O⁶-benzyl-N²-[[[[4''-[(β-D-glucopyranuronosyl)oxy]-3''-nitrophenyl]methyl]oxy]carbonyl]-2'-deoxyguanosine monosodium salt

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: O⁶-benzyl-N²-[[[[4''-[(β-D-glucopyranuronosyl)oxy]-3''-nitrophenyl]methyl]oxy]carbonyl]-2'-deoxyguanosine monosodium salt
• 英文别名: O6-benzyl-N2[[[[4'-[(β-D-glucopyranuronosyl)oxy]-3'-nitrophenyl]methyl]oxy]carbonyl]guanine monosodium salt；sodium;(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[4-[[9-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-phenylmethoxypurin-2-yl]carbamoyloxymethyl]-2-nitrophenoxy]oxane-2-carboxylate
• 化学式: C₃₁H₃₁N₆O₁₅*Na
• 分子量: 750.608
• InChiKey: NTNDVDBYGYKTLX-HLBIFANBSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -4.36
• 重原子数：
  53
• 可旋转键数：
  11
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  306
• 氢给体数：
  6
• 氢受体数：
  18

反应信息

• 作为反应物：
  描述：

  O⁶-benzyl-N²-[[[[4''-[(β-D-glucopyranuronosyl)oxy]-3''-nitrophenyl]methyl]oxy]carbonyl]-2'-deoxyguanosine monosodium salt 在 bovine liver β-glucuronidase type B-10 水 作用下， 生成 (2R,3S,5R)-5-[2-氨基-6-(苯基甲氧基)嘌呤-9-基]-2-(羟基甲基)四氢呋喃-3-醇
  参考文献：
  名称：

  [EN] BETA-GLUGURONIDASE CLEAVABLE PRODRUGS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE INACTIVATORS
  [FR] PROMEDICAMENTS A BASE D'AGENTS D'INACTIVATION DE L'O6-ALKYLGUANINE-ADN ALKYLTRANSFERASE, CLIVABLES PAR LA BETA-GLUCURONIDASE

  摘要：

  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。

  公开号：

  WO2006029065A1
• 作为产物：
  描述：

  3',5'-di-O-acetyl-O6-benzyl-N2-[[[[4''-[(2''',3''',4'''-tri-O-acetyl-6'''-methyl-β-D-glucopyranuronosyl)oxy]-3''-nitrophenyl]methyl]oxy]carbonyl]-2'-deoxyguanosine 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 0.5h， 以64%的产率得到O⁶-benzyl-N²-[[[[4''-[(β-D-glucopyranuronosyl)oxy]-3''-nitrophenyl]methyl]oxy]carbonyl]-2'-deoxyguanosine monosodium salt
  参考文献：
  名称：

  β-Glucuronidase-Cleavable Prodrugs of O⁶-Benzylguanine and O⁶-Benzyl-2‘-deoxyguanosine

  摘要：

  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.

  DOI：

  10.1021/jm0493865

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。
• 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.