍，但在还原后有效地释放了PARPi。这项对PARPi潜在前药方法的调查确定了一种有用的前药策略，供未来探索。
• 2-Nitroimidazol-5-ylmethyl as a potential bioreductively activated prodrug system: reductively triggered release of the parp inhibitor 5-bromoisoquinolinone
  作者：Ifat Parveen、Declan P Naughton、William J.D Whish、Michael D Threadgill

  DOI：10.1016/s0960-894x(99)00306-6

  日期：1999.7

  5-Chloromethyl-1-methyl-2-nitroimidazole reacted efficiently with the anion derived from 5-bromo-isoquinolin-1-one to give 5-bromo-2-((1-methyl-2-nitroimidazol-5-yl)methyl)isoquinolin-1-one. Biomimetic reduction effected release of the 5-bromoisoquinolin-1-one. The 2-nitroimidazol-5-ylmethyl unit thus has potential for development as a general prodrug system for selective drug delivery to hypoxic tissues. (C) 1999 Elsevier Science Ltd. All rights reserved.