2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-benzimidazole | 188860-26-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-benzimidazole
• 英文别名: 2,5'-Bi-1H-benzimidazole, 2'-(3,4-dimethoxyphenyl)-5-(4-methyl-1-piperazinyl)-；2-(3,4-dimethoxyphenyl)-6-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-benzimidazole
• CAS: 188860-26-6
• 化学式: C₂₇H₂₈N₆O₂
• 分子量: 468.558
• InChiKey: BMRRDFCQNOZNNR-UHFFFAOYSA-N

物化性质

• 熔点：
  220 °C
• 沸点：
  737.3±70.0 °C(Predicted)
• 密度：
  1.292±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：≥54mg/mL（115.25mM）；

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  82.3
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

DMA 是一种荧光化合物（激发波长 λex=340 nm，发射波长 λem=478 nm）。

靶点

• IC50: HeLa 细胞为 3.4 μM，MCF7 细胞为 5.3 μM

体外研究

新合成的二苯并咪唑衍生物 DMA (6c) 对人类肿瘤细胞系的细胞毒性进行了评估，包括宫颈癌细胞系（HeLa）、乳腺癌细胞系（MCF7）和脑胶质瘤细胞系（U87），并与 Hoechst 进行了比较。在 MCF7 细胞中，DMA 的 IC50 值为 5.3 μM；而在 HeLa 细胞中的 IC50 值为 3.4 μM。

反应信息

• 作为产物：
  描述：

  3,4-二氨基苯甲腈 在 sodium metabisulfite 、 甲酸 、 nickel/aluminium alloy 作用下， 以 乙醇 、 水 为溶剂， 反应 16.0h， 生成 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-benzimidazole
  参考文献：
  名称：

  新型拓扑异构酶抑制剂I的合成及其生物学活性：2-芳基取代的2-双-1H-苯并咪唑

  摘要：

  拓扑异构酶I的抑制剂构成了新的抗肿瘤剂家族。一类苯并咪唑衍生物包含对DNA具有亲和力的化合物。例如，荧光染料Hoechst 33342和Hoechst 33258作为配体与DNA相互作用，并对包括DNA拓扑异构酶和DNA解旋酶在内的许多参与DNA合成的酶的催化活性产生非特异性抑制。合成了几种2-芳基-5-取代的2,5-双苯并咪唑衍生物，并在体外评价了在拓扑异构酶I存在下这些衍生物诱导DNA裂解的能力。还测定了这些类似物对U87，MCF7和HeLa人肿瘤细胞的细胞毒性。四种化合物对所有细胞系均显示出有效的生长抑制作用，采用ICμM范围内为50。

  DOI：

  10.1016/j.ejmech.2010.11.046

文献信息

• [EN] A PROCESS FOR THE SYNTHESIS OF BISBENZIMIDAZOLES AND ITS DERIVATIONS<br/>[FR] PROCESSUS DE SYNTHÈSE DE BISBENZIMIDAZOLES ET DE SES DÉRIVÉS
  申请人：UNIV DELHI

  公开号：WO2004063170A1

  公开（公告）日：2004-07-29

  A process for the synthesis of bisbenzimidazoles and its derivations comprising; (i) reacting 5 chloroaniline with zinc dust and acetic anhydride to produce 5 chloroacetanilide; (ii) reacting 5 chloroacetanilide with HN03 to produce 2-nitro-5-chloroacetanilide; (ix) adding sodium methoxide to 2-nitro-5-ch1oroaniline; (x) heating 2-nitro-5-chloroaniline, methyl piperazine, anhydrous K2CO3 and Dimethyl formamide at 100-120°C produce a mixture which is cooled by pouring ice and is filtered to obtain 5-(4'-methylpiperazin-1'-yl)-2-nitroaniline; (xi) treating 5-(4'-methylpiperazin-l'yl)-2-nitroaniline with Pd/C to produce 2-amino-4-(4'-methylpiperazin-1'-yl) aniline; (xii) refluxing a mixture of 2-amino-4-(4'-methylpiperazin-1'yl) aniline and ethyl-4-amino-3-nitrobenzenecarboximidate hydrochloride in presence of ethanol/glacial acetic acid to produce 4-[5'-(4'-methylpiperazin-1'-yl) 15 benzimidazol-2'-yl)-2-nitroaniline; (xiii) treating a solution of 4-[5'-(4'-methylpiperazin-1'-yi) benzimidazol-2'-yl)-2-nitroaniline with palladium on carbon to yield 2-amino-4-[5'-(4'-Methylpiperazin-1'-yl)benzimidazol-2'-yl]aniline; (xiv) heating 2-amino-4-[5'-(4'-Methylpiperazin-1'-yl)benzimidazol-2'-yl]aniline and 3-4-dimethoxy benzaldehyde using nitrobenzene as a solvent at 110-150°C to produce (DMA) i.e 5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'-benzimidazolyl] benzimidazole; (ix) heating 2-amino-4-[5'-(4'-Methylpiperazin-1'-yl) benzimidazol-2'-YI] aniline and 5-Formyl-[3-methoxy-4-hydroxy benzimidazole] using nitrobenzene at 110°C to 150°C in presence of argon to produce (TBZ) i.e 5-(4-methylpiperazine-1-yl)-2-[2' (2'-(4-hydroxy-3methoxyphenyl)5'benzimidazolyl) -5'- benzimidazolyl] benzimidazole.

  一种合成双苯并咪唑及其衍生物的方法，包括：(i)将5-氯苯胺与锌粉和乙酸酐反应，生成5-氯乙酰苯胺；(ii)将5-氯乙酰苯胺与硝酸反应，生成2-硝基-5-氯乙酰苯胺；(ix)将甲醇钠加入2-硝基-5-氯苯胺；(x)将2-硝基-5-氯苯胺、甲基哌嗪、无水K2CO3和二甲基甲酰胺加热至100-120°C，冷却后加入冰并过滤，得到5-(4'-甲基哌嗪基)-2-硝基苯胺；(xi)用Pd/C处理5-(4'-甲基哌嗪基)-2-硝基苯胺，得到2-氨基-4-(4'-甲基哌嗪基)苯胺；(xii)在乙醇/冰乙酸存在下，回流2-氨基-4-(4'-甲基哌嗪基)苯胺和乙酰基-4-氨基-3-硝基苯甲酰胺混合物，生成4-[5'-(4'-甲基哌嗪基)-2-硝基苯胺；(xiii)用碳载钯处理4-[5'-(4'-甲基哌嗪基)-2-硝基苯胺的溶液，得到2-氨基-4-[5'-(4'-甲基哌嗪基)苯并咪唑-2-基]苯胺；(xiv)将2-氨基-4-[5'-(4'-甲基哌嗪基)苯并咪唑-2-基]苯胺和3-4-二甲氧基苯甲醛在110-150°C下用硝基苯作溶剂加热，生成(DMA)即5-(4-甲基哌嗪基)-2-[2'-(3,4-二甲氧基苯基)-5'-苯并咪唑基]苯并咪唑；(ix)将2-氨基-4-[5'-(4'-甲基哌嗪基)苯并咪唑-2-基]苯胺和5-甲酰基-[3-甲氧基-4-羟基苯并咪唑]在110°C至150°C下用硝基苯在氩气存在下加热，生成(TBZ)即5-(4-甲基哌嗪基)-2-[2'-(2'-(4-羟基-3-甲氧基苯基)-5'-苯并咪唑基)-5'-苯并咪唑基]苯并咪唑。
• DMA, a bis-benzimidazole, confers radioprotection to the intestine via Akt/NFκB dual pathway activation
  申请人：Tandon Vibha

  公开号：US10016515B2

  公开（公告）日：2018-07-10

  The present invention relates to dual activation of Akt/NFκB pathway by DMA (5-(4-methylpiperazin-1-yl)-2-[2′-(3,4-dimethoxyphenyl)-5′-benzimidazolyl]benzimidazole) to render radioprotection both in mammalian cells and in Balb/c mice. Further it selectively protects normal cells overs tumor tissues against lethal total body irradiation (TBI) and there was no activation of Akt/NFκB pathway by DMA in response to radiation in tumor tissues. A single dose of DMA before TBI protect mice from GI and HP acute radiation syndrome (ARS) and offered radioprotection through oral, i.v., i.p., and s.c route of administration. The half life of DMA in plasma is 3.5 h at oral dose and 90% clearance was observed in 16 h. DMA accumulates in high concentration in intestine, liver, kidney and spleen tissues, justifying the observed radioprotection to normal tissue even at single dose. This data provide molecular rationale that DMA is selective radioprotector to normal tissue and has the potential to improve clinical outcome of radiotherapy, valuable as adjuvants in cancer therapy and management of radiation emergencies.

  本发明涉及DMA（5-(4-甲基哌嗪-1-基)-2-[2′-(3,4-二甲氧基苯基)-5′-苯并咪唑基]苯并咪唑）对Akt/NFκB通路的双重激活，从而在哺乳动物细胞和Balb/c小鼠体内产生辐射保护作用。此外，它还能选择性地保护正常细胞和肿瘤组织免受致命的全身辐照（TBI），而且在肿瘤组织的辐射反应中，DMA 不会激活 Akt/NFκB 通路。在全身照射前服用单剂量DMA可保护小鼠免于消化道和腹腔急性辐射综合征（ARS），并通过口服、静脉注射、静注和静脉给药途径提供辐射保护。口服剂量下，DMA在血浆中的半衰期为3.5小时，16小时内90%的清除率被观察到。DMA在肠、肝、肾和脾组织中的高浓度蓄积，证明了即使单剂量给药也能观察到对正常组织的辐射保护作用。这些数据从分子角度证明，DMA 对正常组织具有选择性放射保护作用，有可能改善放射治疗的临床效果，在癌症治疗和放射紧急情况处理中具有重要的辅助作用。
• Influence of Phenyl Ring Disubstitution on Bisbenzimidazole and Terbenzimidazole Cytotoxicity:  Synthesis and Biological Evaluation as Radioprotectors
  作者：Urmila Tawar、Akash K. Jain、B. S. Dwarakanath、Ramesh Chandra、Yogendra Singh、N. K. Chaudhury、Divya Khaitan、Vibha Tandon

  DOI：10.1021/jm030114w

  日期：2003.8.1

  DNA minor groove binders, Hoechst 33258 and Hoechst 33342, have been reported to protect against radiation-induced DNA-strand breakage, but their mutagenicity and cytotoxicity limit their use as protectors of normal tissue during radiotherapy and as biological radioprotectors during accidental radiation exposure. On the basis of these observations, two new nontoxic disubstituted benzimidazoles were synthesized, one having two methoxy groups (5-(4methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'-benzimidazolyllbenzimidazole, 5) and another having a methoxy and a hydroxyl group (5-(4-methylpiperazin-1-yl)-2- [2' 2"-(4-hydroxy-3-methoxyphenyl)-5"-benzimidazolyl)-5'-benzimidazolyllbenzimidazole, 6) ortho to each other on the phenyl ring. The radiomodifying effects of these nontoxic ligands were investigated with a human glioma cell line exposed to low linear energy transfer radiation by determining cell survival and cell proliferation compared with effects of the parent compound, Hoechst 33342. Cytotoxicity assayed by analyzing clonogenicity, cell growth, and metabolic viability showed that both 5 and 6 were nontoxic at 100 muM after 72 h of exposure, whereas Hoechst 33342 resulted in lysis of 77% of these cells in 24 h. Macrocolony assay (clonogenicity) showed that 73%, 92%, and 10% of the cells survived when treated with 100 muM 5, 6, and Hoechst 33342, respectively. Both 5 and 6 did not affect the growth of BMG-1 cells. At 10 muM, 5 and 6 showed 82% and 37% protection against radiation-induced cell death (macrocolony assay) while 100% protection was observed against growth inhibition. Disubstitution of the phenyl ring has not only reduced cytotoxicity but also enhanced DNA-ligand stability, conferring high degree of radioprotection.
• Ebrahimi, S. E. Sadat; Wilton, Amanda N.; Douglas, Kenneth T., Chemical Communications, 1997, # 4, p. 385 - 386
  作者：Ebrahimi, S. E. Sadat、Wilton, Amanda N.、Douglas, Kenneth T.

  DOI：——

  日期：——
• A PROCESS FOR THE SYNTHESIS OF BISBENZIMIDAZOLES AND THEIR DERIVATIVES.
  申请人：University of Delhi

  公开号：EP1590332B1

  公开（公告）日：2011-04-27