2-亚硝基-6-苄氧基-9-boc-嘌呤 | 825615-09-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 2-亚硝基-6-苄氧基-9-boc-嘌呤
• 英文名称: 2-nitroso-6-benzyloxy-9-Boc-purine
• 英文别名: Tert-butyl 2-nitroso-6-phenylmethoxypurine-9-carboxylate
• CAS: 825615-09-6
• 化学式: C₁₇H₁₇N₅O₄
• 分子量: 355.353
• InChiKey: YLYRHXCKFRMIQK-UHFFFAOYSA-N

物化性质

• 熔点：
  200-205 °C
• 沸点：
  547.0±60.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  109
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-亚硝基-6-苄氧基-9-boc-嘌呤 在 哌啶 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 36.0h， 生成 2-(3-Ethylcarbamoyl-3-methyltriazenyl)-6-benzyloxypurine
  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：

  6-苄氧基嘌呤 在 palladium on activated charcoal 4-二甲氨基吡啶 、 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， 20.0 ℃ 、101.33 kPa 条件下， 反应 17.5h， 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

文献信息

• Targeting the Parasite's DNA with Methyltriazenyl Purine Analogs Is a Safe, Selective, and Efficacious Antitrypanosomal Strategy
  作者：Boris Rodenko、Martin J. Wanner、Abdulsalam A. M. Alkhaldi、Godwin U. Ebiloma、Rebecca L. Barnes、Marcel Kaiser、Reto Brun、Richard McCulloch、Gerrit-Jan Koomen、Harry P. de Koning

  DOI：10.1128/aac.00596-15

  日期：2015.11

  The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a nontoxic and naturally occurring purine nucleobase, a simple triazene-stabilizing group, and the active toxin: a methyldiazonium cation capable of damaging DNA by alkylation. We identified 2-(3-acetyl-3-methyltriazen-1-yl)-6-hydroxypurine (compound 1) as a new lead compound, which showed submicromolar potency against Trypanosoma brucei , with a selectivity index of >500, and it demonstrated a curative effect in animal models of acute trypanosomiasis. We investigated the mechanism of action of this lead compound and showed that this molecule has significantly higher affinity for parasites over mammalian nucleobase transporters, and it does not show cross-resistance with current first-line drugs. Once selectively accumulated inside the parasite, the prodrug releases a DNA-damaging methyldiazonium cation. We propose that ensuing futile cycles of attempted mismatch repair then lead to G ₂ /M phase arrest and eventually cell death, as evidenced by the reduced efficacy of this purine analog against a mismatch repair-deficient ( MSH2 ^−/− ) trypanosome cell line. The observed absence of genotoxicity, hepatotoxicity, and cytotoxicity against mammalian cells revitalizes the idea of pursuing parasite-selective DNA alkylators as a safe chemotherapeutic option for the treatment of human and animal trypanosomiasis.

  摘要 被称为非洲锥虫病的人类和兽医综合疾病继续在全球造成严重的发病率、死亡率和经济困难。旧药的耐药性和毒副作用要求我们采用新颖、非正统的策略来寻找新的安全治疗方案。我们设计的甲基三嗪基嘌呤原药可被寄生虫快速、选择性地内化，然后分解成一种无毒的天然嘌呤核碱基、一个简单的三嗪稳定基团和活性毒素：一种能通过烷基化破坏 DNA 的甲基二氮阳离子。我们发现了 2-(3-乙酰基-3-甲基三氮烯-1-基)-6-羟基嘌呤（化合物 1）作为一种新的先导化合物，该化合物对布氏锥虫的毒性为亚摩尔级。 布氏锥虫 在急性锥虫病动物模型中显示出治疗效果。我们对这种先导化合物的作用机制进行了研究，结果表明这种分子对寄生虫的亲和力明显高于哺乳动物核碱基转运体，而且不会与目前的一线药物产生交叉耐药性。一旦选择性地在寄生虫体内蓄积，该原药就会释放出破坏 DNA 的甲基偶氮阳离子。我们认为，随后尝试错配修复的徒劳循环会导致 G 2 /M期停滞，最终导致细胞死亡。 MSH2 -/- ）锥虫细胞系的疗效降低就证明了这一点。观察到这种嘌呤类似物对哺乳动物细胞没有遗传毒性、肝毒性和细胞毒性，这使我们重新燃起了将寄生虫选择性DNA烷化剂作为治疗人类和动物锥虫病的安全化疗选择的想法。
• 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.