3-methyl-5-nitroisoquinolin-1-one | 1280188-30-8

• 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: 3-methyl-5-nitroisoquinolin-1-one
• 英文别名: 3-methyl-5-nitroisoquinolin-1(2H)-one；3-methyl-5-nitro-2H-isoquinolin-1-one
• CAS: 1280188-30-8
• 化学式: C₁₀H₈N₂O₃
• 分子量: 204.185
• InChiKey: XLNZGYXOGLXRIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  74.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-methyl-5-nitroisoquinolin-1-one 在 氯化亚锡 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以59%的产率得到5-amino-3-methylisoquinolin-1-one
  参考文献：
  名称：

  One-pot tandem Hurtley–retro-Claisen–cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs

  摘要：

  Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of beta-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/ v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50 = 0.23 mu M vs IC50 = 1.6 mu M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.031
• 作为产物：
  描述：

  2-溴-3-硝基苯甲酸 在 potassium tert-butylate 、 氨 、 铜 作用下， 以 乙二醇甲醚 、 叔丁醇 为溶剂， 反应 20.0h， 生成 3-methyl-5-nitroisoquinolin-1-one
  参考文献：
  名称：

  One-pot tandem Hurtley–retro-Claisen–cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs

  摘要：

  Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of beta-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/ v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50 = 0.23 mu M vs IC50 = 1.6 mu M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.031

文献信息

• 5-Benzamidoisoquinolin-1-ones and 5-(ω-Carboxyalkyl)isoquinolin-1-ones as Isoform-Selective Inhibitors of Poly(ADP-ribose) Polymerase 2 (PARP-2)
  作者：Peter T. Sunderland、Esther C. Y. Woon、Archana Dhami、Aoife B. Bergin、Mary F. Mahon、Pauline J. Wood、Louise A. Jones、Sophie R. Tully、Matthew D. Lloyd、Andrew S. Thompson、Hashim Javaid、Niall M. B. Martin、Michael D. Threadgill

  DOI：10.1021/jm1010918

  日期：2011.4.14

  PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolind-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH = CHCO(2)H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using Flash Plate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(omega-carboxyalkl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC(50(PARP-1))/IC(50(PARP-2)) = 9.3) to date, in a comparative study.
• One-pot tandem Hurtley–retro-Claisen–cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs
  作者：Esther C.Y. Woon、Peter T. Sunderland、Helen A. Paine、Matthew D. Lloyd、Andrew S. Thompson、Michael D. Threadgill

  DOI：10.1016/j.bmc.2013.06.031

  日期：2013.9

  Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of beta-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/ v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50 = 0.23 mu M vs IC50 = 1.6 mu M for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling. (C) 2013 Elsevier Ltd. All rights reserved.