4-(3,4-difluoro-5-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)phthalazin-1-(2H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(3,4-difluoro-5-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)phthalazin-1-(2H)-one
• 英文别名: 4-[[3,4-difluoro-5-[4-(1,3-thiazol-2-yl)piperazine-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
• 化学式: C₂₃H₁₉F₂N₅O₂S
• 分子量: 467.499
• InChiKey: BPCIWLGINCOGSS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3,4-二氟甲苯 在 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 、 copper(l) cyanide 、 1-羟基苯并三唑 、 silver nitrate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 四氯化碳 、 甲基叔丁基醚 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 92.5h， 生成 4-(3,4-difluoro-5-(4-(thiazol-2-yl)piperazine-1-carbonyl)benzyl)phthalazin-1-(2H)-one
  参考文献：
  名称：

  Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy

  摘要：

  Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARPI inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 13 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARPI-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.06.053

文献信息

• Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy
  作者：Wenhua Chen、Ne Guo、Minghui Qi、Haiying Dai、Minghuang Hong、Longfei Guan、Xiajuan Huan、Shanshan Song、Jinxue He、Yingqing Wang、Yong Xi、Xinying Yang、Yanyan Shen、Yi Su、Yiming Sun、Yinglei Gao、Yi Chen、Jian Ding、Yun Tang、Guobin Ren、Zehong Miao、Jian Li

  DOI：10.1016/j.ejmech.2017.06.053

  日期：2017.9

  Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARPI inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 13 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARPI-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors. (C) 2017 Elsevier Masson SAS. All rights reserved.