hexyl-kinked bis-tacrine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: hexyl-kinked bis-tacrine
• 英文别名: MMV019555；N,N'-di[(9Z)-1,3,4,10-tetrahydroacridin-9(2H)-ylidene]hexane-1,6-diamine；N,N'-bis(1,2,3,4-tetrahydroacridin-9-yl)hexane-1,6-diamine
• 化学式: C₃₂H₃₈N₄
• 分子量: 478.681
• InChiKey: IYNUCVAQGDCTFO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  49.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  邻氨基苯甲酸 在 sodium iodide 、 三氯氧磷 作用下， 以 苯酚 为溶剂， 生成 hexyl-kinked bis-tacrine
  参考文献：
  名称：

  Bistacrine衍生物作为新的有效抗疟药

  摘要：

  与单体相比，连接两个他克林分子导致抗疟原虫的活性大大增加。这一发现促进了单体和二聚他克林衍生物库的合成，以推导结构-活性关系。对氯喹敏感的疟原虫菌株3D7和对氯喹耐药的菌株Dd2最具活性的化合物在纳摩尔浓度范围内显示IC 50值，细胞毒性低，并靶向半胱氨酸蛋白酶falcipain-2，这对寄生虫的生长至关重要。

  DOI：

  10.1016/j.bmc.2016.06.003

文献信息

• Synthesis and in-vitro anticancer evaluation of bistacrine congeners
  作者：Ming-Kuan Hu

  DOI：10.1211/0022357011775046

  日期：2010.2.18

  In the search for potential new anticancer drugs, an efficient synthesis of bis-tetrahydroaminoacridine (bis-tacrine) and its congeners was accomplished by bis-amination of 9-chlorotetrahydroacridine and its congeners under heated conditions.

  The critical chlorides were efficiently prepared from o-aminoaromatic acids and cycloketones in-situ in the presence of phosphorus oxychloride. In-vitro cytotoxic evaluation of the compounds was carried out against a panel of 60 human cancer cell lines. Among them, butyllinked bis-tacrine (5b) exhibited the strongest cytotoxic profile with GI50 (concentration causing 50% growth inhibition) values of approximately 0.04-0.08 μM against breast, colon, melanoma and non-small lung cancer cells. Congeners bearing a longer alkyl chain were on average 30- to 100-fold less cytotoxic against these cancer cells. Shorter connecting alkyl chains of bis-tacrine or its congeners dramatically decreased the cytotoxic effects.

  Compound 5b has been selected for further biological evaluation of its anticancer profile.

  在寻找潜在新抗癌药物的过程中，通过9-氯四氢喹啉及其同系物的双胺化，在加热条件下成功合成了双-四氢喹啉（双-他克林）及其同系物。这些关键氯化物是通过邻氨基芳香酸和环酮在磷氯化氢存在下原位高效制备的。对这些化合物进行了体外细胞毒性评估，针对60种人类癌细胞系。其中，丁基连接的双-他克林（5b）在乳腺癌、结肠癌、黑色素瘤和非小细胞肺癌细胞中表现出最强的细胞毒性，GI50（引起50%生长抑制的浓度）值约为0.04-0.08μM。具有较长烷基链的同系物对这些癌细胞的毒性平均降低了30到100倍。双-他克林或其同系物较短的连接烷基链显著降低了细胞毒性效果。化合物5b已被选中进一步评估其抗癌特性。
• Homodimeric Tacrine Congeners as Acetylcholinesterase Inhibitors
  作者：Ming-Kuan Hu、Li-Ju Wu、George Hsiao、Mao-Hsiung Yen

  DOI：10.1021/jm010308g

  日期：2002.5.1

  search for highly selective and potent derivatives of tacrine (1a), a number of homodimeric tacrine congeners were synthesized and conducted for their effects on rat acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE) inhibitions. Heptylene-linked bis-(6-chloro)tacrine (3h) was found up to 3000- and 3-fold more potent in inhibiting rat AChE than tacrine and the unsubstituted bis-tacrine 3b

  在寻找他克林（1a）的高选择性和有效衍生物的过程中，合成了许多同二聚他克林同源物，并研究了它们对大鼠乙酰胆碱酯酶（AChE）和人丁酰胆碱酯酶（BChE）的抑制作用。发现庚烯连接的双-（6-氯）他克林（3h）抑制大鼠AChE的效力分别比他克林和未取代的双-他克林3b高3000倍和3倍。与3b相比，二聚他克林碳环的大小变化降低了AChE抑制的选择性和效力。将氮杂作为所需的等位基因3j-m插入他克林核中会产生中等效力，但往往对选择性有害。通过在同源二聚啶的6-位掺入卤素，可以显着提高AChE抑制能力和AChE / BChE选择性。3a-m的测定结果也提供了证据，表明7-亚甲基系链倾向于AChE抑制能力最佳。
• A facile synthesis of bis-tacrine isosteres
  作者：Ming-Kuan Hu、Chih-Feng Lu

  DOI：10.1016/s0040-4039(00)00036-8

  日期：2000.3

  An efficient synthesis of highly potent and selective acetylcholinesterase (AChE) inhibitors, bis-tacrines and their isosteres 2-4, has been accomplished by bis-amination of 9-chloro-tetrahydroacridine (9a) and its analogs. The critical intermediates were concisely prepared in situ by heating the corresponding ortho-amino aromatic acids and cycloketones in the presence of phosphorus oxychloride. (C) 2000 Elsevier Science Ltd. All rights reserved.
• Bistacrine derivatives as new potent antimalarials
  作者：Ines Schmidt、Gabriele Pradel、Ludmilla Sologub、Alexandra Golzmann、Che J. Ngwa、Anna Kucharski、Tanja Schirmeister、Ulrike Holzgrabe

  DOI：10.1016/j.bmc.2016.06.003

  日期：2016.8

  Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure–activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50 values

  与单体相比，连接两个他克林分子导致抗疟原虫的活性大大增加。这一发现促进了单体和二聚他克林衍生物库的合成，以推导结构-活性关系。对氯喹敏感的疟原虫菌株3D7和对氯喹耐药的菌株Dd2最具活性的化合物在纳摩尔浓度范围内显示IC 50值，细胞毒性低，并靶向半胱氨酸蛋白酶falcipain-2，这对寄生虫的生长至关重要。