4-(苯基甲基)-1-哌嗪乙酸 2-[[2-羟基-3-(2-烯丙-1-基)苯基]亚甲基]酰肼 | 315183-21-2

• 物质功能分类: 生物化工 - 抑制剂 - 细胞凋亡(Apoptosis)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 4-(苯基甲基)-1-哌嗪乙酸 2-[[2-羟基-3-(2-烯丙-1-基)苯基]亚甲基]酰肼
• 中文别名: 4-(苯基甲基)-1-哌嗪乙酸2-[[2-羟基-3-(2-烯丙-1-基)苯基]亚甲基]酰肼；PAC1(4-(苯基甲基)-1-哌嗪乙酸2-[[2-羟基-3-(2-烯丙-1-基)苯基]亚甲基]酰肼)
• 英文名称: 2-(4-benzylpiperazin-1-yl)-N-[(2-hydroxy-3-prop-2-enylphenyl)methylideneamino]acetamide
• 英文别名: PAC-1；2-[[[2-(4-Benzylpiperazin-1-ium-1-yl)acetyl]hydrazinylidene]methyl]-6-prop-2-enylphenolate
• CAS: 315183-21-2
• 化学式: C₂₃H₂₈N₄O₂
• mdl: MFCD02051977
• 分子量: 392.501
• InChiKey: YQNRVGJCPCNMKT-UHFFFAOYSA-N

物化性质

• 密度：
  1.14
• 溶解度：
  二甲基亚砜：≥10mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  68.2
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 危险品标志：
  Xn,N
• 安全说明：
  S26,S36/37,S60,S61
• 危险类别码：
  R22,R36/37/38,R50/53
• WGK Germany：
  3
• 海关编码：
  29335990
• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P501,P273,P260,P270,P264,P280,P391,P314,P337+P313,P305+P351+P338,P301+P312+P330
• 危险品运输编号：
  3077
• 危险性描述：
  H302,H319,H372,H410

制备方法与用途

生物活性

PAC-1 是一种有效的 procaspase-3（酶原-3）激活剂，EC50 值为 0.22 μM，是第一个已知的可以直接激活 procaspase-3 成为 caspase-3 的小分子。

靶点

Target	Value
Procaspase-3	0.22 μM (EC50)

体外研究

PAC-1 能激活 procaspase-3，产生 caspase-3，并且其 EC50 值为 0.22 μM。此外，它还能激活 procaspase-7，此时的 EC50 值为 4.5 μM。在癌细胞系中，caspase 3 水平升高使得 PAC-1 能够选择性地诱导凋亡，并且这种作用与 procaspase-3 浓度成比例，IC50 值范围从针对 NCI-H226 细胞的 0.35 μM 到 UACC-62 细胞的约 3.5 μM。PAC-1 对原发性癌细胞的作用 IC50 值为 3 nM 至 1.41 μM，而对邻近非癌细胞的作用则更高，IC50 值范围在 5.02 μM 到 9.98 μM 之间。PAC-1 的作用与不同的 procaspase-3 浓度直接相关。它通过螯合锌离子来激活 procaspase-3，从而缓解锌介导的抑制，并使 procaspase-3 激活为 caspase-3。

此外，PAC-1 能够诱导 Bax/Bak 双基因敲除细胞和 Bcl-2、Bcl-xL 过表达细胞的死亡。它以 caspase-3 非依赖性的方式诱导细胞色素 c 释放，从而触发下游 caspase-3 激活和细胞死亡。在 Apaf-1 基因敲除细胞中，PAC-1 不会诱导细胞凋亡或 caspase-3 的激活，这表明通过 PAC-1 介导的细胞死亡形成凋亡体对激活 caspase-3 是必不可少的。

体内研究

给予小鼠 5 mg 的稳定释放低剂量 PAC-1 处理可以显著抑制 ACHN 肾移植瘤的生长。在口服处理中，使用 50 或 100 mg/kg 剂量的 PAC-1 显著阻碍 NCI-H226 肺癌移植瘤的生长，并且这种作用具有剂量依赖性，还能显著阻止癌细胞侵入肺组织。PAC-1 的体内抗肿瘤效果与其体外活性一致。

用途

PAC-1 是一种 caspase-3 激活剂，在癌症治疗中作为 caspase 激活策略的关键方法至关重要。caspase-3 是一个关键的执行者酶，直接诱导凋亡。许多癌症的一个特征是执行者 caspase 的激活信号通路受到阻断和凋亡反应丧失。PAC-1 通过在癌细胞系中诱导 caspase-3 激活来选择性地引起组织内的凋亡，其 EC50 值为 0.33 μM，caspase-7 的 EC50 值为 4.5 μM。PAC-1 引起细胞凋亡的 IC50 值为 0.92 μM，而癌性细胞系和组织中的 caspase-3 水平升高使其成为 PAC-1 可以选择性地诱导细胞凋亡的有效工具。

反应信息

• 作为反应物：
  描述：

  4-(苯基甲基)-1-哌嗪乙酸 2-[[2-羟基-3-(2-烯丙-1-基)苯基]亚甲基]酰肼 在 硫酰氟 、 三乙胺 作用下， 以 二甲基亚砜 、 乙腈 为溶剂， 以100%的产率得到
  参考文献：
  名称：

  SuFEx 点击化学实现后期药物功能化

  摘要：

  硫 (VI) 氟化物交换 (SuFEx) 是一个新的点击化学转化系列，它依赖于现成的材料来生产带有 SVI-F 基序的化合物。SuFEx 在药物发现中的潜力才刚刚开始被探索。我们报告了 SuFEx 化学的第一种方法，用于在 96 孔板中原位将酚类化合物转化为其各自的芳基氟硫酸盐衍生物。该方法与自动合成和筛选兼容，可快速评估原位生成的粗产物的生物活性。使用这种方法，我们对一组已知的抗癌药物进行后期功能化，以生成相应的芳基氟硫酸盐。这些原位生成的芳基氟硫酸盐与其酚类前体在癌细胞生长抑制试验中直接进行测试。我们发现了三种芳基氟硫酸盐，与其苯酚前体相比，具有更好的抗癌细胞增殖活性。在这三种化合物中，氟维司群的氟硫酸盐衍生物具有显着增强的下调 ER+ 乳腺癌细胞系 MCF-7 中雌激素受体 (ER) 表达的活性，以及​​目前正在临床评估的通用抗癌药物 Combretastatin A4 的氟硫酸盐衍生物。试验显示抗药性结肠癌细胞系

  DOI：

  10.1021/jacs.7b12788
• 作为产物：
  描述：

  1-苄基-4-(乙氧基羰基甲基)哌嗪 在 盐酸 、 肼 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 1.5h， 生成 4-(苯基甲基)-1-哌嗪乙酸 2-[[2-羟基-3-(2-烯丙-1-基)苯基]亚甲基]酰肼
  参考文献：
  名称：

  WO2008/134474

  摘要：

  公开号：

文献信息

• [EN] DESIGN, SYNTHESIS AND EVALUATION OF PROCASPASE ACTIVATING COMPOUNDS AS PERSONALIZED ANTI-CANCER DRUGS<br/>[FR] CONCEPTION, SYNTHÈSE ET ÉVALUATION DE COMPOSÉS ACTIVATEURS DE PROCASPASE EN TANT QUE MÉDICAMENTS ANTICANCÉREUX PERSONNALISÉS
  申请人：UNIV ILLINOIS

  公开号：WO2010091382A1

  公开（公告）日：2010-08-12

  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。
• Hexafluoroisopropanol for the Selective Deactivation of Poisonous Nucleophiles Enabling Catalytic Asymmetric Cyclopropanation of Complex Molecules
  作者：Jack C. Sharland、David Dunstan、Dyuti Majumdar、Jinhai Gao、Kian Tan、Hasnain A. Malik、Huw M. L. Davies

  DOI：10.1021/acscatal.2c03909

  日期：2022.10.21

  reactive reagents are prevented from interacting with a rhodium carbene, allowing asymmetric cyclopropanation to occur with high yield and stereoselectivity on a variety of compounds. A high-throughput screen was conducted on cyclopropanation with a complementary catalytic system in the presence of 90 different poisonous nucleophiles and varying amounts of HFIP (10 equiv, used as reaction solvent)

  在 1,1,1,3,3,3-六氟异丙醇 (HFIP) 存在下，可防止亲核试剂和反应试剂与铑卡宾相互作用，从而以高产率和立体选择性对各种化合物进行不对称环丙烷化。在存在 90 种不同的有毒亲核试剂和不同量的 HFIP（10 equiv，用作反应溶剂）的情况下，对具有互补催化体系的环丙烷化进行高通量筛选。芳基/杂芳基重氮乙酸酯和烯烃的范围都得到了扩展，研究最终导致了包括 API 和天然产物在内的复杂分子的对映选择性功能化。
• Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)
  作者：Danny C. Hsu、Howard S. Roth、Diana C. West、Rachel C. Botham、Chris J. Novotny、Steven C. Schmid、Paul J. Hergenrother

  DOI：10.1021/co2001372

  日期：2012.1.9

  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.
• Procaspase-3 Activation as an Anti-Cancer Strategy: Structure−Activity Relationship of Procaspase-Activating Compound 1 (PAC-1) and Its Cellular Co-Localization with Caspase-3
  作者：Quinn P. Peterson、Danny C. Hsu、David R. Goode、Chris J. Novotny、Ryan K. Totten、Paul J. Hergenrother

  DOI：10.1021/jm900722z

  日期：2009.9.24

  A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound I (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.
• 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.