(3E,5E)-3,5-bis(3,4-dichlorobenzylidene)-piperidin-4-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (3E,5E)-3,5-bis(3,4-dichlorobenzylidene)-piperidin-4-one
• 英文别名: 3,5-bis((E)-3,4-dichlorobenzylidene)-4-oxopiperidin；(3E,5E)-3,5-bis[(3,4-dichlorophenyl)methylidene]piperidin-4-one
• 化学式: C₁₉H₁₃Cl₄NO
• 分子量: 413.13
• InChiKey: GJPXGFGIFQWUOC-ACFHMISVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3E,5E)-3,5-bis(3,4-dichlorobenzylidene)-piperidin-4-one 在 potassium carbonate 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 48.0h， 生成 (3-{E},5-{E})-3,5-bis[(3,4-dichlorophenyl)methylene]-1-[3-(4-hydroximino-1-piperidyl)propanoyl]piperidin-4-one hydrochloride
  参考文献：
  名称：

  新型1-[3-{3,5-双(亚苄基)-4-氧代-1-哌啶基}-3-氧代丙基]-4-哌啶酮肟及相关季铵盐的设计、合成及肿瘤选择性毒性

  摘要：

  制备了一系列新型 1-[3-{3,5-双(亚苄基)-4-氧代-1-哌啶基}-3-氧代丙基]-4-哌啶酮肟3a – h和相关季铵盐4a – h作为候选抗肿瘤药物。针对肿瘤性 Ca9-22、HSC-2 和 HSC-4 细胞的评估表明，系列3和系列4中的化合物几乎在所有情况下都是有效的细胞毒素，其 CC 50值为亚微摩尔。相比之下，这些化合物对 HGF、HPLF 和 HPC 非恶性细胞的杀细胞作用较小，显示出它们的肿瘤选择性毒性。定量结构-活性关系表明，一般来说，细胞毒性效力和选择性指数随着哈米特西格玛值大小的增加而增加。此外， 3a – h对许多白血病细胞和结肠癌细胞具有细胞毒性。 4b 、 c降低CEM细胞中的线粒体膜电位， 4d诱导Ca9-22细胞中瞬时G2/M积累。五种化合物，即3 c 、 d和4c – e ，被确定为具有药物样特性的先导分子。

  DOI：

  10.3390/molecules26237132
• 作为产物：
  描述：

  4-氧代哌啶酮盐酸盐 、 3,4-二氯苯甲醛 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 24.0h， 生成 (3E,5E)-3,5-bis(3,4-dichlorobenzylidene)-piperidin-4-one
  参考文献：
  名称：

  3,5-双（亚苄基）-4-哌啶酮和二氯乙酸的新型杂合分子，显示出强大的肿瘤选择性细胞毒性。

  摘要：

  从二氯乙酸中设计了一类新型的杂合分子2a-o作为候选抗肿瘤药，二氯乙酸是丙酮酸脱氢酶激酶和许多具有细胞毒性的3,5-双（亚苄基）-4-哌啶酮1的抑制剂。杂合分子是针对人HCT116结肠癌细胞的有效细胞毒素。出现了许多铅分子，其IC50值在两位数纳摩尔范围内。这些化合物中的大多数对人CRL1790非恶性结肠细胞的毒性较小，因此，大多数化合物的选择性指数（SI）值很高。在2c-g，m，n的情况下，SI值超过100。与参考药物5-FU相比，化合物2g，2j，2m和2n的效价高100倍以上。定量的构效关系表明，随着Hammettσ和Taftσ*值的增加，系列2中化合物的效能也增加。代表性化合物2c的X射线晶体学揭示了可能影响细胞毒性的各种结构特征。几种代表性化合物降低了HCT116细胞中的线粒体膜电位，并增加了活性氧的产生。在改变细胞周期不同阶段中的细胞百分比方面，注意到最小的作用。已经为模拟开发

  DOI：

  10.1016/j.bmcl.2019.126878

文献信息

• Two novel piperidones induce apoptosis and antiproliferative effects on human prostate and lymphoma cancer cell lines
  作者：Risa Mia Swain、Lisett Contreras、Armando Varela-Ramirez、Mohammad Hossain、Umashankar Das、Carlos A. Valenzuela、Manuel L. Penichet、Jonathan R. Dimmock、Renato J Aguilera

  DOI：10.1007/s10637-022-01266-y

  日期：2022.10

  Cancer remains the second most common cause of death in the US. Due to a recurrent problem with anticancer drug resistance, there is a current need for anticancer drugs with distinct modes of action for combination drug therapy We have tested two novel piperidone compounds, named 2608 (1-dichloroacetyl − 3,5-bis(3,4-difluorobenzylidene)-4-piperidone) and 2610 (1-dichloroacetyl-3,5-bis(3,4-dichlorobenzylidene)-4-piperidone), for their potential cytotoxicity on numerous human cancer cell lines. We found that both compounds were cytotoxic for breast, pancreatic, leukemia, lymphoma, colon, and fibroblast cell lines, with a cytotoxic concentration 50% (CC50) in the low micromolar to nanomolar concentration range. Further assays focused primarily on an acute lymphoblastic lymphoma and colon cancer cell lines since they were the most sensitive and resistant to the experimental piperidones. The cell death mechanism was evaluated through assays commonly used to detect the induction of apoptosis. These assays revealed that both 2608 and 2610 induced reactive oxygen species (ROS) accumulation, mitochondrial depolarization, and activated caspase-3/7. Our findings suggest that the piperidones induced cell death via the intrinsic apoptotic pathway. Additional assays revealed that both piperidones cause cell cycle alteration in lymphoma and colon cell lines. Both piperidones elicited DNA fragmentation, as evidenced by an increment in the sub-G0/G1 subpopulation in both cell lines. Similar to other related compounds, both piperidones were found to act as proteasome inhibitors by increasing the levels of poly-ubiquitinated proteins in both lymphoma and colon cell lines. Hence, the two piperidones exhibited attractive cytotoxic properties and suitable mechanisms of action, which makes them good candidates as anticancer drugs.

  癌症仍是美国第二大常见死因。由于抗癌药物耐药性反复出现，目前需要作用机理不同的抗癌药物进行联合用药。我们测试了两种新型哌啶酮化合物，分别是2608（1-二氯乙酰基-3,5-双（3,4-二氟苄叉）-4-哌啶酮）和2610（1-二氯乙酰基-3,5-双（3,4-二氯苄叉）-4-哌啶酮），测试它们对多种人类癌细胞系的潜在细胞毒性。我们发现这两种化合物对乳腺癌、胰腺癌、白血病、淋巴瘤、结肠癌和成纤维细胞系具有细胞毒性，细胞毒性浓度50%（CC50）在低微摩尔至纳摩尔浓度范围内。进一步的实验主要集中于急性淋巴细胞白血病和结肠癌细胞系，因为它们对实验性哌啶酮最敏感且耐受性最强。通过常用检测细胞凋亡诱导的实验评估细胞死亡机制。这些实验表明，2608和2610均诱导活性氧（ROS）积累、线粒体去极化和激活的半胱天冬酶-3/7。我们的研究结果表明，哌啶酮通过固有凋亡途径诱导细胞死亡。其他实验表明，
• Spiro and cyclic bis-benzylidene proteasome inhibitor for the treatment of cancer, diabetes and neurological disorders
  申请人：UP THERAPEUTICS, INC.

  公开号：US10947199B2

  公开（公告）日：2021-03-16

  Described herein are spiro and cyclic bis-benzylidine proteasome inhibitors, which inhibit the proteasome function through either ubiquitin receptor ADRM1/RPN13 or proteasome DUB enzymes (USP14, UCH37 and RPN11), and which can be used for the treatment of cancers/diabetes/neurological disorders.

  本文描述了螺环和环双苄啶蛋白酶体抑制剂，它们通过泛素受体 ADRM1/RPN13 或蛋白酶体 DUB 酶（USP14、UCH37 和 RPN11）抑制蛋白酶体功能，可用于治疗癌症/糖尿病/神经系统疾病。
• A Conformational and Structure−Activity Relationship Study of Cytotoxic 3,5-Bis(arylidene)-4-piperidones and Related <i>N</i>-Acryloyl Analogues
  作者：Jonathan R. Dimmock、Maniyan P. Padmanilayam、Ramanan N. Puthucode、Adil J. Nazarali、Narasimhan L. Motaganahalli、Gordon A. Zello、J. Wilson Quail、Eliud O. Oloo、Heinz-Bernhard Kraatz、Jared S. Prisciak、Theresa M. Allen、Cheryl L. Santos、Jan Balzarini、Erik De Clercq、Elias K. Manavathu

  DOI：10.1021/jm0002580

  日期：2001.2.1

  A series of 3,5-bis(arylidene)-4-piperidones 1 and related N-acryloyl analogues 2 were prepared as candidate cytotoxic agents with a view to discerning those structural features which contributed to bioactivity. A number of the compounds were markedly cytotoxic toward murine P388 and L1210 leukemic cells and also to human Molt 4/C8 and CEM neoplasms. Approximately 40% of the IC50 values generated were lower than the figures obtained for melphalan. In virtually all cases, the N-acyl compounds were significantly more bioactive than the analogues 1. In general, structure-activity relationships revealed that the cytotoxicity of series 1 was correlated positively with the size of the aryl substituents, while in series 2, a -sigma relationship was established. In particular, various angles and interatomic distances were obtained by molecular modeling, and the presence of an acryloyl group on the piperidyl nitrogen atom in series 2 affected the relative locations of the two aryl rings. This observation, along with some differences in distances between various atoms in series 1 and 2, may have contributed to the disparity in cytotoxicity between 1 and 2. The results obtained by X-ray crystallography of representative compounds were mainly in accordance with the observations noted by molecular modeling. Selected compounds interfered with the biosynthesis of DNA, RNA, and protein in murine L1210 cells, while others were shown to cause apoptosis in the human Jurkat leukemic cell line. This study has revealed the potential of these molecules for development as cytotoxic and anticancer agents.
• Novel Spiro and Cyclic Bis-Benzylidine Proteasome Inhibitor for the Treatment of Cancer, Diabetes and Neurological Disorders
  申请人：UP THERAPEUTICS, INC.

  公开号：US20210163420A1

  公开（公告）日：2021-06-03

  Described herein are spiro and cyclic bis-benzylidine proteasome inhibitors, which inhibit the proteasome function through either ubiquitin receptor ADRM1/RPN13 or proteasome DUB enzymes (USP14, UCH37 and RPN11), and which can be used for the treatment of cancers/diabetes/neurological disorders.
• Novel hybrid molecules of 3,5-bis(benzylidene)-4-piperidones and dichloroacetic acid which demonstrate potent tumour-selective cytotoxicity
  作者：Mohammad Hossain、Swagatika Das、Umashankar Das、Alireza Doroudi、Jianfeng Zhu、Jonathan R. Dimmock

  DOI：10.1016/j.bmcl.2019.126878

  日期：2020.2

  A novel class of hybrid molecules 2a-o was designed as candidate antineoplastic agents from dichloroacetic acid which is a known inhibitor of pyruvate dehydrogenase kinase and a number of cytotoxic 3,5-bis(benzylidene)-4-piperidones 1. In general these new hybrid molecules are potent cytotoxins towards human HCT116 colon cancer cells. A number of lead molecules emerged having the IC50 values in the

  从二氯乙酸中设计了一类新型的杂合分子2a-o作为候选抗肿瘤药，二氯乙酸是丙酮酸脱氢酶激酶和许多具有细胞毒性的3,5-双（亚苄基）-4-哌啶酮1的抑制剂。杂合分子是针对人HCT116结肠癌细胞的有效细胞毒素。出现了许多铅分子，其IC50值在两位数纳摩尔范围内。这些化合物中的大多数对人CRL1790非恶性结肠细胞的毒性较小，因此，大多数化合物的选择性指数（SI）值很高。在2c-g，m，n的情况下，SI值超过100。与参考药物5-FU相比，化合物2g，2j，2m和2n的效价高100倍以上。定量的构效关系表明，随着Hammettσ和Taftσ*值的增加，系列2中化合物的效能也增加。代表性化合物2c的X射线晶体学揭示了可能影响细胞毒性的各种结构特征。几种代表性化合物降低了HCT116细胞中的线粒体膜电位，并增加了活性氧的产生。在改变细胞周期不同阶段中的细胞百分比方面，注意到最小的作用。已经为模拟开发