6-[(5-bromothiophen-2-yl)methoxy]-7H-purin-2-amine | 162320-53-8

• 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-[(5-bromothiophen-2-yl)methoxy]-7H-purin-2-amine
• CAS: 162320-53-8
• 化学式: C₁₀H₈BrN₅OS
• 分子量: 326.176
• InChiKey: MLZTTYQIIKNDBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-[(5-bromothiophen-2-yl)methoxy]-7H-purin-2-amine 在 4 A molecular sieve 、 sodium methylate 、 lithium hydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 (2R,3R,4S,5S,6R)-2-[8-[2-amino-6-[(5-bromothiophen-2-yl)methoxy]purin-9-yl]octoxy]-6-(hydroxymethyl)oxane-3,4,5-triol
  参考文献：
  名称：

  Synthesis of ¹³¹I-Labeled Glucose-Conjugated Inhibitors of O⁶-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging

  摘要：

  O-6-Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C-8-alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O-6-(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O-6-(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC50 values) of 0.8 and 0.45 mu M for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the I-131-(hetero)arylmethylene group at the O-6-position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [I-131]I- were performed with radiochemical yields of > 70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [I-131]ITGG, [(131)]IBGG, [I-131]ITG, and [I-131]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [I-131]IBG and [I-131]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.

  DOI：

  10.1021/jm050588q
• 作为产物：
  描述：

  5-溴噻吩-2-甲醛 在 sodium tetrahydroborate 、 sodium hydride 作用下， 反应 2.0h， 生成 6-[(5-bromothiophen-2-yl)methoxy]-7H-purin-2-amine
  参考文献：
  名称：

  Inactivation of O⁶-Alkylguanine-DNA Alkyltransferase. 1. Novel O⁶-(Hetarylmethyl)guanines Having Basic Rings in the Side Chain

  摘要：

  A number of novel guanine derivatives containing heterocyclic moieties at the O-6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O-6-substituents were investigated in which the benzene ring of the known agent, O-6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O-6-benzylguanine. The present paper focuses on O-6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O-6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.

  DOI：

  10.1021/jm9708644

文献信息

• Dimethylpyridin-4-ylamine-Catalysed Alcoholysis of 2-Amino-N,N,N-Trimethyl-9H-purine-6-ylammonium Chloride: An Effective Route to O6-Substituted Guanine Derivatives from Alcohols with Poor Nucleophilicity
  作者：Ralf Schirrmacher、Björn Wängler、Esther Schirrmacher、Thorsten August、F. Rösch

  DOI：10.1055/s-2002-20970

  日期：——

  (DMAP)-catalysed reactions of 2-amino-N,N,N-trimethyl-9H-purine-6-ylammonium chloride with fluoropyridine methoxides and various other alkoxides in DMSO at 60 °C gave the corresponding coupling products in moderate to good yields between 20-87%. Under these reaction conditions, fluorinated O 6 -substituted Guanine derivatives have been synthesized which could not be obtained via known analogous literature

  二甲基吡啶-4-基胺 (DMAP) 催化 2-氨基-N,N,N-三甲基-9H-嘌呤-6-基氯化铵与氟吡啶甲醇盐和各种其他醇盐在 DMSO 中在 60 °C 反应得到相应的偶联产物中等至良好的产量在 20-87% 之间。在这些反应条件下，合成了氟化的O 6 -取代的鸟嘌呤衍生物，其不能通过已知的类似文献程序获得。使用该方法可以显着提高已知O 6 取代鸟嘌呤衍生物的各自产率。因此已经证明了在 O 6 取代的鸟嘌呤衍生物的合成中，DMAP 作为一种优异的亲核催化剂的有效使用。
• Synthesis of ¹³¹I-Labeled Glucose-Conjugated Inhibitors of <i>O</i>⁶-Methylguanine-DNA Methyltransferase (MGMT) and Comparison with Nonconjugated Inhibitors as Potential Tools for in Vivo MGMT Imaging
  作者：Ute Mühlhausen、Ralf Schirrmacher、Markus Piel、Bernd Lecher、Manuela Briegert、Andrea Piee-Staffa、Bernd Kaina、Frank Rösch

  DOI：10.1021/jm050588q

  日期：2006.1.1

  O-6-Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C-8-alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O-6-(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O-6-(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC50 values) of 0.8 and 0.45 mu M for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the I-131-(hetero)arylmethylene group at the O-6-position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [I-131]I- were performed with radiochemical yields of > 70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [I-131]ITGG, [(131)]IBGG, [I-131]ITG, and [I-131]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [I-131]IBG and [I-131]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.
• Inactivation of <i>O</i>⁶-Alkylguanine-DNA Alkyltransferase. 1. Novel <i>O</i>⁶-(Hetarylmethyl)guanines Having Basic Rings in the Side Chain
  作者：R. Stanley McElhinney、Dorothy J. Donnelly、Joan E. McCormick、Jane Kelly、Amanda J. Watson、Joseph A. Rafferty、Rhoderick H. Elder、Mark R. Middleton、Mark A. Willington、T. Brian H. McMurry、Geoffrey P. Margison

  DOI：10.1021/jm9708644

  日期：1998.12.1

  A number of novel guanine derivatives containing heterocyclic moieties at the O-6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O-6-substituents were investigated in which the benzene ring of the known agent, O-6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O-6-benzylguanine. The present paper focuses on O-6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O-6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.