p-6-O⁶-[(hydroxymethyl)benzyl]guanine | 152832-96-7

• 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: p-6-O⁶-[(hydroxymethyl)benzyl]guanine
• 英文别名: O⁶-(p-(hydroxymethyl)benzyl)guanine；O⁶-[4-(hydroxymethyl)benzyl]guanine；O⁶-[p-(hydroxymethyl)benzyl]guanine；O6-[4-(hydroxymethyl)benzyl]guanine；[4-[(2-amino-7H-purin-6-yl)oxymethyl]phenyl]methanol
• CAS: 152832-96-7
• 化学式: C₁₃H₁₃N₅O₂
• 分子量: 271.279
• InChiKey: WDCALJFMCDAVTL-UHFFFAOYSA-N

物化性质

• 熔点：
  226-229 °C(Solv: methanol (67-56-1); water (7732-18-5))
• 沸点：
  538.2±60.0 °C(Predicted)
• 密度：
  1.54±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  20
• 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：
  110
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  p-6-O⁶-[(hydroxymethyl)benzyl]guanine 在 吡啶 、 4-二甲氨基吡啶 、 sodium acetate 、 三乙胺 、 pyridinium chlorochromate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 N2,9-bis-(p-anisyldiphenylmethyl)-O6-(4-formylbenzyl)guanine
  参考文献：
  名称：

  Synthesis and preliminary biological evaluation of O6-[4-(2-[18F]fluoroethoxymethyl)benzyl]guanine as a novel potential PET probe for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in cancer chemotherapy

  摘要：

  A novel fluorine- 18-labeled O-6 -benzylguanine (O-6-BG) derivative, 0(6)-[4-(2-[F-18]fluoroetboxymethyl)benzyl[guanine (O-6-[F-18]FEMBG, [[F-18]1), has been synthesized for evaluation as a potential positron emission tomography (PET) probe for the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT) in cancer chemotherapy. The appropriate radiolabeling precursor N-2,(9)-bis(p-anisyldiphenylmethyl)-O-6-[4-(hydroxymethyl)benzyl]guanine (6) and reference standard O-6-[4-(2-fluoroethoxymethyl)benzyl]guanine (O-6 -FEMBG, 1) were synthesized from 1,4-benzenedimethanol and 2-amino-6-chloropurine in four or six steps, respectively, with moderate to excellent chemical yields. The target tracer O-6-[F-18]FEMBG was prepared in 20-35% radiochemical yields by reaction of MTr-protected precursor 6 with [F-18]fluoroethyl bromide followed by quick deprotection reaction and purification with a simplified Silica Sep-Pak method. Total synthesis time was 60-70 min from the end of bombardment. Radiochemical purity of the formulated product was >95%, with a specific radioactivity of >1.0 Ci/mu mol at the end of synthesis. The activity of unlabeled O-6-FEMBG was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate that the synthesized analogue has similarly strong inhibiting effect on AGT in comparison with O-6-BG and O-6-4-fluorobenzylguanine (O-6-FBG). The results warrant further in vivo evaluation of O-6-[F-18]FEMBG as a new potential PET probe for AGT. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.05.061
• 作为产物：
  描述：

  2-氨基-6-氯嘌呤 在 sodium hydride 、 二甲基亚砜 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 p-6-O⁶-[(hydroxymethyl)benzyl]guanine
  参考文献：
  名称：

  Synthesis and preliminary biological evaluation of 6-O-[11C]-[(methoxymethyl)benzyl]guanines, new potential PET breast cancer imaging agents for the DNA repair protein AGT

  摘要：

  Novel radiolabeled O-6-benzylguanine derivatives, 6-O-[C-11]-[(methoxymethyl)benzyl]guanines ([C-11]p-O-MMBG. 1a: [C-11]m-O-6-MMBG. 1b: ([C-11]m-O-6-MMBG. 1c), have been synthesized for evaluation as new potential positron emission tomograph (PET) breast cancer imaging agents for DNA repair protein. O-6-alkylguanine-DNA alkyltransferase (AGT). (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)01048-x

文献信息

• INACTIVATORS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE
  申请人：Moschel Robert C.

  公开号：US20100204172A1

  公开（公告）日：2010-08-12

  Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X 1 , X 2 , R 1 , and R 2 are as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I).

  本发明涉及一种包括叶酸残基的AGT失活剂化合物，例如式(I)的化合物，其中X1、X2、R1和R2如本文所述。本发明还涉及一种包括本发明化合物和药学上可接受的载体的制药组合物。本发明还涉及增强肿瘤细胞化疗治疗和失活肿瘤细胞中AGT的方法。该方法包括，除其他外，给予式(I)的化合物或药学上可接受的盐。
• Substituted O6-Benzylguanine Derivatives and Their Inactivation of Human O6-Alkylguanine-DNA Alkyltransferase
  作者：Mi Young Chae、Mark G. McDougall、M. Eileen Dolan、Kristin Swenn、Anthony E. Pegg、Robert C. Moschel

  DOI：10.1021/jm00029a005

  日期：1994.2

  Several new O-6-benzylguanine analogs bearing increasingly bulky substituent groups on the benzene ring or at position 9 were tested for their ability to inactivate the human DNA repair protein, O-6-alkylguanine-DNA alkyltransferase. Substitution on the benzene ring was well tolerated although activity varied considerably with structural changes in groups attached to position 9. For this site, activity was preserved with large or small lipophilic groups while introduction of non-carbohydrate polar groups generally reduced activity regardless of their size.
• Inactivation of <i>O</i>⁶-Alkylguanine-DNA Alkyltransferase by Folate Esters of <i>O</i>⁶-Benzyl-2‘-deoxyguanosine and of <i>O</i>⁶-[4-(Hydroxymethyl)benzyl]guanine
  作者：Sahar Javanmard、Natalia A. Loktionova、Qingming Fang、Gary T. Pauly、Anthony E. Pegg、Robert C. Moschel

  DOI：10.1021/jm0705859

  日期：2007.10.1

  O-6-Alkylguanine-DNA alkyltransferase (alkyltransferase) provides an important source of resistance to some cancer chemotherapeutic alkylating agents. Folate ester derivatives of O-6-benzyl-2'-deoxyguanosine and of O-6- [4-(hydroxymethyl)benzyl] guanine were synthesized and tested for their ability to inactivate human alkyltransferase. Inactivation of alkyltransferase by the gamma-folate ester of O-6-[4-(hydroxymethyl)benzyl]guanine was similar to that of the parent base. The gamma-folate esters of O-6-benzyl-2'-deoxyguanosine were more potent alkyltransferase inactivators than the parent nucleoside. The 3'-ester was considerably more potent than the 5'-ester and was more than an order of magnitude more active than O-6-benzylguanine, which is currently in clinical trials to enhance therapy with alkylating agents. They were also able to sensitize human tumor cells to killing by 1,3-bis(2-chloroethyl)-1-nitrosourea, with O-6-benzyl-3'-O-(gamma-folyl)-2'- deoxyguanosine being most active. These compounds provide a new class of highly water-soluble alkyltransferase inactivators and form the basis to construct more tumor-specific and potent compounds targeting this DNA repair protein.
• MGMT INHIBITOR COMBINATION FOR THE TREATMENT OF NEOPLASTIC DISORDERS
  申请人：Liu Lili

  公开号：US20100093647A1

  公开（公告）日：2010-04-15

  A method of treating a neoplastic disease in a subject includes administering to neoplastic cells of the subject an MGMT inhibitor and at least one of an antimitotic agent or a DNA damaging agent.
• MGMT INHIBITOR COMBINATIONS FOR THE TREATMENT OF NEOPLASTIC DISORDERS
  申请人：Case Western Reserve University

  公开号：US20140296264A1

  公开（公告）日：2014-10-02

  A method of treating a neoplastic disease in a subject includes administering to neoplastic cells of the subject an MGMT inhibitor and at least one of an antimitotic agent or a DNA damaging agent.