6-benzyloxy-9-Boc-purine | 825615-07-4

• 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: 6-benzyloxy-9-Boc-purine
• 英文别名: tert-butyl 6-phenylmethoxypurine-9-carboxylate
• CAS: 825615-07-4
• 化学式: C₁₇H₁₈N₄O₃
• 分子量: 326.355
• InChiKey: HNTICSMPCNTZBC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.19
• 重原子数：
  24.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  79.13
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  6-benzyloxy-9-Boc-purine 在 palladium on activated charcoal sodium periodate 、 氢气 、 四丁基硝酸铵 、 溶剂黄146 、 三氟乙酸酐 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 1.5h， 生成 2-亚硝基-6-苄氧基-9-boc-嘌呤
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Methyltriazene Prodrugs Simultaneously Releasing DNA-Methylating Agents and the Antiresistance Drug O⁶-Benzylguanine

  摘要：

  Active resistance of tumor cells against DNA alkylating agents arises by the production of high levels of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). This resistance during treatment with, for example, the anticancer agent temozolomide can be reversed by administration of O-6-benzylguanine, a purine that transfers its benzyl group to AGT and irreversibly inactivates it. Stimulated by the favorable therapeutic properties of temozolomide we designed and synthesized DNA-methylating triazenes built on the anti-resistance benzylguanine ring system. The condensation reaction between 2-nitrosopurines and acylhydrazines proved to be very suitable to prepare acylated methyltriazenes. Fine-tuning of the release rate of both the methylating agent (diazomethane) and of O-6-benzylguanine was accomplished by variation of the hydrolysis-sensitive acyl substituent in 5. Hydrolysis studies were performed with H-1 NMR and revealed that the p-nitrophenyl substituted triazene 26 showed an optimal hydrolysis rate (t(1/2) = 23 min) and almost 100% selectivity for the desired fragmentation route. In vitro antitumor studies in the 60 human tumor cell line panel of the National Cancer Institute confirmed the superior properties of p-nitrophenyl-protected methyl triazene 26, showing mean IC50 values of 10 muM compared to 100 muM for temozolomide. In analogy with temozolomide, triazene 26 showed however low preference for each of the cancer subpanels, with IC50 values between 8 and 14 muM.

  DOI：

  10.1021/jm049556d
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 6-苄氧基嘌呤 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以82%的产率得到6-benzyloxy-9-Boc-purine
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Methyltriazene Prodrugs Simultaneously Releasing DNA-Methylating Agents and the Antiresistance Drug O⁶-Benzylguanine

  摘要：

  Active resistance of tumor cells against DNA alkylating agents arises by the production of high levels of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). This resistance during treatment with, for example, the anticancer agent temozolomide can be reversed by administration of O-6-benzylguanine, a purine that transfers its benzyl group to AGT and irreversibly inactivates it. Stimulated by the favorable therapeutic properties of temozolomide we designed and synthesized DNA-methylating triazenes built on the anti-resistance benzylguanine ring system. The condensation reaction between 2-nitrosopurines and acylhydrazines proved to be very suitable to prepare acylated methyltriazenes. Fine-tuning of the release rate of both the methylating agent (diazomethane) and of O-6-benzylguanine was accomplished by variation of the hydrolysis-sensitive acyl substituent in 5. Hydrolysis studies were performed with H-1 NMR and revealed that the p-nitrophenyl substituted triazene 26 showed an optimal hydrolysis rate (t(1/2) = 23 min) and almost 100% selectivity for the desired fragmentation route. In vitro antitumor studies in the 60 human tumor cell line panel of the National Cancer Institute confirmed the superior properties of p-nitrophenyl-protected methyl triazene 26, showing mean IC50 values of 10 muM compared to 100 muM for temozolomide. In analogy with temozolomide, triazene 26 showed however low preference for each of the cancer subpanels, with IC50 values between 8 and 14 muM.

  DOI：

  10.1021/jm049556d

文献信息

• Synthesis and Antitumor Activity of Methyltriazene Prodrugs Simultaneously Releasing DNA-Methylating Agents and the Antiresistance Drug <i>O</i>⁶-Benzylguanine
  作者：Martin J. Wanner、Melle Koch、Gerrit-Jan Koomen

  DOI：10.1021/jm049556d

  日期：2004.12.1

  Active resistance of tumor cells against DNA alkylating agents arises by the production of high levels of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). This resistance during treatment with, for example, the anticancer agent temozolomide can be reversed by administration of O-6-benzylguanine, a purine that transfers its benzyl group to AGT and irreversibly inactivates it. Stimulated by the favorable therapeutic properties of temozolomide we designed and synthesized DNA-methylating triazenes built on the anti-resistance benzylguanine ring system. The condensation reaction between 2-nitrosopurines and acylhydrazines proved to be very suitable to prepare acylated methyltriazenes. Fine-tuning of the release rate of both the methylating agent (diazomethane) and of O-6-benzylguanine was accomplished by variation of the hydrolysis-sensitive acyl substituent in 5. Hydrolysis studies were performed with H-1 NMR and revealed that the p-nitrophenyl substituted triazene 26 showed an optimal hydrolysis rate (t(1/2) = 23 min) and almost 100% selectivity for the desired fragmentation route. In vitro antitumor studies in the 60 human tumor cell line panel of the National Cancer Institute confirmed the superior properties of p-nitrophenyl-protected methyl triazene 26, showing mean IC50 values of 10 muM compared to 100 muM for temozolomide. In analogy with temozolomide, triazene 26 showed however low preference for each of the cancer subpanels, with IC50 values between 8 and 14 muM.
• Hypoxia-Selective <i>O</i>⁶-Alkylguanine-DNA Alkyltransferase Inhibitors: Design, Synthesis, and Evaluation of 6-(Benzyloxy)-2-(aryldiazenyl)-9<i>H</i>-purines as Prodrugs of <i>O</i>⁶-Benzylguanine
  作者：Rui Zhu、Raymond P. Baumann、Philip G. Penketh、Krishnamurthy Shyam、Alan C. Sartorelli

  DOI：10.1021/jm301804p

  日期：2013.2.14

  O-6-Alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein which removes alkyl groups from the O-6 position of guanine, thereby providing strong resistance to anticancer agents which alkylate this position. The clinical usefulness of these anticancer agents would be substantially augmented if AGT could be selectively inhibited in tumor tissue, without a corresponding depletion in normal tissue. We report the synthesis of a new AGT inhibitor (5c) which selectively depletes AGT in hypoxic tumor cells.