diethyl N-[4-[[2-(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate | 939436-99-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: diethyl N-[4-[[2-(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate
• 英文别名: diethyl N-{4-[(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl}-L-glutamate；diethyl (2S)-2-[[4-[(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]amino]pentanedioate
• CAS: 939436-99-4
• 化学式: C₂₄H₃₃N₇O₅
• 分子量: 499.57
• InChiKey: XAMFXQVPECOAGV-DAFXYXGESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  36
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  184
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  diethyl N-[4-[[2-(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate 在 溴 、 碳酸氢钠 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 diethyl N-[4-[[2-(2,4-diamino-5-(2,3-dibromopropane)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]3-bromo-benzoyl]-L-glutamate
  参考文献：
  名称：

  通过氮丙啶中间体新型合成 8-Deaza-5,6,7,8-四氢氨基蝶呤类似物

  摘要：

  描述了一种构建四氢叶酸骨架的有效方法。从蝶呤类似物和芳香胺开始，通过新型氮丙啶中间体合成了 8-deaza-5,6,7,8-四氢氨基蝶呤衍生物和杂环苯甲酰基等排体。采用这种方法可以完全避免传统合成策略中碳氮键氢解的副产物。

  DOI：

  10.3390/molecules17055604
• 作为产物：
  描述：

  2,4-二氯-吡啶并(3,2-d)嘧啶-6-甲醇乙酸酯(酯) 在 platinum(IV) oxide 、 氨 、 氢气 、 三溴化磷 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基乙酰胺 为溶剂， 20.0~150.0 ℃ 、400.01 kPa 条件下， 反应 48.0h， 生成 diethyl N-[4-[[2-(2,4-diamino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamate
  参考文献：
  名称：

  N 5取代的四氢叶酸类似物作为钴胺素依赖性蛋氨酸合酶抑制剂和潜在抗癌药的基于机理的设计，合成和生物学研究

  摘要：

  基于蛋氨酸合酶的作用机理，设计合成了许多在N 5上带有亲电基团的8-脱氮氢叶酸，并对其生物学活性进行了研究。化合物（11b，12b和16）对甲硫氨酸合酶表现出最强的活性（IC 50：8.11μM，1.73μM，1.43μM）。此外，还评估了目标化合物对人肿瘤细胞系的细胞毒性和二氢叶酸还原酶（DHFR）的抑制作用。

  DOI：

  10.1016/j.ejmech.2012.09.027

文献信息

• Synthesis, Antifolate and Anticancer Activities of<i>N</i>^<i>5</i>-Substituted 8,10-Dideazatetrahydrofolate Analogues
  作者：Chao Tian、Zhili Zhang、Shouxin Zhou、Mengmeng Yuan、Xiaowei Wang、Junyi Liu

  DOI：10.1111/cbdd.12681

  日期：2016.3

  previous work, seven N(5) -substituted 8,10-dideazatetrahydrofolate analogues and one 8-deazatetrahydrofolate analogue were designed and synthesized as human dihydrofolate reductase (hDHFR) inhibitors. All compounds were assayed versus DHFR and five different cancer cell lines. The biological assay indicated that replacing N(10) with carbon would significantly increase inhibitory activities against DHFR and

  根据我们之前的工作，设计并合成了7种N（5）-取代的8,10-二叠氮基氢叶酸类似物和一种8-脱氮基氢叶酸类似物作为人二氢叶酸还原酶（hDHFR）抑制剂。针对DHFR和五种不同的癌细胞系分析了所有化合物。生物学测定表明，用碳取代N（10）将显着增加对DHFR的抑制活性和对癌细胞系的细胞毒性。具有4-氨基和N（5）-甲酰基的化合物19a对HL-60，Bel-7402和BGC823表现出极大的抗肿瘤活性，远优于MTX。
• Novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives as dihydrofolate inhibitor: Design, synthesis and antifolate activity
  作者：Zhili Zhang、Jun Wu、Fuxiang Ran、Ying Guo、Ran Tian、Shouxin Zhou、Xiaowei Wang、Zhenming Liu、Liangren Zhang、Jingrong Cui、Junyi Liu

  DOI：10.1016/j.ejmech.2008.04.017

  日期：2009.2

  We report, for the first time, the synthesis and biological activities of 8-deaza-5,6,7,8-tetrahydroaminopterin 9, and the 5-substituted and 5,10-disubstituted analogues 11, 13, 15, and 17. The analogues were obtained from key compound diethyl 8-deaza-5,6,7,8-tetrahydroaminopterin 8 following the catalytic reduction of the pyridine ring of diethyl 8-deaza aminopterin 5. The five novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives were assayed in vitro for their cytotoxicity on BGC-823, HL-60, Bel-7402 and Hela tumor cell lines, and inhibition on recombinant human dihydrofolate reductase (DHFR), among which the most potent molecule (compound 9) was about 4- to 10-fold poorer than MTX on the four kinds of tumor cell lines, and its effect on DHFR was about 17-fold poorer than MTX. The docking studies were followed to explain the biological testing results. (c) 2008 Elsevier Masson SAS. All rights reserved.
• Mechanism-based design, synthesis and biological studies of N5-substituted tetrahydrofolate analogs as inhibitors of cobalamin-dependent methionine synthase and potential anticancer agents
  作者：Zhili Zhang、Chao Tian、Shouxin Zhou、Wei Wang、Ying Guo、Jie Xia、Zhenming Liu、Biao Wang、Xiaowei Wang、Bernard T. Golding、Roger J. Griff、Yansheng Du、Junyi Liu

  DOI：10.1016/j.ejmech.2012.09.027

  日期：2012.12

  8-deazatetrahydrofolates bearing electrophilic groups on N5 were designed and synthesized based on the action mechanism of methionine synthase, and their biological activities were investigated as well. Compounds (11b, 12b and 16) showed the most active against methionine synthase (IC50: 8.11 μM, 1.73 μM, 1.43 μM). In addition, the cytotoxicity to human tumor cell lines and dihydrofolate reductase (DHFR)

  基于蛋氨酸合酶的作用机理，设计合成了许多在N 5上带有亲电基团的8-脱氮氢叶酸，并对其生物学活性进行了研究。化合物（11b，12b和16）对甲硫氨酸合酶表现出最强的活性（IC 50：8.11μM，1.73μM，1.43μM）。此外，还评估了目标化合物对人肿瘤细胞系的细胞毒性和二氢叶酸还原酶（DHFR）的抑制作用。
• Novel Synthesis of 8-Deaza-5,6,7,8-tetrahydroaminopterin Analogues via an Aziridine Intermediate
  作者：Shouxin Zhou、Chao Tian、Chao Li、Ying Guo、Xiaowei Wang、Junyi Liu、Zhili Zhang

  DOI：10.3390/molecules17055604

  日期：——

  An efficient method for the construction of the tetrahydrofolate skeleton is described. Starting from pterin analogues and aromatic amines, 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives and the heterocyclic benzoyl isosteres were synthesized via a novel aziridine intermediate. Following this method, the byproducts of carbon-nitrogen bond hydrogenolysis in traditional synthetic strategy can be completely

  描述了一种构建四氢叶酸骨架的有效方法。从蝶呤类似物和芳香胺开始，通过新型氮丙啶中间体合成了 8-deaza-5,6,7,8-四氢氨基蝶呤衍生物和杂环苯甲酰基等排体。采用这种方法可以完全避免传统合成策略中碳氮键氢解的副产物。