6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-amine | 1400941-90-3

• 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-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-amine
• 英文别名: 6-[[3-[(dimethylamino)methyl]phenyl]methoxy]-7H-purin-2-amine
• CAS: 1400941-90-3
• 化学式: C₁₅H₁₈N₆O
• 分子量: 298.348
• InChiKey: SGMHYUAQYLJKMP-UHFFFAOYSA-N

物化性质

• 沸点：
  596.3±60.0 °C(Predicted)
• 密度：
  1.325±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  93
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1,3-苯二甲醇 在 盐酸 、 4-二甲氨基吡啶 、 sodium hydride 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 生成 6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-amine
  参考文献：
  名称：

  Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase

  摘要：

  The efficacy of agents that alkylate the O-6 position of guanine is inhibited by O-6-alkylguanine-DNA alkyltransferase (AGT) which removes these lesions from the tumor DNA. To increase differential toxicity, inhibitors must selectively deplete AGT in tumors, while sparing normal tissues where this protein serves a protective function. A newly synthesized prodrug of the AGT inhibitor O-6-benzylguanine (O-6-BG) with an alpha,alpha-dimethyl-4-nitrobenzyloxycarbonyl moiety masking the essential 2-amino group has demonstrated the feasibility of targeting hypoxic regions that are unique to solid tumors, for drug delivery. However, these modifications resulted in greatly decreased solubility. Recently, new potent global AGT inhibitors with improved formulatability such as O-6-[(3-aminomethyl)benzylguanine (1) have been developed. However, acetylamino (N-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)acetamide) (2) exhibits a pronounced decrease in activity. Thus, 1 would be inactivated by N-acetylation and probably N-glucuronidation. To combat potential conjugational inactivation while retaining favorable solubility, we synthesized 6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-amine (3) in which the 3-aminomethyl moiety is protected by methylation; and to impart tumor selectivity we synthesized 2-(4-nitrophenyl) propan-2-yl(6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-yl)carbamate (7), a hypoxia targeted prodrug of 3 utilizing an alpha,alpha-dimethyl-4-nitrobenzyloxycarbonyl moiety. Consistent with this design, 7 demonstrates both hypoxia selective conversion by EMT6 cells of 7 to 3 and hypoxic sensitization of AGT containing DU145 cells to the cytotoxic actions of laromustine, while exhibiting improved solubility. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.08.008

文献信息

• Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase
  作者：Rui Zhu、Helen A. Seow、Raymond P. Baumann、Kimiko Ishiguro、Philip G. Penketh、Krishnamurthy Shyam、Alan C. Sartorelli

  DOI：10.1016/j.bmcl.2012.08.008

  日期：2012.10

  The efficacy of agents that alkylate the O-6 position of guanine is inhibited by O-6-alkylguanine-DNA alkyltransferase (AGT) which removes these lesions from the tumor DNA. To increase differential toxicity, inhibitors must selectively deplete AGT in tumors, while sparing normal tissues where this protein serves a protective function. A newly synthesized prodrug of the AGT inhibitor O-6-benzylguanine (O-6-BG) with an alpha,alpha-dimethyl-4-nitrobenzyloxycarbonyl moiety masking the essential 2-amino group has demonstrated the feasibility of targeting hypoxic regions that are unique to solid tumors, for drug delivery. However, these modifications resulted in greatly decreased solubility. Recently, new potent global AGT inhibitors with improved formulatability such as O-6-[(3-aminomethyl)benzylguanine (1) have been developed. However, acetylamino (N-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)acetamide) (2) exhibits a pronounced decrease in activity. Thus, 1 would be inactivated by N-acetylation and probably N-glucuronidation. To combat potential conjugational inactivation while retaining favorable solubility, we synthesized 6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-amine (3) in which the 3-aminomethyl moiety is protected by methylation; and to impart tumor selectivity we synthesized 2-(4-nitrophenyl) propan-2-yl(6-((3-((dimethylamino)methyl)benzyl)oxy)-9H-purin-2-yl)carbamate (7), a hypoxia targeted prodrug of 3 utilizing an alpha,alpha-dimethyl-4-nitrobenzyloxycarbonyl moiety. Consistent with this design, 7 demonstrates both hypoxia selective conversion by EMT6 cells of 7 to 3 and hypoxic sensitization of AGT containing DU145 cells to the cytotoxic actions of laromustine, while exhibiting improved solubility. (C) 2012 Elsevier Ltd. All rights reserved.