丙酸,2,2-二甲基-,[2-氨基-6-(苯基甲氧基)-9H-嘌呤-9-基]甲基酯 | 152833-02-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 丙酸,2,2-二甲基-,[2-氨基-6-(苯基甲氧基)-9H-嘌呤-9-基]甲基酯
• 英文名称: (2-amino-6-(benzyloxy)-9H-purin-9-yl)methyl pivalate
• 英文别名: O⁶-benzyl-9-((pivaloyloxy)methyl)guanine；O⁶-benzyl-9-[(pivaloyloxy)methyl]guanine；O⁶-benzyl-9-(pivaloyloxymethyl)guanine；2-amino-6-(benzyloxy)-9-(pivaloyloxymethyl)purine；2-amino-6-benzyloxy-9-pivaloyloxymethylpurine；O6-benzyl-9-[(pivaloyloxy)methyl]guanine；(2-amino-6-phenylmethoxypurin-9-yl)methyl 2,2-dimethylpropanoate
• CAS: 152833-02-8
• 化学式: C₁₈H₂₁N₅O₃
• 分子量: 355.396
• InChiKey: MRTSJAUEUHJSRN-UHFFFAOYSA-N

物化性质

• 沸点：
  579.4±60.0 °C(Predicted)
• 密度：
  1.30±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：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  丙酸,2,2-二甲基-,[2-氨基-6-(苯基甲氧基)-9H-嘌呤-9-基]甲基酯 在 吡啶 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 6.0h， 生成 (6-(benzyloxy)-2-(((1-(4-nitrophenyl)ethoxy)carbonyl)-amino)-9H-purin-9-yl)methyl pivalate
  参考文献：
  名称：

  4-Nitrobenzyloxycarbonyl Derivatives of O⁶-Benzylguanine as Hypoxia-Activated Prodrug Inhibitors of O⁶-Alkylguanine-DNA Alkyltransferase (AGT), Which Produces Resistance to Agents Targeting the O-6 Position of DNA Guanine

  摘要：

  A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O-6-benzylguanine (O-6-BG), conceived as pro-drugs of O-6-BG, an inhibitor of the resistance protein O-6-alkylguanine-DNA alkyltransferase (ACT), were synthesized and evaluated for their ability to undergo bioreductive activation by reductase enzymes under oxygen deficiency. Three agents of this class, 4-nitrobenzyl (6-(benzyloxy)-9H-purin-2-yl)carbamate (1) and its monomethyl (2) and gem-dimethyl analogues (3), were tested for activation by reductase enzyme systems under oxygen deficient conditions. Compound 3, the most water-soluble of these agents, gave the highest yield of O-6-BG following reduction of the nitro group trigger. Compound 3 was also evaluated for its ability to sensitize 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine)-resistant DU145 human prostate carcinoma cells, which express high levels of AGT, to the cytotoxic effects of this agent under normoxic and oxygen deficient conditions. While 3 had little or no effect on laromustine cytotoxicity under aerobic conditions, significant enhancement occurred under oxygen deficiency, providing evidence for the preferential release of the AGT inhibitor O-6-BG under hypoxia.

  DOI：

  10.1021/jm201115f
• 作为产物：
  描述：

  特戊酸氯甲酯 、 O-6-苄基鸟嘌呤 在 sodium ethanolate 作用下， 生成 丙酸,2,2-二甲基-,[2-氨基-6-(苯基甲氧基)-9H-嘌呤-9-基]甲基酯
  参考文献：
  名称：

  Substituted O6-Benzylguanine Derivatives and Their Inactivation of Human O6-Alkylguanine-DNA Alkyltransferase

  摘要：

  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.

  DOI：

  10.1021/jm00029a005

文献信息

• [EN] BETA-GLUGURONIDASE CLEAVABLE PRODRUGS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE INACTIVATORS<br/>[FR] PROMEDICAMENTS A BASE D'AGENTS D'INACTIVATION DE L'O6-ALKYLGUANINE-ADN ALKYLTRANSFERASE, CLIVABLES PAR LA BETA-GLUCURONIDASE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2006029065A1

  公开（公告）日：2006-03-16

  Disclosed are prodrugs of inactivators of 06-alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the (3-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring­ substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted 06-benzylguanine or 06-benzyl-2'-deoxyguanosine. Also disclosed are pharmaceutical compositions comprising a prodrug and a pharmaceutically acceptable carrier, and a method of use of the prodrugs in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the 06-position of guanine.

  本发明公开了06-烷基鸟嘌呤-DNA烷基转移酶（AGT）失活剂的前药。这些前药可以被（3-葡萄糖醛酸酶酶）水解，该酶可以被注射到患者体内或由坏死肿瘤细胞产生。前药由公式A-B-C表示，其中A是通过其1-氧原子与B的苯环连接的葡萄糖醛酸残基；B是苄氧羰基基团，可以选择性地被一个或多个电子提取基团取代；而C是AGT的失活剂，例如取代或未取代的06-苄基鸟嘌呤或06-苄基-2'-脱氧鸟苷。本发明还公开了包含前药和药学上可接受的载体的制药组合物，以及在增强哺乳动物（例如人类）中肿瘤细胞的化疗治疗中使用前药的方法，该方法使用一种抗肿瘤烷基化剂，在鸟嘌呤的06位引起细胞毒性损伤。
• O.sup.6 -substituted guanine compositions and methods for depleting O.sup.6
  申请人：The United States of America as represented by the Department of Health

  公开号：US05691307A1

  公开（公告）日：1997-11-25

  Novel O.sup.6 -substituted guanine compounds and pharmaceutical compositions thereof are useful for effectively reducing O.sup.6 -alkylguanine-DNA alkyltransferase (AGT). The novel compounds are useful for treating tumors and when used with anti-neoplastic alkylating agents enhance the chemotherapeutic treatment of tumor cells in a host.

  Novel O.sup.6-取代鸟嘌呤化合物及其制药组合物可有效减少O.sup.6-烷基鸟嘌呤-DNA烷基转移酶（AGT）。这些新型化合物可用于治疗肿瘤，在与抗肿瘤烷基化剂一起使用时可增强宿主体内肿瘤细胞的化疗治疗效果。
• THERAPEUTIC BENEFIT OF SUBOPTIMALLY ADMINISTERED CHEMICAL COMPOUNDS
  申请人：BROWN Dennis M.

  公开号：US20160045502A1

  公开（公告）日：2016-02-18

  The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to mustard-based alkylating agents such as uracil mustard and analogs, derivatives, or prodrugs thereof, including 6-methyluracil mustard and 6-ethyluracil mustard.

  本发明描述了一种改善先前受到治疗性能不佳限制的治疗剂的治疗效果的方法和组合物，通过改善单药疗法的功效或减少副作用。这种方法和组合物特别适用于芥子碱基烷基化剂，例如尿嘧啶芥和其类似物、衍生物或前药，包括6-甲基尿嘧啶芥和6-乙基尿嘧啶芥。
• Use of dianhydrogalactitol and analogs and derivatives thereof to treat recurrent malignant glioma or progressive secondary brain tumor
  申请人：DelMar Pharmaceuticals, Inc.

  公开号：US11026914B2

  公开（公告）日：2021-06-08

  Methods and compositions suitable for the treatment of malignancies such as recurrent glioma and progressive secondary brain tumor are disclosed. These methods employ a hexitol derivative such as dianhydrogalactitol, a derivative or analog of dianhydrogalactitol, diacetyldianhydrogalactitol, or a derivative or analog of diacetyldianhydrogalactitol. The compositions can include such hexitol derivatives.

  本发明公开了适用于治疗复发性胶质瘤和进行性继发性脑瘤等恶性肿瘤的方法和组合物。这些方法采用己糖醇衍生物，如二氢半乳糖醇、二氢半乳糖醇的衍生物或类似物、二乙酰二氢半乳糖醇或二乙酰二氢半乳糖醇的衍生物或类似物。组合物可以包括此类己糖醇衍生物。
• β-Glucuronidase-Cleavable Prodrugs of <i>O</i>⁶-Benzylguanine and <i>O</i>⁶-Benzyl-2‘-deoxyguanosine
  作者：Guangping Wei、Natalia A. Loktionova、Anthony E. Pegg、Robert C. Moschel

  DOI：10.1021/jm0493865

  日期：2005.1.1

  Glucuronic acid linked prodrugs of O-6-benzylguanine and O-6-benzyl-2'-deoxyguanosine were synthesized. The prodrugs were found to be quite stable at physiological pH and were more than 200-fold less active as inactivators of O-6-alkylguanine-DNA alkyltransferase (alkyltransferase) than either O-6-benzylguanine or O-6-benzyl-2'-deoxyguanosine. beta-Glucuronidase from both Escherichia coli and bovine liver cleaved the prodrugs efficiently to release O-6-benzylguanine and O-6-benzyl-2'-deoxyguanosine, respectively. In combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), the prodrugs were not effective adjuvants for HT29 cell killing. However, as expected, incubation of these prodrugs with beta-glucuronidase in the culture medium led to much more efficient cell killing by BCNU as a result of the liberation of the more potent inactivators, O-6-benzylguanine and O-6-benzyl-2'-deoxyguanosine. These prodrugs may be useful for prodrug monotherapy of necrotic tumors that liberate beta-glucuronidase or for antibody-directed enzyme prodrug therapy with antibodies that can deliver beta-glucuronidase to target tumor cells.