O⁶-2-(4-nitrophenyl)ethylguanine | 213902-34-2

• 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: O⁶-2-(4-nitrophenyl)ethylguanine
• 英文别名: 2-amino-6-[4-(nitro)phenethyloxy]purine；6-[2-(4-nitrophenyl)ethoxy]-7H-purin-2-amine
• CAS: 213902-34-2
• 化学式: C₁₃H₁₂N₆O₃
• 分子量: 300.277
• InChiKey: BFSSXPWPYOUQLD-UHFFFAOYSA-N

物化性质

• 熔点：
  >300 °C (decomp)
• 沸点：
  551.3±60.0 °C(Predicted)
• 密度：
  1.63±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  22
• 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：
  136
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  O⁶-2-(4-nitrophenyl)ethylguanine 在 吡啶 、 4-二甲氨基吡啶 、 trimethylsilyl trifluorosulfonate 、 四丁基氟化铵 、 氨 、 溶剂黄146 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 174.0h， 生成 O6-[2-(4-nitrophenyl)ethyl]-N2-[2-(4-nitrophenyl)ethoxycarbonyl]-9-{5-O-(4,4'-dimethoxytrityl)-2-O-[2-(4-nitrophenyl)ethoxycarbonyl]-α-D-arabinofuranosyl}guanine
  参考文献：
  名称：

  Nucleotides. LXXIV Synthesis of a-D-Arabino-oligonucleotides

  摘要：

  The 5 alpha-D-arabinofuranosylnucleosides alpha-araU (15), alpha-araT (18), alpha-araC (22), alpha-araA (25), and alpha-araG (28) have been synthesized by the modified silyl-method. The amino groups at the nucleobases and the 2'-hydroxy group at the sugar moiety were protected by the 2-(4-nitro-phenyl) ethoxycarbonyl (npeoc) group (37-40) and the amide function in alpha-araG was additionally blocked by the 2-(4-nitrophenyl)ethyl group (63) to improve solubility in organic solvents. Mono-and dimethoxytritylation of the 5'-OH group was performed in the usual manner to give 41-48, 64, and 65 in high yields and further substitution of the 3'-OH group led to the monomeric building blocks 66-75 as well as the 3'-O-succinoyl derivatives 76-85 functioning as starting units in solid-support oligonucleotide synthesis. A large number of oligo-alpha-arabinonucleotides have been prepared on modified CPG-material applying the npeoc/npe strategy as a very efficient synthetic tool for highly purified, homogenous oligomers. Hybridizations between alpha-arabinonucleotide strands revealed in analogy to earlier findings an antiparallel orientation whereas the combination of an oligo-alpha-D-arabinonucleotide with a complementary oligo-2'-deoxy-beta-D-ribofuranosylnucleotide showed base-pairing only if a parallel polarity was present. The advantages in oligo-alpha-arabinonucleotide synthesis were furthermore demonstrated by the synthesis of the t alpha-ANA(his) a structural analog of the natural tRNA(his) of the phage T5.

  DOI：

  10.1080/15257770500267113
• 作为产物：
  描述：

  N,9-二乙酰鸟嘌呤 在 盐酸 、 ethyl azodicarboxylate 、 三苯基膦 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 72.0h， 生成 O⁶-2-(4-nitrophenyl)ethylguanine
  参考文献：
  名称：

  Nucleotides. LXXIV Synthesis of a-D-Arabino-oligonucleotides

  摘要：

  The 5 alpha-D-arabinofuranosylnucleosides alpha-araU (15), alpha-araT (18), alpha-araC (22), alpha-araA (25), and alpha-araG (28) have been synthesized by the modified silyl-method. The amino groups at the nucleobases and the 2'-hydroxy group at the sugar moiety were protected by the 2-(4-nitro-phenyl) ethoxycarbonyl (npeoc) group (37-40) and the amide function in alpha-araG was additionally blocked by the 2-(4-nitrophenyl)ethyl group (63) to improve solubility in organic solvents. Mono-and dimethoxytritylation of the 5'-OH group was performed in the usual manner to give 41-48, 64, and 65 in high yields and further substitution of the 3'-OH group led to the monomeric building blocks 66-75 as well as the 3'-O-succinoyl derivatives 76-85 functioning as starting units in solid-support oligonucleotide synthesis. A large number of oligo-alpha-arabinonucleotides have been prepared on modified CPG-material applying the npeoc/npe strategy as a very efficient synthetic tool for highly purified, homogenous oligomers. Hybridizations between alpha-arabinonucleotide strands revealed in analogy to earlier findings an antiparallel orientation whereas the combination of an oligo-alpha-D-arabinonucleotide with a complementary oligo-2'-deoxy-beta-D-ribofuranosylnucleotide showed base-pairing only if a parallel polarity was present. The advantages in oligo-alpha-arabinonucleotide synthesis were furthermore demonstrated by the synthesis of the t alpha-ANA(his) a structural analog of the natural tRNA(his) of the phage T5.

  DOI：

  10.1080/15257770500267113

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。
• Nucleotides. Part LVII.. Synthesis of phosphoramidite building blocks of 2?-amino-2?-deoxyribonucleosides: New compounds for oligonucleotide synthesis
  作者：Beate Greiner、Wolfgang Pfleiderer

  DOI：10.1002/hlca.19980810556

  日期：——

  The chemical synthesis of 2′-amino-2′-deoxyribonucleosides of uracil, cytosine, adenine, and guanine, and their conversion into suitably protected 3′-phosphoramidite building blocks 35–40 for oligonucleotide synthesis are described. The aglycone and the 2′-amino functions were protected using the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group. The synthesis of the 3′-O-succinyl (3′-O-(3-carboxypropanoyl))-substituted

  化学合成的尿嘧啶，胞嘧啶，腺嘌呤，鸟嘌呤和2'-氨基-2'-脱氧核糖核苷，和其转化为适当保护的3'-亚磷酰胺构建模块35 - 40用于寡核苷酸合成进行说明。使用2-（4-硝基苯基）乙氧羰基（npeoc）基团保护糖苷配基和2'-氨基官能团。3'- O-琥珀酰基（3' - O-（3-羧基丙酰基））取代的起始核苷41的合成描述了1,8-二氮杂双环[5.4.0]十一碳-7-烯（DBU）脱保护过程中预期迁移的溶液和固相行为，并对其进行了研究。使用新的结构单元制备了寡核苷酸，并通过紫外熔融技术研究了它们的杂交特性。
• Regioselective synthesis of 9-substituted purine acyclonucleoside derivatives
  申请人：Merck & Co., Inc.

  公开号：EP0184473A1

  公开（公告）日：1986-06-11

  A process for preparing 9-substituted guanine- containing acyclonucleosides comprising selective alkylation at the 9-position of the purine by utilizing a blocking group at the 6-position.

  一种制备含有9-取代鸟嘌呤的无环核苷的方法，包括利用在6-位置使用阻断基团进行纯嘌呤的选择性烷基化。
• US4801710A
  申请人：——

  公开号：US4801710A

  公开（公告）日：1989-01-31
• Nucleotides. LXXIV Synthesis of a-D-Arabino-oligonucleotides
  作者：Christoph Henke、Wolfgang Pfleiderer

  DOI：10.1080/15257770500267113

  日期：2005.9.1

  The 5 alpha-D-arabinofuranosylnucleosides alpha-araU (15), alpha-araT (18), alpha-araC (22), alpha-araA (25), and alpha-araG (28) have been synthesized by the modified silyl-method. The amino groups at the nucleobases and the 2'-hydroxy group at the sugar moiety were protected by the 2-(4-nitro-phenyl) ethoxycarbonyl (npeoc) group (37-40) and the amide function in alpha-araG was additionally blocked by the 2-(4-nitrophenyl)ethyl group (63) to improve solubility in organic solvents. Mono-and dimethoxytritylation of the 5'-OH group was performed in the usual manner to give 41-48, 64, and 65 in high yields and further substitution of the 3'-OH group led to the monomeric building blocks 66-75 as well as the 3'-O-succinoyl derivatives 76-85 functioning as starting units in solid-support oligonucleotide synthesis. A large number of oligo-alpha-arabinonucleotides have been prepared on modified CPG-material applying the npeoc/npe strategy as a very efficient synthetic tool for highly purified, homogenous oligomers. Hybridizations between alpha-arabinonucleotide strands revealed in analogy to earlier findings an antiparallel orientation whereas the combination of an oligo-alpha-D-arabinonucleotide with a complementary oligo-2'-deoxy-beta-D-ribofuranosylnucleotide showed base-pairing only if a parallel polarity was present. The advantages in oligo-alpha-arabinonucleotide synthesis were furthermore demonstrated by the synthesis of the t alpha-ANA(his) a structural analog of the natural tRNA(his) of the phage T5.