2-(piperidin-2-ylidene)malononitrile | 78807-02-0

• 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: 2-(piperidin-2-ylidene)malononitrile
• 英文别名: 2-dicyanomethylidene-2,3,4,5-tetrahydro-1H,6H-pyridine；2-piperidin-2-ylidenepropanedinitrile
• CAS: 78807-02-0
• 化学式: C₈H₉N₃
• mdl: MFCD19217289
• 分子量: 147.18
• InChiKey: SFAFIKXLBMHPCT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  59.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(piperidin-2-ylidene)malononitrile 在 sodium tetrahydroborate 作用下， 以 乙醇 为溶剂， 生成 3-Amino-2-butyl-1-oxo-2,4a,5,6,7,8-hexahydro-1H-pyrido[1,2-c]pyrimidine-4-carbonitrile
  参考文献：
  名称：

  Synthesis of some non-antimonial compounds bioisosteric to praziquantel

  摘要：

  DOI：

  10.1016/0223-5234(96)88265-1
• 作为产物：
  描述：

  哌啶酮 以 乙醇 、 苯 为溶剂， 反应 4.0h， 生成 2-(piperidin-2-ylidene)malononitrile
  参考文献：
  名称：

  吡咯并嘧啶衍生物作为多药耐药相关蛋白1（MRP1，ABCC1）的新型抑制剂。

  摘要：

  合成了五个系列的吡咯并[3,2- d ]嘧啶，并评估了其与多药耐药相关蛋白1（MRP1，ABCC1）的效力和选择性。该转运蛋白是克服癌症患者多药耐药性的主要靶标。我们在钙黄绿素AM和柔红霉素细胞蓄积试验中，使用选定的阿霉素和过表达MRP1的小细胞肺癌细胞株H69 AR，研究了不同取代的吡咯并嘧啶类化合物。鉴定出具有高效力和选择性的新化合物。位置4的哌嗪残基带有大的苯基烷基侧链，被证明对MRP1抑制是有益的。其被氨基取代导致活性降低。位置5和6的脂族和脂族-芳族变异揭示了具有IC的化合物高纳摩尔范围内有50个值。所有研究的化合物对P-糖蛋白（P-gp，ABCB1）均具有低亲和力。具有小的取代基的吡咯并嘧啶显示出对乳腺癌抗性蛋白（BCRP，ABCG2）的中等抑制作用。

  DOI：

  10.1021/acs.jmedchem.5b01644

文献信息

• Synthesis of novel indolizine, diazepinoindolizine and Pyrimidoindolizine derivatives as potent and selective anticancer agents
  作者：Amany Belal、Ahmed M. Gouda、Ahmed Safwat Ahmed、Nagwa M. Abdel Gawad

  DOI：10.1007/s11164-015-1958-9

  日期：2015.12

  A series of new indolizine 9a–c, 10a–c, diazepinoindolizine 7a–c, 8a–c, and pyrimidoindolizine 11 derivatives were synthesized and structures of the newly synthesized compounds were confirmed by spectral and elemental analyses. Antitumor activity evaluation was carried out using sulphorhodamine-B assay method against lung adenocarcinoma (A549), breast (MCF7), hepatoma (Hep3B) cancer cell lines and normal fibroblast cells. Compounds 7a, 9c, 10a,c and 11 showed to be the most active against the lung cancer cell line with IC50 in nanomole range (16–85 nmol/ml) and compound 11 was the best selective one (S. I. = 19). The most potent compounds against MCF7 are 8c, 9b,c, 10a,b, and 11. Their IC50 range is 4–46 nmol/ml and the best selectivity was assigned for compound 11 (S. I. = 133). As for the hepatoma cancer cell line, compounds 7a, 8a–c, 9a–c, and 10a,b were found to be the most potent with IC50 range 3–90 nmol/ml and compound 8c was the most selective one (S. I. = 42), the rest of the new compounds showed IC50 value >100 nmol/ml. Compound 10a showed a broad spectrum activity and selectivity against the tested cell lines with a much lesser effect on normal fibroblast cells (IC50 > 200 nmol/ml).

  合成了一系列新的吲哚啉衍生物9a–c、10a–c、二氮杂吲哚啉衍生物7a–c、8a–c和嘧啶吲哚啉衍生物11，并通过光谱和元素分析确认了新合成化合物的结构。采用硫罗丹明-B测定法评估了它们对肺腺癌(A549)、乳腺癌(MCF7)、肝癌(Hep3B)细胞系和正常成纤维细胞的抗肿瘤活性。化合物7a、9c、10a、c和11对肺癌细胞系表现出最强的活性，IC50在纳摩尔范围内(16–85 nmol/ml)，其中化合物11具有最佳选择性(S. I. = 19)。对MCF7细胞系最有效的化合物是8c、9b、c、10a、b和11。它们的IC50范围为4–46 nmol/ml，最佳选择性为化合物11(S. I. = 133)。对于肝癌细胞系，化合物7a、8a–c、9a–c和10a、b被发现是最有效的，IC50范围为3–90 nmol/ml，化合物8c则是选择性最高的(S. I. = 42)，其余新化合物的IC50值均大于100 nmol/ml。化合物10a对所测试的细胞系表现出广谱活性和选择性，对正常成纤维细胞的影响明显较小(IC50 > 200 nmol/ml)。
• [EN] PYRROLOPYRIMIDINE DERIVATIVES USEFUL AS MODULATORS OF MULTIDRUG RESISTANCE<br/>[FR] DERIVES DE PYRROLOPYRIMIDINE POUVANT ETRE UTILISES EN TANT QUE MODULATEURS DE LA MULTIRESISTANCE AUX MEDICAMENTS
  申请人：XENOVA LTD

  公开号：WO2004065389A1

  公开（公告）日：2004-08-05

  A compound which is a pyrrolopyrimidine of formula (I) wherein: R1 is selected from R9 and halogen; R2 is NR6R7; R3 is selected from H, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nAr; R4 is selected from H, C1-C6 alkyl and -(CH2)„ Ar; or R3 and R4 form, together with the N and C atoms to which they are attached, a fused five-, six-, seven- or eight-membered N-containing saturated ring which is unsubstituted or substituted; R5 is selected from CN, C02R9, C(O)NR10R11, -(CH2)nOH, -(CH2)nR10Rn, -C=CH, -C(S)NR10R11, -C(NH2)=NOR9, -C(R9)=NOR9, -C(NH2)NH, -C(O)R9 and an unsaturated 5- or 6-membered heterocyclic group which contains 1, 2 or 3 heteroatoms selected from N, O and S and which is unsubstituted or substituted; R6 and R7, which are the same or different, are selected from C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nX and -(CH2)nAr; or R6 and R7 form, together with the nitrogen atom to which they are attached, a saturated five-, six-, seven- or eight-membered heterocyclic group which contains one nitrogen atom and 0 or from 1 to 3 additional heteroatoms selected from N, O and S, which is unsubstituted or substituted and which optionally contains one or two bridgehead atoms; R10 and R11, which are the same or different, are selected from H, C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nC3-C10 cycloalkyl and -(CH2) nAr; or R10 and R11 form, together with the nitrogen atom to which they are attached, a saturated five or six membered heterocyclic group which contains a nitrogen atom and 0 or from to 3 additional heteroatoms selected from O, S and N, which is unsubstituted or substituted and which is optionally fused to a benzene ring which is unsubstituted or substituted; n is the same or different when more than one is present within a given substituent group and is 0 or an integer of from 1 to 6; X is selected from -CN, -C02R9 and -NR10R11; R9 is the same or different when more than one is present within a given substituent group and is selected from -H, -QAr, -(CH2) nAr, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nC3-C10cycloalkyl, wherein the cycloalkyl moiety is optionally fused to a benzene ring which is unsubstituted or substituted; Q is C2-C6 alkenylene or alkynylene; and Ar is an unsaturated C6-C10 membered carbocyclic group or an unsaturated 5-11 membered heterocyclic group, which groups are unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. These compounds have activity as inhibitors of MRP (multidrug resistant protein) and may thus be used to modulate multidrug resistance, for instance in potentiating the cytotoxicity of a chemotherapeutic agent.

  一种具有以下结构式(I)的吡咯吡嘧啶化合物，其中：R1从R9和卤素中选择；R2为NR6R7；R3从H、未取代或取代的C1-C6烷基和-(CH2) nAr中选择；R4从H、C1-C6烷基和-(CH2) nAr中选择；或者R3和R4与它们连接的N和C原子一起形成未取代或取代的融合的含氮饱和环，该环为五、六、七或八元环；R5从CN、C02R9、C(O)NR10R11、-(CH2)nOH、-(CH2)nR10Rn、-C=CH、-C(S)NR10R11、-C(NH2)=NOR9、-C(R9)=NOR9、-C(NH2)NH、-C(O)R9和一个含有1、2或3个异原子（N、O和S）且未取代或取代的不饱和5-或6元杂环基中选择；R6和R7相同或不同，从未取代或取代的C1-C6烷基、-(CH2)nX和-(CH2)nAr中选择；或者R6和R7与它们连接的氮原子一起形成含有一个氮原子和0或1至3个额外异原子（N、O和S）的饱和五、六、七或八元杂环基，该环未取代或取代，可选地包含一个或两个桥头原子；R10和R11相同或不同，从未取代或取代的H、C1-C6烷基、-(CH2)nC3-C10环烷基和-(CH2)nAr中选择；或者R10和R11与它们连接的氮原子一起形成含有一个氮原子和0或1至3个额外异原子（O、S和N）的饱和五或六元杂环基，该环未取代或取代，可选地与未取代或取代的苯环融合；n在给定取代基中的多个存在时相同或不同，为0或1至6的整数；X从-CN、-C02R9和-NR10R11中选择；R9在给定取代基中的多个存在时相同或不同，从-H、-QAr、-(CH2)nAr、未取代或取代的C1-C6烷基和-(CH2)nC3-C10环烷基中选择，其中环烷基部分可选地与未取代或取代的苯环融合；Q为C2-C6烯基或炔基；Ar为未取代或取代的不饱和C6-C10环烷基或不饱和5-11元杂环基，或其药学上可接受的盐。这些化合物具有作为MRP（多药耐药蛋白）抑制剂的活性，因此可用于调节多药耐药性，例如增强化疗药物的细胞毒性。
• Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents
  作者：Ahmed M. Shawky、Nashwa A. Ibrahim、Ashraf N. Abdalla、Mohammed A. S. Abourehab、Ahmed M. Gouda

  DOI：10.1080/14756366.2021.1937618

  日期：2021.1.1

  present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a–e showed higher cytotoxicity than their corresponding Schiff bases 15a–e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC50 in the range of 0.52–6.26 μM. Interestingly, the new compounds were less

  摘要 在本研究中，设计、合成了两个新系列的带有 3,4,5-三甲氧基苯基部分的吡咯嗪，并评估了它们的细胞毒活性。苯甲酰胺衍生物16a-e显示出比其相应的希夫碱15a-e更高的细胞毒性。化合物16a、b、d也抑制 MCF-7/ADR 细胞的生长，IC 50范围为 0.52–6.26 μM。有趣的是，新化合物对正常 MRC-5 细胞的细胞毒性较小（IC 50 = 0.155–17.08 μM）。机理研究揭示了化合物16a , b , d的能力抑制微管蛋白聚合和多种致癌激酶。此外，化合物16a、b、d在MCF-7细胞中诱导preG 1和G 2 /M细胞周期停滞和早期凋亡。与共结晶配体相比，化合物16a、b、d进入微管蛋白、CDK-2 和 EGFR 蛋白中的活性位点的分子对接分析显示出更高的结合亲和力。这些初步结果表明，化合物16a、b、d可以作为有前景的先导化合物，用于未来开发新的强效抗癌剂。 强调
• Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
  作者：Mohammed A. S. Abourehab、Alaa M. Alqahtani、Faisal A. Almalki、Dana M. Zaher、Ashraf N. Abdalla、Ahmed M. Gouda、Eman A. M. Beshr

  DOI：10.3390/molecules26216582

  日期：——

  In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where 8a,e,f were the most active. In addition, an investigation of the antiproliferative activity of 8a,e,f against MCF-7 cells revealed IC50 values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds 5a,c and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of 8a,e,f into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds 8a,e,f deserve additional investigation as potential anticancer candidates.

  在当前研究中，设计并合成了NSAIDs布洛芬和氯吡格雷的八种新杂交物，与五种吡咯烷/吲哚烷衍生物结合。这些杂交物的化学结构经过光谱和元素分析确认。对这些杂交物（5μM）在MCF-7、A549和HT-29癌细胞系上的抗增殖活性进行了研究，使用细胞活力分析MTT法。结果显示，这些杂交物对三种癌细胞系的生长抑制率为4-71%，其中8a、e、f活性最高。此外，对8a、e、f对MCF-7细胞的抗增殖活性研究显示，其IC50值分别为7.61、1.07和3.16μM。对以5μM处理的MCF-7细胞的细胞周期分析显示，这三种杂交物导致前G1期细胞的凋亡增加，以及G1期和S期的细胞周期阻滞。此外，这三种杂交物还诱导了MCF-7细胞的早期凋亡事件。对这三种杂交物与COX-1/2的分子对接结果显示，其结合自由能高于其母化合物5a、c和共结晶配体布洛芬和SC-558。结果还表明，这些杂交物对COX-2的结合自由能高于对COX-1的结合自由能。此外，对8a、e、f与COX-2的结合方式分析显示，与共结晶配体SC-558部分重叠，并与关键氨基酸His90和Arg513形成必要的氢键、静电或疏水相互作用。这些新杂交物的药物样性评分在1.06-2.03范围内，与布洛芬（0.65）和氯吡格雷（0.57）相比。以上结果表明，化合物8a、e、f值得进一步研究作为潜在的抗癌候选物。
• Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and <i>in silico</i> studies
  作者：Amr L. AbdelSamad、Mohammed T. El-Saadi、Ahmed M. Gouda、Asmaa M. AboulMagd

  DOI：10.1039/d3ra05310e

  日期：——

  Two new series of pyrrolizine/indolizine derivative-bearing (un)substituted isoindole moiety were designed, synthesized and evaluated as possible anticancer agents.

  我们设计、合成并评估了两个新系列的吡咯烷/吲哚利嗪衍生物，它们含有（未）取代的异吲哚分子，可作为抗癌药物。