2,4-diamino-5-(4'-[2-aminoethylamino]-3'-nitrophenyl)-6-ethylpyrimidine | 123240-27-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2,4-diamino-5-(4'-[2-aminoethylamino]-3'-nitrophenyl)-6-ethylpyrimidine
• 英文别名: NSC 372939；5-[4-(2-Amino-ethylamino)-3-nitro-phenyl]-6-ethyl-pyrimidine-2,4-diamine；5-[4-(2-aminoethylamino)-3-nitrophenyl]-6-ethylpyrimidine-2,4-diamine
• CAS: 123240-27-7
• 化学式: C₁₄H₁₉N₇O₂
• 分子量: 317.351
• InChiKey: XYSUDZRZSXTBRQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  162
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2,4-diamino-5-(4'-[2-aminoethylamino]-3'-nitrophenyl)-6-ethylpyrimidine 在 tin(ll) chloride 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以62%的产率得到5-[3-Amino-4-(2-amino-ethylamino)-phenyl]-6-ethyl-pyrimidine-2,4-diamine
  参考文献：
  名称：

  生物活性化合物的结构研究。8.具有抗甲氨蝶呤抗性肿瘤细胞系的体内活性的一系列新的2，4-二氨基-5-芳基-6-乙基嘧啶二氢叶酸还原酶抑制剂的合成，晶体结构和生物学特性。

  摘要：

  合成了一系列在5-芳基环中包含碱性取代基的2,4-二氨基-5-芳基-6-乙基嘧啶，并评估了其对大鼠肝二氢叶酸还原酶（DHFR）的抑制活性。对于在苯环的4位带有苄氨基（19）或N-烷基苄基氨基取代基（29和30）而在3位带有硝基的化合物（相应的3-氨基，3-叠氮基或未取代的类似物，仅被证明是弱活性或无活性的DHFR抑制剂。还筛选了针对甲氨蝶呤耐药性肿瘤，M5076鼠网状肉瘤的体内所选化合物，以及针对DHFR，（3,4-二氯苄基）氨基类似物26的一般平行活性的抗肿瘤活性，该化合物被证明毒性最低，显示出显着的抗肿瘤活性。

  DOI：

  10.1021/jm00131a009
• 作为产物：
  描述：

  2,4-二氨基-5-(3-氨基-4-氯-5-硝基苯基)-6-乙基嘧啶 、 乙二胺 反应 6.0h， 以83%的产率得到2,4-diamino-5-(4'-[2-aminoethylamino]-3'-nitrophenyl)-6-ethylpyrimidine
  参考文献：
  名称：

  生物活性化合物的结构研究。8.具有抗甲氨蝶呤抗性肿瘤细胞系的体内活性的一系列新的2，4-二氨基-5-芳基-6-乙基嘧啶二氢叶酸还原酶抑制剂的合成，晶体结构和生物学特性。

  摘要：

  合成了一系列在5-芳基环中包含碱性取代基的2,4-二氨基-5-芳基-6-乙基嘧啶，并评估了其对大鼠肝二氢叶酸还原酶（DHFR）的抑制活性。对于在苯环的4位带有苄氨基（19）或N-烷基苄基氨基取代基（29和30）而在3位带有硝基的化合物（相应的3-氨基，3-叠氮基或未取代的类似物，仅被证明是弱活性或无活性的DHFR抑制剂。还筛选了针对甲氨蝶呤耐药性肿瘤，M5076鼠网状肉瘤的体内所选化合物，以及针对DHFR，（3,4-二氯苄基）氨基类似物26的一般平行活性的抗肿瘤活性，该化合物被证明毒性最低，显示出显着的抗肿瘤活性。

  DOI：

  10.1021/jm00131a009

文献信息

• Chemical synthesis and biological properties of novel fluorescent antifolates in pgp- and mrp-overexpressing tumour cell lines
  作者：Claire Robson、KarenA Wright、PeterR Twentyman、PeterA Lambert、RogerJ Griffin

  DOI：10.1016/s0006-2952(98)00068-9

  日期：1998.10

  We have synthesised a series of fluorescent analogues of methylbenzoprim, a diaminopyrimidine antifolate which we have previously shown to exhibit in vivo antitumour activity in a methotrexate (MTX) "transport-resistant" tumour cell line. The analogues bear the dansyl, nitrobenzoxodiazole or methoxycoumarin fluorophores. The cytotoxicity of the compounds was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay against two human lung cancer cell lines, together with their multidrug resistant (MDR) sublines. H69/P is a small cell line and its multidrug resistant subline H69/LX4 overexpresses P-glycoprotein (Pgp). COR-L23/P is a large cell line and its multidrug resistant subline COR-L23/R overexpresses the multidrug resistance associated protein (MRP). IC50 values for the compounds (i.e. concentration to reduce cell growth by 50%) in the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay ranged from 0.20 to 0.81 mu M in the H69 parental line and from 0.83 to 5.10 mu M in the COR-L23 parent line. The MDR sublines both showed clear cross-resistance to each of the compounds, with resistance factors (ratio of IC50 value in resistant vs parental cell line) ranging from 16 to 137 in H69/LX4 and from 5 to 16 in COR-L23/R. For compounds (10) and (11) where drug accumulation was studied using flow cytometry, resistance was associated with an approximately 10-fold reduction in cellular drug accumulation over a period of 30 min. The drug resistance modifiers verapamil (used at 6.6 mu M) and cyclosporin A (used at 4.2 mu M) were tested for their ability to sensitise the resistant lines. Whereas verapamil showed little activity, cyclosporin A partially restored the activity of compound (10), and fully restored the activity of compound (11) in H69/LX4 cells. This sensitisation of H69/LX4 by cyclosporin A was associated with a partial restoration of the drug accumulation deficit in this line. Hence, these novel lipophilic antifolates appear to be substrates for both the P-glycoprotein and MRP resistance mechanisms. Therefore, although they have been designed to overcome one mechanism of methotrexate resistance, namely impaired drug transport, this has been achieved only at the cost of rendering them susceptible to alternative mechanisms. BIOCHEM PHARMACOL 56;7:807-816, 1998. Crown Copyright (C) 1998. Published by Elsevier Science Inc.
• Structural studies on bioactive compounds. 8. Synthesis, crystal structure and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line
  作者：Roger J. Griffin、Michelle A. Meek、Carl H. Schwalbe、Malcolm F. G. Stevens

  DOI：10.1021/jm00131a009

  日期：1989.11

  A series of 2,4-diamino-5-aryl-6-ethylpyrimidines embracing basic substituents in the 5-aryl ring was synthesized and evaluated for inhibitory activity against rat liver dihydrofolate reductase (DHFR). Maximal enzyme inhibition was observed for compounds bearing a benzylamino (19) or N-alkylbenzylamino substituent (29 and 30) in the 4-position of the phenyl ring and a nitro group in the 3-position

  合成了一系列在5-芳基环中包含碱性取代基的2,4-二氨基-5-芳基-6-乙基嘧啶，并评估了其对大鼠肝二氢叶酸还原酶（DHFR）的抑制活性。对于在苯环的4位带有苄氨基（19）或N-烷基苄基氨基取代基（29和30）而在3位带有硝基的化合物（相应的3-氨基，3-叠氮基或未取代的类似物，仅被证明是弱活性或无活性的DHFR抑制剂。还筛选了针对甲氨蝶呤耐药性肿瘤，M5076鼠网状肉瘤的体内所选化合物，以及针对DHFR，（3,4-二氯苄基）氨基类似物26的一般平行活性的抗肿瘤活性，该化合物被证明毒性最低，显示出显着的抗肿瘤活性。