3,5-bis(4-chlorobenzylidene)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: 3,5-bis(4-chlorobenzylidene)piperidin-4-one
• 英文别名: 3,5-bis[(4-chlorophenyl)methylidene]piperidin-4-one
• 化学式: C₁₉H₁₅Cl₂NO
• 分子量: 344.24
• InChiKey: LBNHBGZGFHYLAA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  23
• 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：

  3,5-bis(4-chlorobenzylidene)piperidin-4-one 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 2.0h， 生成 spiro-[2.3']-oxindole-spiro[3.3"]-1"-carbonyl(spiro[2.3']oxindole-5-phenylpyrrolo)-5"-(4-chlorophenylmethylidene)tetrahydro-4"-(1H)-pyridinone-4-(4-chlorophenyl)-5-phenylpyrrolidine
  参考文献：
  名称：

  Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors

  摘要：

  Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 mu M, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 mu M, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. (c) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.02.019
• 作为产物：
  描述：

  3,5-bis(4-chlorobenzylidene)-4-piperidone hydrochloride 在 potassium carbonate 作用下， 以1.5 g的产率得到3,5-bis(4-chlorobenzylidene)piperidin-4-one
  参考文献：
  名称：

  CLEFMA—An anti-proliferative curcuminoid from structure–activity relationship studies on 3,5-bis(benzylidene)-4-piperidones

  摘要：

  3,5-Bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anti-cancer and anti-inflammatory properties. We performed structure-activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC50 <30 mu M), and 16 compounds possessed reduced cell-killing efficacy (IC50 >50 mu M). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzyl-idene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.055

文献信息

• Structure activity relationship analysis of antiproliferative cyclic C5-curcuminoids without DNA binding: Design, synthesis, lipophilicity and biological activity
  作者：Imre Huber、Zsuzsanna Rozmer、Zoltán Gyöngyi、Ferenc Budán、Péter Horváth、Eszter Kiss、Pál Perjési

  DOI：10.1016/j.molstruc.2019.127661

  日期：2020.4

  shortcomings. The synthesis of twenty cyclic C5-curcuminoids is described in this study in order to gain more insight into their anticancer structure-activity relationship (SAR). The design of their synthesis included four different cyclanones and five substituted aromatic aldehydes to form four, five-membered subgroups. These model compounds were evaluated in vitro for antiproliferative activity in an XTT

  摘要 姜黄素结构中两个芳环之间的 β-二酮接头对水解和代谢的化学敏感性使得研究没有这些缺点的姜黄素结构修饰类似物变得至关重要。本研究描述了 20 种环状 C5-姜黄素的合成，以便更深入地了解它们的抗癌结构-活性关系 (SAR)。他们的合成设计包括四种不同的环酮和五种取代的芳香醛，以形成四个五元亚组。在针对 MCF-7 人非侵入性乳腺癌细胞和 Jurkat 人 T 淋巴细胞白血病细胞的 XTT 细胞活力测定中，在体外评估了这些模型化合物在五种不同浓度（10 nM、100 nM、1 μM、10 μM 和 20 μM）。大多数研究的化合物显示出显着的细胞毒性，IC50 值在 120 nM 和 2 μM 范围内，对姜黄素的相对毒性值非常高。得出并总结了 SAR 结论。开发了一种方法并应用于基于 TLC 的实验 logP 测量，这是此类 C5-姜黄素的新方法。logP 数据和结构修改显示出很强的相关性。根据
• Synthesis, human topoisomerase IIα inhibitory properties and molecular modeling studies of anti-proliferative curcumin mimics
  作者：Nehmedo G. Fawzy、Siva S. Panda、Walid Fayad、ElSayed M. Shalaby、Aladdin M. Srour、Adel S. Girgis

  DOI：10.1039/c9ra05661k

  日期：——

  Piperidinecarboxamides (curcumin mimics) show promising anti-proliferative properties against HCT116 (colon), MCF7 (breast) and A431 (squamous skin) carcinoma cell lines with potency higher than that of 5-fluorouracil.

  吡啶甲酰胺（姜黄素类似物）显示出对HCT116（结肠）、MCF7（乳腺）和A431（鳞状皮肤）癌细胞系有很好的抗增殖特性，其效力高于5-氟尿嘧啶。
• Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and their molecular docking simulation
  作者：Natarajan Arumugam、Abdulrahman I. Almansour、Raju Suresh Kumar、D. Kotresha、R. Saiswaroop、S. Venketesh

  DOI：10.1016/j.bmc.2019.03.058

  日期：2019.6

  indono[1,2-b]quinoxaline heterocyclic hybrids 7a-j were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomethine ylide employed is first of its kind and generated in situ from indenoquinoxalinone and l-tryptophan, a combination that has not been employed previously for the in situ generation of azomethine ylides. The synthesized heterocyclic hybrids 7a-j were evaluated

  使用[bmim] Br中的多组分1,3-偶极环加成策略合成了一个小型的新型双螺并吡咯烷基-哌啶酮系链的吲哚[1,2-b]喹喔啉杂环杂种7a-j。所使用的偶氮甲碱叶立德是这种类型的，并且是由茚并喹喔啉酮和1-色氨酸原位产生的，这是先前尚未用于原位产生偶氮甲碱的组合。评价了合成的杂环杂种7a-j的体外乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）抑制活性，其中化合物7h和7j比标准药物对AChE和BChE的酶抑制作用更强，IC50值为3.22、2.01，分别为12.40和10.45 mM。
• A One-Pot Three-Component Synthesis and Investigation of the In Vitro Mechanistic Anticancer Activity of Highly Functionalized Spirooxindole-Pyrrolidine Heterocyclic Hybrids
  作者：Raju Suresh Kumar、Dhaifallah M. Al-thamili、Abdulrahman I. Almansour、Natarajan Arumugam、Faruq Mohammad

  DOI：10.3390/molecules25235581

  日期：——

  good yields through a one-pot three-component (3+2) cycloaddition strategy. The synthesized compounds were characterized thoroughly for the physicochemical properties by making use of FT-IR, NMR spectroscopy, and mass spectrometry. Further, these compounds have been evaluated for the influence of anticancer activity against HepG2 cells up to 200 µg/mL concentration. The highly active molecular scaffold

  为了开发具有独特作用机制的更有效且价格合理的抗癌剂，我们通过一锅三组分 (3+2) 环加成策略以良好的收率设计并合成了螺羟吲哚-吡咯烷杂环杂化物的衍生物。利用傅立叶变换红外光谱、核磁共振光谱和质谱对合成化合物的理化性质进行了彻底的表征。此外，还评估了这些化合物对浓度高达 200 µg/mL 的 HepG2 细胞的抗癌活性的影响。对高活性分子支架进行了深入的机理研究，发现细胞死亡的主要途径是细胞凋亡，细胞凋亡是通过诱导活性氧并随后参与半胱天冬酶而发生的。
• Synthesis, Biological Evaluation and Molecular Docking Studies Against EGFR Tyrosine Kinase of 3,5-bis(substituted benzylidene)-1- ethylpiperidin-4-one Analogues
  作者：Mohamed Jawed Ahsan、Deepak Saini、Piush Sharma、Surender Singh Jadav、Mohammad Afroz Bakht、Salahuddin、Ramesh Alluri、Md Faiyazuddin

  DOI：10.2174/1570178617999201020220400

  日期：2021.7.29

  The compound 4g showed significant anticancer activity with GI₅₀ of 28.2 μM against MCF-7 (Breast cancer cell line). The antioxidant activity of compound 4g (IC₅₀ = 14.98±0.91 μM) was found to be comparable to the standard drug ascorbic acid. The binding modes of compounds 4a-g against the molecular target EGFR tyrosine kinase were also studied. The structure-activity relationship (SAR) was also studied.

  The compound 4g showed significant anticancer activity with GI₅₀ of 28.2 μM against MCF-7 (Breast cancer cell line). The antioxidant activity of the compound, 4g was found to be comparable to the standard drug ascorbic acid, while its anticancer activity was found to be less than that of the standard drug adriamycin.

  癌症是死亡的主要原因之一。本研究的目的是合成和研究一些3,5-双(取代苯甲醛基)-1-乙基哌啶-4-酮类似物(4a-g)的抗癌和抗氧化活性。 3,5-双(取代苯甲醛基)-1-乙基哌啶-4-酮类似物(4a-g)是从前体哌啶-4-酮盐酸盐(1)制备而来。首先合成中间体3,5-双(取代苯甲醛基)哌啶-4-酮类似物(3a-g)，然后在丙酮和K2CO3中与C2H5I进行乙基化反应，得到目标化合物(4a-g)。傅里叶变换红外(FTIR)、核磁共振(1H和13C NMR)、质谱和显微分析被用来表征目标化合物(4a-g)。所有化合物都通过SRB测定和NCI US方案进行了抗癌活性评估，通过DPPH自由基测定进行了抗氧化活性评估。所有目标化合物(4a-g)还被用于分子对接研究，以研究我们的化合物与分子靶点的可能相互作用方式。 化合物4g对MCF-7(乳腺癌细胞系)显示出显著的抗癌活性，GI50为28.2μM。化合物4g的抗氧化活性(IC50 = 14.98±0.91μM)与标准药物抗坏血酸相当。还研究了化合物4a-g与分子靶点EGFR酪氨酸激酶的结合模式，同时还研究了结构-活性关系(SAR)。 化合物4g对MCF-7(乳腺癌细胞系)显示出显著的抗癌活性，GI50为28.2μM。化合物4g的抗氧化活性与标准药物抗坏血酸相当，而其抗癌活性则低于标准药物阿霉素。