O₆-(p-fluorobenzyl)guanine

• 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: O₆-(p-fluorobenzyl)guanine
• 英文别名: 6-[(4-fluorophenyl)methoxy]-7H-purin-2-amine
• 化学式: C₁₂H₁₀FN₅O
• 分子量: 259.243
• InChiKey: PBBYGMLEPNAXFG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  89.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  苯硫酚 、 O₆-(p-fluorobenzyl)guanine 在 三乙胺 作用下， 以 甲醇 为溶剂， 生成 鸟嘌呤 、 4-氟代苄基-硫苯
  参考文献：
  名称：

  O6-芳基甲基鸟嘌呤增强氯乙基亚硝基脲的细胞毒性。

  摘要：

  最近有报道说，单体O6-苄基鸟嘌呤（1）作为DNA修复酶O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）的替代底物，因此用1预处理细胞会诱导AGT耗竭，从而增加细胞毒性。对烷基化抗肿瘤药的反应。为了研究O6-苄基鸟嘌呤衍生物与AGT的相互作用并获得更大的AGT消耗，我们合成了以下O6-芳基甲基鸟嘌呤衍生物和相关化合物：O6-（4-，3-和2-氟苄基）鸟嘌呤（2，3 ，4），O6-（4-，3-和2-三氟甲基苄基）鸟嘌呤（5、6、7），O6-（4-，3-和2-吡啶基甲基）鸟嘌呤（8、9、10），O6- （2-和1-萘甲基甲基）鸟嘌呤（11、12），O6-联苯基甲基鸟嘌呤（13），O6-苄基鸟嘌呤（14、15）和O6-苯基鸟嘌呤（16）的S和Se类似物。其中十个是新化合物。使用HeLa S3和C6测试了所有这些化合物对N'-[（4-氨基-2-甲基-5-嘧啶基）甲基] -N-（2-氯乙基）-N-亚硝基

  DOI：

  10.1248/bpb.18.424
• 作为产物：
  描述：

  鸟嘌呤 在 溶剂黄146 、 三氯氧磷 作用下， 以 二甲基亚砜 、 1,2-二氯乙烷 、 PEG-2000 为溶剂， 反应 23.83h， 生成 O₆-(p-fluorobenzyl)guanine
  参考文献：
  名称：

  Hu, Yu Lin; Ge, Qiang; Lu, Ming, Bulletin of the Chemical Society of Ethiopia, 2010, vol. 24, # 3, p. 425 - 432

  摘要：

  DOI：

文献信息

• Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability
  作者：Patrick-Denis St-Coeur、Marc Cormier、Veronique LeBlanc、Pier Morin、Mohamed Touaibia

  DOI：10.2174/1573406412666160710210907

  日期：2016.12.22

  Background: Glioblastoma multiforme (GBM) is often associated with a poor survival prognostic for patients. The main reason seems to be the acquired or inherent resistance to the chemotherapeutic agent used to treat the tumor, temozolomide (TMZ). To this day, the most recognized pathway of resistance is the DNA Direct Repair pathway by the means of the protein O6- methylguanine DNA-methyltransferase (MGMT). Objectives: To design and synthesize a series of MGMT inhibitors that can sensitize GBM cells to TMZ. Methods: Twenty-five O6-alkyl, O6-aryl and O6-substituted-aryl guanine analogs including nine novel compounds were synthesized, characterized, analyzed by molecular docking and tested on the T98G GBM cells viability. Results: Following molecular modeling with MGMT, the newly designed compounds 19, 22, and 24 emerged as the most promising MGMT ligands and displayed modest cytotoxicity. Guanine analog (19), bearing a p-nitrobenzyl moiety, reduced considerably the O6-methylguanine DNAmethyltransferase expression level. When combined with TMZ (1), which is used as first line treatment for brain tumors, compounds 19, 22, and 24 decreased T98G cellsproliferation by 32%, 68% and 50%, respectively. TMZ (1) displayed negligible effect on the proliferation of these cells further supporting the notion that this cell model is resistant to this alkylating agent. Conclusion: Overall, these results notably highlight a group of MGMT inhibitors that warrants further exploration in the development of therapeutic options to circumvent TMZ resistance in brain tumors.

  背景：胶质母细胞瘤（GBM）通常与患者的生存预后不良相关。主要原因似乎是患者对用于治疗该肿瘤的化疗药物替莫唑胺（TMZ）产生了获得性或固有的耐药性。迄今为止，最被认可的耐药途径是通过O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）进行的直接DNA修复途径。 目的：设计并合成一系列MGMT抑制剂，以增强GBM细胞对TMZ的敏感性。 方法：合成了二十五个O6-烷基、O6-芳基和O6-取代芳基鸟嘌呤类似物，包括九个新化合物，并对它们进行了表征、分子对接分析，并在T98G GBM细胞上测试了其细胞毒性。 结果：通过与MGMT的分子建模，新设计的化合物19、22和24成为最有前景的MGMT配体，并显示出适度的细胞毒性。含有对硝基苄基的鸟嘌呤类似物（19）显著降低了O6-甲基鸟嘌呤DNA甲基转移酶的表达水平。当与用于脑肿瘤一线治疗的TMZ（1）联合使用时，化合物19、22和24分别使T98G细胞的增殖减少了32%、68%和50%。TMZ（1）对这些细胞的增殖显示出微弱的影响，这进一步支持了这种细胞模型对这种烷基化剂具有耐药性的观点。 结论：总的来说，这些结果显著突出了一些值得进一步探索的MGMT抑制剂，以开发克服脑肿瘤中TMZ耐药性的治疗方案。
• A Convenient Procedure for the Synthesis of O⁶-Benzylguanine Derivatives by Phase Transfer Catalysis
  作者：Xuan Liu、Qi-Huang Zheng、Gary D. Hutchins、Xiangshu Fei、Leonard C. Erickson、Kathy D. Miller、Bruce H. Mock、Barbara E. Glick-Wilson、Wendy L. Winkle、K. Lee Stone、Kathy A. Carlson

  DOI：10.1081/scc-120016358

  日期：2003.1.4

  Abstract A convenient procedure by phase transfer catalysis has been developed for the synthesis of O6-BG (1) and its derivatives hydroxymethyl-BG (2a–c), halo-BG (3a–c, 4a–c, 5a–c, 6a–c), methoxy-BG (7), and methyl-BG (8). Compounds 2b, 2c, 4b, 4c, 5b, 5c, 6a, and 6c are new compounds.

  摘要 已经开发了一种方便的相转移催化方法用于合成 O6-BG (1) 及其衍生物羟甲基-BG (2a-c)、卤代-BG (3a-c, 4a-c, 5a-c, 6a -c)、甲氧基-BG (7) 和甲基-BG (8)。化合物 2b、2c、4b、4c、5b、5c、6a 和 6c 是新化合物。
• [EN] COMPOSITIONS, METHODS, AND KITS FOR DETERMINING AN ALKYL TRANSFERASE<br/>[FR] COMPOSITIONS, PROCÉDÉS ET TROUSSES POUR DÉTERMINER UNE ALKYL TRANSFÉRASE
  申请人：UNIV DUKE

  公开号：WO2011028507A3

  公开（公告）日：2011-07-14
• Structural features of substituted purine derivatives compatible with depletion of human O6-alkylguanine-DNA alkyltransferase
  作者：Robert C. Moschel、Mark G. McDougall、M. Eileen Dolan、Linda Stine、Anthony E. Pegg

  DOI：10.1021/jm00101a028

  日期：1992.11

  A series of O6- and S6-substituted purine derivatives were tested for their ability to deplete the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in cell-free extracts from HT29 colon tumor cells and intact HT29 cells. The order of potency was O6-(p-Y-benzyl)-guanine (Y = H, F, Cl, and CH3) > O6-benzyl-2'-deoxyguanosine > O6-(p-Y-benzyl)guanosine (Y = H, Cl, and CH3) greater-than-or-equal-to a series of 9-substituted O6-benzylguanine derivatives greater-than-or-equal-to O6-allylguanine > O6-benzylhypoxanthine > O6-methylguanine. A series of 7-substituted O6-benzylguanine derivatives, 2-amino-6-(p-Y-benzylthio)purine (Y = H, CH3),2-amino-6-[(p-nitrobenzyl)thiol-9-beta-D-ribofuranosylpurine, and 7-benzylguanine were inactive. It is concluded that for efficient AGT depletion, an allyl or benzyl group attached through exocyclic oxygen at position 6 of a 2-aminopurine derivative is required. Activity is preserved with a variety of substituent groups attached to position 9 while substitution at position 7 leads to a complete loss of activity.
• COMPOSITIONS, METHODS, AND KITS FOR DETERMINING AN ALKYL TRANSFERASE
  申请人：Duke University

  公开号：EP2470535A2

  公开（公告）日：2012-07-04