ZR2002

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: ZR2002
• 英文别名: N⁴-(3-bromophenyl)-N⁶-(2-chloroethyl)quinazoline-4,6-diamine；N4-(3-Bromophenyl)-N6-(2-chloroethyl)-4,6-quinazolinediamine；4-N-(3-bromophenyl)-6-N-(2-chloroethyl)quinazoline-4,6-diamine
• 化学式: C₁₆H₁₄BrClN₄
• 分子量: 377.671
• InChiKey: NPLZGCKBBUBACR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 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：

  2-氰基-4-硝基苯胺 在 盐酸 、 乙醇 、 铁粉 、 sodium cyanoborohydride 、 氯化铵 、 溶剂黄146 作用下， 以 甲醇 、 水 为溶剂， 生成 ZR2002
  参考文献：
  名称：

  EGFR/DNA双靶向策略治疗EGFRL858R/T790M突变肺癌的抗肿瘤活性及机制

  摘要：

  双靶点或多靶点 EGFR 抑制剂作为单一药物可以克服 EGFR 抑制剂耐药性并规避联合治疗的许多缺点。在这项工作中，设计并合成了 15 个带有氮芥或半芥部分的 4-苯胺基喹唑啉衍生物作为双 EGFR-DNA 靶向抗癌剂。目标分子的结构通过1 H NMR、13 C NMR 和 HR-MS确证，并使用 MTT 法评估其体外抗增殖活性。化合物6g成为针对突变型 H1975 细胞的最有效衍生物，IC 为50值为 1.45 μM，其效力比 Chl/Gef（苯丁酸氮芥和吉非替尼的等摩尔组合）强 4 倍。激酶抑制研究表明，6g对 EGFR L858R/T790M酶有极好的抑制作用，是吉非替尼的 8.6 倍。机理研究表明，6g以剂量依赖的方式诱导 H1975 细胞凋亡，并引起 DNA 损伤。重要的是，6g可显着抑制H1975细胞中p-EGFR及其下游p-AKT和p-ERK的表达。还进行了分子对接以深入了解EGFR

  DOI：

  10.1016/j.bioorg.2023.106510

文献信息

• Novel combi-molecules having EGFR and DNA targeting properties
  申请人：Jean-Claude Bertrand

  公开号：US20060003970A1

  公开（公告）日：2006-01-05

  A series of new chemical agents that demonstrate anti-tumor activity are described. The new chemical agents combine two major mechanisms of anti-tumor action. In an embodiment, the agents are capable of both inhibiting EGFR and damaging DNA while also, upon degradation, degrading to an inhibitor of EGFR and to an agent capable of damaging DNA. Moreover, a novel series of molecules capable of releasing two moles of EGFR inhibitor and a potent bi-functional alkylating agent are also described.

  描述了一系列展示抗肿瘤活性的新化学试剂。这些新化学试剂结合了两种主要的抗肿瘤作用机制。在一个实施例中，这些试剂既能够抑制EGFR又能够损伤DNA，同时，在降解时，会降解为EGFR抑制剂和能够损伤DNA的试剂。此外，还描述了一系列新颖的分子，能够释放两摩尔的EGFR抑制剂和一种强效的双功能烷基化剂。
• Comparative analysis of the dual EGFR-DNA targeting and growth inhibitory properties of 6-mono-alkylamino- and 6,6-dialkylaminoquinazoline-based type II combi-molecules
  作者：Julie Schmitt、Elliot Goodfellow、Shanlong Huang、Christopher Williams、Izabela N.F. Gomes、Marcela N. Rosa、Rui M. Reis、Richard Yang、Hatem M. Titi、Bertrand J. Jean-Claude

  DOI：10.1016/j.ejmech.2020.112185

  日期：2020.4

  Over the past decade, we described a novel tumour targeted approach that sought to design "combimolecules" to hit two distinct targets in tumour cells. Here, to generate small combi-molecules with strong DNA damaging potential while retaining EGFR inhibitory potency, we developed the first synthetic strategy to access the 6-N, N-disubstituted quinazoline scaffold and designed JS61 to possess a nitrogen mustard function directly attached to the 6-position of the quinazoline ring. We compared its biological activity with that of structures containing either a hemi mustard or a non-alkylating substituent. Surprisingly, the results showed that JS61, while capable of inducing strong DNA damage, exhibited moderate EGFR inhibitory potency. In contrast, "combi-molecules" with no bulky substituent at the N-6 position (e.g. ZR2002 and JS84) showed stronger EGFR and growth inhibitory potency than JS61 in a panel of lung cancer cells. To rationalize these results, X-ray crystallography and molecular modeling studies were undertaken, and the data obtained indicated that bulkiness of the 6-N,N-disubstituted moieties hinder its binding to the ATP site and affects binding reversibility. (c) 2020 Published by Elsevier Masson SAS.
• Novel Nitrogen Mustard-Armed Combi-Molecules for the Selective Targeting of Epidermal Growth Factor Receptor Overexperessing Solid Tumors:  Discovery of an Unusual Structure−Activity Relationship
  作者：Zakaria Rachid、Fouad Brahimi、Qiyu Qiu、Christopher Williams、Janet M. Hartley、John A. Hartley、Bertrand J. Jean-Claude

  DOI：10.1021/jm070144p

  日期：2007.5.1

  To enhance the potency of "combi-molecules", we designed 6a-d and 18 to release an inhibitor of EGFR TK and a bifunctional alkylator. The combi-molecules blocked EGFR TK with potency increasing with the basicity of the mustard moiety. They selectively killed cells transfected with EGFR and were potent against the DU145 prostate cancer cells. Combi-molecule 6a blocked EGFR phosphorylation in an irreversible manner, induced DNA-cross-links, and arrested the cells in mid-S.
• Synthesis of half-mustard combi-molecules with fluorescence properties: correlation with EGFR status
  作者：Zakaria Rachid、Fouad Brahimi、Juozas Domarkas、Bertrand Jacques Jean-Claude

  DOI：10.1016/j.bmcl.2004.12.015

  日期：2005.2

  The synthesis of 6-(2-chloroethylamino)-4-anilinoquinazolines ZR2002 and ZR2003 designed to block EGFR tyrosine kinase and to damage genomic DNA is described. These compounds present fluorescence properties that permitted the quantitation of their subcellular uptake by flow cytometry. Fluorescence intensities increased with increasing levels of EGFR in a panel of isogenic and established cell lines. (C) 2004 Elsevier Ltd. All rights reserved.
• US7879861B2
  申请人：——

  公开号：US7879861B2

  公开（公告）日：2011-02-01