O-6-[2-(aminomethyl)benzyl]guanine | 948903-70-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: O-6-[2-(aminomethyl)benzyl]guanine
• 英文别名: O6-[2-(Aminomethyl)benzyl]guanine；6-[[2-(aminomethyl)phenyl]methoxy]-7H-purin-2-amine
• CAS: 948903-70-6
• 化学式: C₁₃H₁₄N₆O
• 分子量: 270.294
• InChiKey: ZPNFLTRENSJFNF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  O-6-[2-(aminomethyl)benzyl]guanine 以 水 为溶剂， 反应 168.0h， 生成 N6-[2-(hydroxymethyl)benzyl]-2-aminoadenine
  参考文献：
  名称：

  Substitution of Aminomethyl at the Meta-Position Enhances the Inactivation of O⁶-Alkylguanine-DNA Alkyltransferase by O⁶-Benzylguanine

  摘要：

  O-6-Benzylguanine is an irreversible inactivator of O-6-alkylguanine-DNA alkyltransferase currently in clinical trials to overcome alkyltransferase-mediated resistance to certain cancer chemotherapeutic alkylating agents. In order to produce more soluble alkyltransferase inhibitors, we have synthesized three aminomethyl-substituted O-6-benzylguanines and the three methyl analogs and found that the substitution of aminomethyl at the meta-position greatly enhances inactivation of alkyltransferase, whereas para-substitution has little effect and ortho-substitution virtually eliminates activity. Molecular modeling of their interactions with alkyltransferase provided a molecular explanation for these results. The square of the correlation coefficient (R-2) obtained between E-model scores (obtained from GLIDE XP/QPLD docking calculations) vs log(ED50) values via a linear regression analysis was 0.96. The models indicate that the ortho-substitution causes a steric clash interfering with binding, whereas the meta-aminomethyl substitution allows an interaction of the amino group to generate an additional hydrogen bond with the protein.

  DOI：

  10.1021/jm800675p
• 作为产物：
  描述：

  2-[(trifluoroacetamido)methyl]benzyl alcohol 在 potassium tert-butylate 、 potassium carbonate 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 O-6-[2-(aminomethyl)benzyl]guanine
  参考文献：
  名称：

  一种β-氯乙基亚硝基脲类化合物及其合成方法 和用途

  摘要：

  本发明涉及一种新型的β-氯乙基亚硝基脲类化合物及其合成方法和用途，所述β-氯乙基亚硝基脲类化合物的结构如通式(Ⅱ)所示。本发明对通式Ⅱ中的化合物进行了体外抗肿瘤筛选试验。结果表明，通式Ι中的化合物对人脑神经胶质瘤细胞SF763、SF767、SF126、SF188，人结肠癌细胞HT29和小鼠白血病细胞L1210等多种肿瘤细胞系均有明显的抑制作用，且比现有的CENU及其与O6-苄基鸟嘌呤的联合用药具有更高的肿瘤抑制活性。

  公开号：

  CN104031048B

文献信息

• O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE INACTIVATORS AND BETA-GLUCURONIDASE CLEAVABLE PRODRUGS
  申请人：MOSCHEL C. Robert

  公开号：US20070213279A1

  公开（公告）日：2007-09-13

  Disclosed are prodrugs of inactivators of O 6 -alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the β-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring-substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted O 6 -benzylguanine or O 6 -benzyl-2′-deoxyguanosine, Also disclosed are additional inactivators of AGT, pharmaceutical compositions comprising an inactivator or prodrug and a pharmaceutically acceptable carrier, and a method of use of the inactivator or prodrug in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6 -position of guanine.

  本发明公开了O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）不活化剂的前药。这些前药可被β-葡萄糖醛酸酶酶水解，该酶可由患者口服或由坏死的肿瘤细胞产生。该前药的化学式为A-B-C，其中A是葡萄糖醛酸残基，通过其1-氧原子与B的苯环连接；B是苄氧羰基基团，可选地带有一个或多个电子吸引基；C是AGT的不活化剂，例如取代或未取代的O6-苄基鸟嘌呤或O6-苄基-2'-脱氧鸟苷。本发明还公开了其他AGT不活化剂、包含不活化剂或前药及其药学可接受载体的制药组合物，以及在使用抗肿瘤烷基化剂在哺乳动物（例如人类）中增强肿瘤细胞的化疗治疗中使用不活化剂或前药的方法。
• US7825096B2
  申请人：——

  公开号：US7825096B2

  公开（公告）日：2010-11-02
• 一种β-氯乙基亚硝基脲类化合物及其合成方法 和用途
  申请人：北京工业大学

  公开号：CN104031048B

  公开（公告）日：2016-03-09

  本发明涉及一种新型的β-氯乙基亚硝基脲类化合物及其合成方法和用途，所述β-氯乙基亚硝基脲类化合物的结构如通式(Ⅱ)所示。本发明对通式Ⅱ中的化合物进行了体外抗肿瘤筛选试验。结果表明，通式Ι中的化合物对人脑神经胶质瘤细胞SF763、SF767、SF126、SF188，人结肠癌细胞HT29和小鼠白血病细胞L1210等多种肿瘤细胞系均有明显的抑制作用，且比现有的CENU及其与O6-苄基鸟嘌呤的联合用药具有更高的肿瘤抑制活性。
• Substitution of Aminomethyl at the Meta-Position Enhances the Inactivation of <i>O</i>⁶-Alkylguanine-DNA Alkyltransferase by <i>O</i>⁶-Benzylguanine
  作者：Gary T. Pauly、Natalia A. Loktionova、Qingming Fang、Sai Lakshmana Vankayala、Wayne C. Guida、Anthony E. Pegg

  DOI：10.1021/jm800675p

  日期：2008.11.27

  O-6-Benzylguanine is an irreversible inactivator of O-6-alkylguanine-DNA alkyltransferase currently in clinical trials to overcome alkyltransferase-mediated resistance to certain cancer chemotherapeutic alkylating agents. In order to produce more soluble alkyltransferase inhibitors, we have synthesized three aminomethyl-substituted O-6-benzylguanines and the three methyl analogs and found that the substitution of aminomethyl at the meta-position greatly enhances inactivation of alkyltransferase, whereas para-substitution has little effect and ortho-substitution virtually eliminates activity. Molecular modeling of their interactions with alkyltransferase provided a molecular explanation for these results. The square of the correlation coefficient (R-2) obtained between E-model scores (obtained from GLIDE XP/QPLD docking calculations) vs log(ED50) values via a linear regression analysis was 0.96. The models indicate that the ortho-substitution causes a steric clash interfering with binding, whereas the meta-aminomethyl substitution allows an interaction of the amino group to generate an additional hydrogen bond with the protein.