tert-butyl 4-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-1,4-diazepane-1-carboxylate | 763111-56-4

• 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 4-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-1,4-diazepane-1-carboxylate
• CAS: 763111-56-4
• 化学式: C₂₆H₃₀N₄O₄
• 分子量: 462.549
• InChiKey: QNZKRMBDAXAJRZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  91.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-1,4-diazepane-1-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以83%的产率得到4-(3-(1,4-diazepane-1-carbonyl)benzyl)phthalazin-1(2H)-one
  参考文献：
  名称：

  4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1

  摘要：

  Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.

  DOI：

  10.1021/jm8001263
• 作为产物：
  描述：

  3-氰基苯甲醛 在 sodium methylate 、 一水合肼 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基乙酰胺 为溶剂， 生成 tert-butyl 4-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-1,4-diazepane-1-carboxylate
  参考文献：
  名称：

  Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase

  摘要：

  We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.10.081

文献信息

• 10.1016/j.bioorg.2024.107556
  作者：Wu, Jie、Wang, Xiaoqian、Yao, Yaning、Du, Nan、Duan, Liancheng、Gong, Ping

  DOI：10.1016/j.bioorg.2024.107556

  日期：——

  widespread attention. In this study, we designed and synthesized two novel phthalazinone PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors, named – containing dithiocarboxylate fragments and – containing hydroxamic acid fragments, and evaluated their inhibitory activities on enzymes and cells. Among the PARP-1 inhibitors, most compounds exhibited high inhibitory activity against the PARP-1 enzyme, with –

  近年来，聚ADP核糖聚合酶1（PARP-1）和组蛋白脱乙酰酶（HDAC）已成为肿瘤治疗的重要靶点，受到广泛关注。在本研究中，我们设计并合成了两种新型二氮杂萘酮PARP-1抑制剂和双PARP-1/HDAC-1抑制剂，分别命名为“含有二硫代羧酸酯片段”和“含有异羟肟酸片段”，并评估了它们对酶和细胞的抑制活性。在 PARP-1 抑制剂中，大多数化合物对 PARP-1 酶表现出高抑制活性，特别值得注意的是，IC 值为 <0.2 nM。值得注意的是，表现出显着的抗增殖活性，抑制 MDA-MB-436、MDA-MB-231 和 MCF-7 细胞增殖的 IC 值分别达到 0.08、26.39 和 1.01 μM。进一步的研究表明，MDA-MB-231 细胞停滞在 G1 期，并以剂量​​依赖性方式诱导细胞凋亡。在设计的 PARP-1/HDAC-1 双抑制剂中，几种化合物表现出有效的双靶点抑制活性，对 PARP-1
• 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2<i>H</i>-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1
  作者：Keith A. Menear、Claire Adcock、Robert Boulter、Xiao-ling Cockcroft、Louise Copsey、Aaron Cranston、Krystyna J. Dillon、Jan Drzewiecki、Sheila Garman、Sylvie Gomez、Hashim Javaid、Frank Kerrigan、Charlotte Knights、Alan Lau、Vincent M. Loh、Ian T. W. Matthews、Stephen Moore、Mark J. O’Connor、Graeme C. M. Smith、Niall M. B. Martin

  DOI：10.1021/jm8001263

  日期：2008.10.23

  Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
• Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase
  作者：Xiao-ling Cockcroft、Krystyna J. Dillon、Lesley Dixon、Jan Drzewiecki、Frank Kerrigan、Vincent M. Loh、Niall M.B. Martin、Keith A. Menear、Graeme C.M. Smith

  DOI：10.1016/j.bmcl.2005.10.081

  日期：2006.2

  We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models. (c) 2005 Elsevier Ltd. All rights reserved.