5-[bis(2-bromoethyl)amino]-N-(2,3-dihydroxypropyl)-2,4-dinitrobenzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-[bis(2-bromoethyl)amino]-N-(2,3-dihydroxypropyl)-2,4-dinitrobenzamide
• 化学式: C₁₄H₁₈Br₂N₄O₇
• 分子量: 514.128
• InChiKey: YERSJWXVDXCPCP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  164
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  methyl 5-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoate 在 氢氧化钾 、 氯化亚砜 、 N,N-二甲基甲酰胺 、 lithium bromide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙酸乙酯 为溶剂， 反应 3.42h， 生成 5-[bis(2-bromoethyl)amino]-N-(2,3-dihydroxypropyl)-2,4-dinitrobenzamide
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships for 2,4-Dinitrobenzamide-5-mustards as Prodrugs for the Escherichia coli nfsB Nitroreductase in Gene Therapy

  摘要：

  A series of 2,4-dinitrobenzamide mustards were prepared from 5-chloro-2,4-dinitrobenzoic acid or the corresponding 5-dimesylate mustard as potential prodrugs for gene-directed enzyme prodrug therapy (GDEPT) with the E. coli nfsB nitroreductase (NTR). The compounds, including 32 new examples, were evaluated in four pairs of NTR+ve/-ve cell lines for selective cytotoxicity (IC50 and IC50 ratios), in multicellular layer (MCL) cultures for bystander effects, and for in vivo activity against tumors grown from stably NTR transfected EMT6 and WiDr cells in nude mice. Multivariate regression analysis of the IC50 results was undertaken using a partial least-squares projection to latent structures model. In NTR-ve lines, cytotoxicity correlated positively with logP, negatively with hydrogen bond acceptors (HA) and donors (HD) in the amide side chain, and positively with the reactivity of the less-reactive leaving group of the mustard function, likely reflecting toxicity due to DNA monoadducts. Potency and selectivity for NTR+ve lines was increased by logP and HD, decreased by HA, and was positively correlated with the leaving group efficiency of the more-reactive group, likely reflecting DNA crosslinking. NTR selectivity was greatest for asymmetric chloro/mesylate and bromo/mesylate mustards. Bystander effects in the MCL assay also correlated positively with logP and negatively with leaving group reactivity, presumably reflecting the transcellular diffusion/reaction properties of the activated metabolites. A total of 18 of 22 mustards showed equal or greater bystander efficiencies in MCLs than the aziridinylbenzamide CB 1954, which is currently in clinical trial for NTR-GDEPT. The dibromo and bromomesylate mustards were surprisingly well tolerated in mice. High MTD/IC50 (NTR+ve) ratios translated into curative activity of several compounds against NTR+ve tumors. A bromomesylate mustard showed superior activity against WiDr tumors grown from 1:9 mixtures of NTR+ve and NTR-ve cells, indicating a strong bystander effect in vivo.

  DOI：

  10.1021/jm061062o

文献信息

• [EN] NITROANILINE-BASED ALKYLATING AGENTS AND THEIR USE AS PRODRUGS<br/>[FR] AGENTS D'ALKYLATION A BASE DE NITROANILINE ET LEUR UTILISATION EN TANT QUE PROMEDICAMENTS
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2004033415A1

  公开（公告）日：2004-04-22

  Nitroaniline-based unsymmetrical mustards of the general formula (I) are provided, together with methods of preparation and methods for their use as produgs for gene-dependent enzyme prodrug therapy (GDEPT) and cell ablation therapy in conjuction with nitroreductase enzymes as hypoxia selective cytotoxins and as anticancer agents.

  基于硝基苯胺的不对称芥末化合物，其通用公式为（I），以及它们的制备方法和使用方法，作为基因依赖性酶前药治疗（GDEPT）和与硝基还原酶酶结合的细胞消融治疗的药物，以及作为缺氧选择性细胞毒素和抗癌药物的使用方法。
• Nitroaniline-based alkylating agents and their use as prodrugs
  申请人：Denny Alexander William

  公开号：US20050256191A1

  公开（公告）日：2005-11-17

  Nitroaniline-based unsymmetrical mustards of the general formula (I) are provided, together with methods of preparation and methods for their use as prodrugs for gene-dependent enzyme prodrug therapy (GDEPT) and cell ablation therapy in conjunction with nitroreductase enzymes as hypoxia selective cytotoxins and as anticancer agents.

  提供了基于硝基苯胺的不对称芥子气的一般式（I），以及其制备方法和用作基因依赖性酶前药治疗（GDEPT）和细胞消融治疗的前药的方法，与硝酸还原酶酶一起使用作为缺氧选择性细胞毒素和抗癌剂。
• Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents
  申请人：Denny William Alexander

  公开号：US20100010094A1

  公开（公告）日：2010-01-14

  The present invention relates to novel nitrophenyl mustard and nitrophenylaziridine alcohols, to their corresponding phosphates, to their use as targeted cytotoxic agents; as bioreductive drugs in hypoxic tumours, and to their use in cell ablation, including gene-directed enzyme-prodrug therapy (GDEPT) and antibody-directed enzyme-prodrug therapy (ADEPT), in conjunction with nitroreductase enzymes.

  本发明涉及新型的硝基苯基芥和硝基苯基环氧丙烷醇，它们对应的磷酸盐，以及它们作为靶向细胞毒性药物的使用；作为缺氧肿瘤中的生物还原药物，并结合硝酸还原酶酶使用于细胞消融，包括基因定向酶前药物治疗（GDEPT）和抗体定向酶前药物治疗（ADEPT）。
• NITROANILINE-BASED ALKYLATING AGENTS AND THEIR USE AS PRODRUGS
  申请人：Auckland Uniservices Limited

  公开号：EP1558568A1

  公开（公告）日：2005-08-03
• EP1558568A4
  申请人：——

  公开号：EP1558568A4

  公开（公告）日：2006-10-18