(3E,5E)-3,5-bis[(4-fluorophenyl)methylidene]-1-(prop-2-enoyl)piperidin-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (3E,5E)-3,5-bis[(4-fluorophenyl)methylidene]-1-(prop-2-enoyl)piperidin-4-one
• 英文别名: VLX1550；(3E,5E)-3,5-bis[(4-fluorophenyl)methylene]-1-prop-2-enoyl-piperidin-4-one；(3E,5E)-3,5-bis[(4-fluorophenyl)methylidene]-1-prop-2-enoylpiperidin-4-one
• 化学式: C₂₂H₁₇F₂NO₂
• 分子量: 365.379
• InChiKey: JTMAQMMHQYJZRV-JYFOCSDGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3E,5E)-3,5-bis[(4-fluorophenyl)methylidene]-1-(prop-2-enoyl)piperidin-4-one 在 potassium carbonate 、 碘甲烷 作用下， 以 四氢呋喃 、 氯仿 为溶剂， 反应 48.0h， 生成 (3-{E},5-{E})-3,5-bis[(4-fluorophenyl)methylene]-1-[3-(4-hydroximino-1-piperidyl)propanoyl]piperidin-4-one methiodide
  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 在 盐酸 、 potassium carbonate 、 溶剂黄146 作用下， 以 丙酮 为溶剂， 反应 24.0h， 生成 (3E,5E)-3,5-bis[(4-fluorophenyl)methylidene]-1-(prop-2-enoyl)piperidin-4-one
  参考文献：
  名称：

  螺旋吡咯并吲哚-吡咯烷嗪-哌啶杂种的化学，区域和立体选择性合成和胆碱酯酶抑制活性

  摘要：

  通过一系列1-丙烯酰基-3,5-双芳基亚甲基哌啶-4-的1,3-偶极环加成反应，以化学，区域和立体选择性高收率合成了一系列新的杂螺环杂环，包括吡咯嗪，螺氧并吲哚和哌啶部分具有在甲醇中由5-胆红素和1-脯氨酸原位产生的甲亚胺基亚胺的化合物。这些环加合物显示出显着的胆碱酯酶抑制活性。在筛选的化合物中，8g和8e表现出对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的最大抑制活性，IC 50值分别为3.33和3.13μM。

  DOI：

  10.1016/j.bmcl.2013.03.027

文献信息

• A facile chemo-, regio- and stereoselective synthesis and cholinesterase inhibitory activity of spirooxindole–pyrrolizine–piperidine hybrids
  作者：Yalda Kia、Hasnah Osman、Raju Suresh Kumar、Vikneswaran Murugaiyah、Alireza Basiri、Subbu Perumal、Ibrahim Abdul Razak

  DOI：10.1016/j.bmcl.2013.03.027

  日期：2013.5

  A series of novel hybrid spiro heterocycles comprising pyrrolizine, spiroxindole and piperidine moieties was synthesized chemo-, regio- and stereoselectively in good yields from 1,3-dipolar cycloaddition reaction of a series of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with azomethine ylides generated in situ from 5-choloroisatin and l-proline in methanol. These cycloadducts displayed significant

  通过一系列1-丙烯酰基-3,5-双芳基亚甲基哌啶-4-的1,3-偶极环加成反应，以化学，区域和立体选择性高收率合成了一系列新的杂螺环杂环，包括吡咯嗪，螺氧并吲哚和哌啶部分具有在甲醇中由5-胆红素和1-脯氨酸原位产生的甲亚胺基亚胺的化合物。这些环加合物显示出显着的胆碱酯酶抑制活性。在筛选的化合物中，8g和8e表现出对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的最大抑制活性，IC 50值分别为3.33和3.13μM。
• 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.
• Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors
  作者：Yalda Kia、Hasnah Osman、Raju Suresh Kumar、Vikneswaran Murugaiyah、Alireza Basiri、Subbu Perumal、Habibah A. Wahab、Choi Sy Bing

  DOI：10.1016/j.bmc.2013.01.066

  日期：2013.4

  Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 mu M than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 mu M, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay. (C) 2013 Elsevier Ltd. All rights reserved.
• Design, Synthesis and Tumour-Selective Toxicity of Novel 1-[3-{3,5-Bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone Oximes and Related Quaternary Ammonium Salts
  作者：Praveen K. Roayapalley、Jonathan R. Dimmock、Lisett Contreras、Karol S. Balderrama、Renato J. Aguilera、Hiroshi Sakagami、Shigeru Amano、Rajendra K. Sharma、Umashankar Das

  DOI：10.3390/molecules26237132

  日期：——

  peridino}-3-oxopropyl]-4-piperidone oximes 3a–h and related quaternary ammonium salts 4a–h were prepared as candidate antineoplastic agents. Evaluation against neoplastic Ca9-22, HSC-2 and HSC-4 cells revealed the compounds in series 3 and 4 to be potent cytotoxins with submicromolar CC50 values in virtually all cases. In contrast, the compounds were less cytocidal towards HGF, HPLF and HPC non-malignant

  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。
• Ionic liquid mediated synthesis of mono- and bis-spirooxindole-hexahydropyrrolidines as cholinesterase inhibitors and their molecular docking studies
  作者：Yalda kia、Hasnah Osman、Raju Suresh Kumar、Alireza Basiri、Vikneswaran Murugaiyah

  DOI：10.1016/j.bmc.2014.01.002

  日期：2014.2

  One pot, three-component reaction of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with isatin and sarcosine in molar ratios of 1: 1: 1 and 1: 2: 2 furnished to mono-and bis-spiropyrrolidine heterocyclic hybrids comprising functionalized piperidine, pyrrolidine and oxindole structural motifs. Both mono and bis-spiropyrrolidines displayed good inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 2.36-9.43 mu M. For butyrylcholinesterase (BChE), mono-cycloadducts in series 8 with IC50 values of lower than 10 mu M displayed better inhibitory activities than their bis-cycloadduct analogs in series 9 with IC50 values of 7.44-19.12 mu M. The cycloadducts 9j and 8e were found to be the most potent AChE and BChE inhibitors with IC50 values of 2.35 and 3.21 mu M, respectively. Compound 9j was found to be competitive inhibitor of AChE while compound 8e was a mixed-mode inhibitor of BChE with calculated K-i values of 2.01 and 6.76 mu M, respectively. Molecular docking on Torpedo californica AChE and human BChE showed good correlation between IC50 values and free binding energy values of the synthesized compounds docked into the active site of the enzymes. (C) 2014 Elsevier Ltd. All rights reserved.