2-{4-[6-bis(2-chloroethyl)amino-3-methylbenzo[d]imidazol-2-yl]butanoyl}oxyethylmaleimide | 1297582-82-1

• 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-{4-[6-bis(2-chloroethyl)amino-3-methylbenzo[d]imidazol-2-yl]butanoyl}oxyethylmaleimide
• 英文别名: Bendamustine-maleimide ester；2-(2,5-dioxopyrrol-1-yl)ethyl 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoate
• CAS: 1297582-82-1
• 化学式: C₂₂H₂₆Cl₂N₄O₄
• 分子量: 481.379
• InChiKey: DDWQUASJLCRUBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  32
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  84.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-{4-[6-bis(2-chloroethyl)amino-3-methylbenzo[d]imidazol-2-yl]butanoyl}oxyethylmaleimide 、 1,3,5-tris(3-aminopropyl)benzene 在 N,N-二异丙基乙胺 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 72.0h， 以79%的产率得到1,3,5-tris{3-{N-{2-{4-[6-bis(2-chloroethyl)amino-3-methylbenzo[d]imidazol-2-yl]butanoyl}oxyethyl}-2,5-dioxopyrrolidine-3-ylamino}propyl}benzene
  参考文献：
  名称：

  Optimization of the N-Lost Drugs Melphalan and Bendamustine: Synthesis and Cytotoxicity of a New Set of Dendrimer−Drug Conjugates as Tumor Therapeutic Agents

  摘要：

  Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3-aminopropyl)-N-(3-{3,5-bis[3-{3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB-231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2-hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro.

  DOI：

  10.1021/bc900453f
• 作为产物：
  描述：

  N-(2-羟乙基)马来酰亚胺 、 宾达氮芥 在 O-[(cyano(ethoxycarbonyl)methylidene)amino]-1,1,3,3-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以1.08 g的产率得到2-{4-[6-bis(2-chloroethyl)amino-3-methylbenzo[d]imidazol-2-yl]butanoyl}oxyethylmaleimide
  参考文献：
  名称：

  负载羧酸抗肿瘤药物的PEG化肝素纳米胶束 及其制备方法

  摘要：

  本发明公开了一种负载羧酸抗肿瘤药物的PEG化肝素纳米胶束，该载药系统为羧酸抗肿瘤药物加载在PEG化肝素分子上的偶联物。将生物可降解、相容性好、利用度高的天然多糖肝素作为药物载体，通过结合PEG改性和羧酸抗肿瘤药物，纳米粒子在体内治疗中呈现出比游离药物显著增强的抗肿瘤治疗指数和生物安全性。

  公开号：

  CN112121177B

文献信息

• Bivalent bendamustine and melphalan derivatives as anticancer agents
  作者：Ana Maria Scutaru、Maxi Wenzel、Ronald Gust

  DOI：10.1016/j.ejmech.2011.02.008

  日期：2011.5

  The alkylating agents bendamustine and melphalan are currently used in the treatment of various tumoral diseases. In order to increase their antitumor potency and tumor selectivity both compounds were integrated in structure activity relationship studies including new drug carrier systems. Here we describe the synthesis and the cytotoxicity of new bivalent bendamustine and melphalan derivatives. Two molecules each esterified with N-(2-hydroxyethyl)maleimide were connected by diamines with various chain lengths (n = 6, 7, 8, 12). It was supposed that these conjugates (5a-d, 10a-d, 11a-d) cause cytotoxic effects preferred as bivalent drug. Indeed the cytotoxicity of the new compounds increased compared to bendamustine and melphalan as determined in concentration-dependent in vitro assays using the human MCF-7 and MDA-MB-231 breast cancer cell lines. (C) 2011 Elsevier Masson SAS. All rights reserved.
• Bendamustine–PAMAM Conjugates for Improved Apoptosis, Efficacy, and <i>in Vivo</i> Pharmacokinetics: A Sustainable Delivery Tactic
  作者：Avinash Gothwal、Iliyas Khan、Pramod Kumar、Kaisar Raza、Ankur Kaul、Anil Kumar Mishra、Umesh Gupta

  DOI：10.1021/acs.molpharmaceut.7b00625

  日期：2018.6.4

  Successful delivery of a chemotherapeutic agent like bendamustine still remains a challenge in clinical conditions like chronic lymphatic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma. We have conjugated bendamustine to polyamidoamine (PAMAM) dendrimers after conjugating with N-(hydroxyethyl)maleimide (spacer) via an ester bond. The particle size of PAMAM bendamustine conjugate was 49.8 +/- 2.5 nm. In vitro drug release resulted in sustained release with improved solution stability of drug up to 72 h. In a 24 h cytotoxicity study by MTT assay against human monoblastic leukemia cells (THP-1), the IC50 value for PAMAM bendamustine was 32.1 +/- 4.8 mu M compared to 50.42 +/- 3.4 mu M and 2303 +/- 106.5 mu M for bendamustine and PAMAM dendrimer, respectively. Significantly higher cell uptake and apoptosis were observed in THP-1 cells by PAMAM bendamustine conjugate which was confirmed by flow cytometry and confocal laser scanning microscopy. Preliminary in vivo studies undertaken included pharmacokinetics studies, organ distribution studies, and tumor inhibition studies. In healthy Wistar rat model (ICBM IV push model), the pharmacokinetic studies revealed that bioavailability and t(1/2) increased significantly, i.e., almost 8.5-fold (193.8 +/- 1.116 vs 22.8 +/- 0.158 mu g mL(-1)/h) and 5.1-fold (0.75 +/- 0.005 vs 3.85 +/- 0.01S h), respectively, for PAMAM bendamustine conjugate compared to pure bendamustine (p < 0.05), however, clearance and volume of distribution were found to be decreased compared to those of free drug. The study suggests that PAMAM bendamustine conjugate was not only stable for the longer period but also least toxic and highly taken up by THP-1 cells to exert an anticancer effect at the reduced dose. Tumor inhibition and biodistribution studies in tumor-bearing BALB/c mice revealed that PAMAM bendamustine conjugate was more effective than the pure drug and showed higher accumulation in the tumor.
• 负载羧酸抗肿瘤药物的PEG化肝素纳米胶束 及其制备方法
  申请人：健进制药有限公司

  公开号：CN112121177B

  公开（公告）日：2021-09-14

  本发明公开了一种负载羧酸抗肿瘤药物的PEG化肝素纳米胶束，该载药系统为羧酸抗肿瘤药物加载在PEG化肝素分子上的偶联物。将生物可降解、相容性好、利用度高的天然多糖肝素作为药物载体，通过结合PEG改性和羧酸抗肿瘤药物，纳米粒子在体内治疗中呈现出比游离药物显著增强的抗肿瘤治疗指数和生物安全性。
• Optimization of the N-Lost Drugs Melphalan and Bendamustine: Synthesis and Cytotoxicity of a New Set of Dendrimer−Drug Conjugates as Tumor Therapeutic Agents
  作者：Ana Maria Scutaru、Maxi Wenzel、Heike Scheffler、Gerhard Wolber、Ronald Gust

  DOI：10.1021/bc900453f

  日期：2010.10.20

  Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3-aminopropyl)-N-(3-3,5-bis[3-3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB-231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2-hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro.