4-((4-(2-hydrazinyl-2-oxoethyl)piperazin-1-yl)methyl)benzenesulfonamide | 1239204-50-2

• 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-((4-(2-hydrazinyl-2-oxoethyl)piperazin-1-yl)methyl)benzenesulfonamide
• 英文别名: 4-[[4-(2-hydrazinyl-2-oxoethyl)piperazin-1-yl]methyl]benzenesulfonamide
• CAS: 1239204-50-2
• 化学式: C₁₃H₂₁N₅O₃S
• 分子量: 327.407
• InChiKey: DVQDKEXWUUWGJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-((4-(2-hydrazinyl-2-oxoethyl)piperazin-1-yl)methyl)benzenesulfonamide 、 2-羟基-5-(三氟甲氧基)苯甲醛 在 盐酸 作用下， 以 乙二醇乙醚 、 水 为溶剂， 生成
  参考文献：
  名称：

  Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)

  摘要：

  Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3.

  DOI：

  10.1021/co2001372
• 作为产物：
  描述：

  ethyl 2-(4-(4-sulfamoylbenzyl)piperazin-1-yl)acetate 在 肼 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 16.0h， 以91%的产率得到4-((4-(2-hydrazinyl-2-oxoethyl)piperazin-1-yl)methyl)benzenesulfonamide
  参考文献：
  名称：

  [EN] DESIGN, SYNTHESIS AND EVALUATION OF PROCASPASE ACTIVATING COMPOUNDS AS PERSONALIZED ANTI-CANCER DRUGS
  [FR] CONCEPTION, SYNTHÈSE ET ÉVALUATION DE COMPOSÉS ACTIVATEURS DE PROCASPASE EN TANT QUE MÉDICAMENTS ANTICANCÉREUX PERSONNALISÉS

  摘要：

  本发明公开了涉及诱导细胞死亡（例如癌细胞）的组合物和方法。公开了用于合成和使用这些化合物的相关方法，包括在癌症治疗中使用化合物以及在细胞中选择性诱导凋亡。公开了具有比其他化合物更低神经毒性效应的化合物。

  公开号：

  WO2010091382A1

文献信息

• [EN] ENZYME-ACTIVATING COMPOUNDS AND COMPOSITIONS<br/>[FR] COMPOSÉS ET COMPOSITIONS ACTIVANT DES ENZYMES
  申请人：HERGENROTHER PAUL J

  公开号：WO2014022858A1

  公开（公告）日：2014-02-06

  The invention provides compounds and compositions useful for the modulation of certain enzymes. The compounds and compositions can induce of cell death, particularly cancer cell death. The invention also provides methods for the synthesis and use of the compounds and compositions, including the use of compounds and compositions in therapy for the treatment of cancer and selective induction of apoptosis in cells.

  这项发明提供了用于调节某些酶的化合物和组合物。这些化合物和组合物可以诱导细胞死亡，特别是癌细胞死亡。该发明还提供了合成和使用这些化合物和组合物的方法，包括在治疗癌症和选择性诱导细胞凋亡中使用这些化合物和组合物的方法。
• DESIGN, SYNTHESIS AND EVALUATION OF PROCASPASE ACTIVATING COMPOUNDS AS PERSONALIZED ANTI-CANCER DRUGS
  申请人：Hergenrother Paul J.

  公开号：US20120040995A1

  公开（公告）日：2012-02-16

  Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed that have lower neurotoxicity effects than other compounds.

  本实施例揭示了与诱导细胞死亡有关的组合物和方法，例如在癌细胞中。揭示了合成和使用相关化合物的方法，包括在治疗癌症和选择性诱导细胞凋亡方面使用化合物的方法。揭示了具有比其他化合物更低神经毒性影响的化合物。
• Design, synthesis and evaluation of procaspase activating compounds as personalized anti-cancer drugs
  申请人：Hergenrother Paul Joseph

  公开号：US08778945B2

  公开（公告）日：2014-07-15

  Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed that have lower neurotoxicity effects than other compounds.

  本实施例揭示了与诱导细胞死亡（如癌细胞）相关的组合物和方法。揭示了合成和使用相关化合物的方法，包括在治疗癌症和选择性诱导细胞凋亡方面使用化合物的方法。揭示了具有比其他化合物更低神经毒性影响的化合物。
• PROCASPASE ACTIVATING COMPOUNDS
  申请人：The Board of Trustees of the University of Illinois

  公开号：US20150344452A1

  公开（公告）日：2015-12-03

  Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed that have lower neurotoxicity effects than other compounds.

  本实施例揭示了与细胞死亡诱导有关的组合物和方法，例如在癌细胞中。揭示了合成和使用相关化合物的方法，包括在治疗癌症和选择性诱导细胞凋亡方面使用化合物的方法。揭示了具有较低神经毒性效应的化合物。
• Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics
  作者：Howard S. Roth、Rachel C. Botham、Steven C. Schmid、Timothy M. Fan、Levent Dirikolu、Paul J. Hergenrother

  DOI：10.1021/acs.jmedchem.5b00413

  日期：2015.5.14

  Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.