3-((4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)oxy)propyl N,N-bis(2-chloroethyl)phosphorodiamidate

• 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: 3-((4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)oxy)propyl N,N-bis(2-chloroethyl)phosphorodiamidate
• 英文别名: 6-[3-[amino-[bis(2-chloroethyl)amino]phosphoryl]oxypropoxy]-N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]quinazolin-4-amine
• 化学式: C₂₈H₃₀Cl₃FN₅O₄P
• 分子量: 656.908
• InChiKey: UWXPWGQSXVNVTA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  42
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  4-氯-6-碘喹唑啉 在 copper(l) iodide 、 正丁基锂 、 三乙胺 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 正己烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 31.5h， 生成 3-((4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)oxy)propyl N,N-bis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs

  摘要：

  A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose). (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.12.055

文献信息

• Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs
  作者：Songwen Lin、Yingbo Li、Yufen Zheng、Laichun Luo、Qi Sun、Zemei Ge、Tieming Cheng、Runtao Li

  DOI：10.1016/j.ejmech.2016.12.055

  日期：2017.2

  A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose). (C) 2017 Elsevier Masson SAS. All rights reserved.