O⁶-benzyl-2-fluorohypoxanthine | 19916-74-6

• 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: O⁶-benzyl-2-fluorohypoxanthine
• 英文别名: 2-fluoro-6-benzyloxy-9H-purine；6-benzyloxy-2-fluoro-9H-purine；2-fluoro-6-benzyloxypurine；6-benzyloxy-2-fluoro-7(9)H-purine；2-Fluor-6-benzyloxy-purin；O6-benzyl-2-fluorohypoxanthine；2-fluoro-6-phenylmethoxy-7H-purine
• CAS: 19916-74-6
• 化学式: C₁₂H₉FN₄O
• 分子量: 244.228
• InChiKey: LBDUBRVDQRTAPK-UHFFFAOYSA-N

物化性质

• 沸点：
  412.1±55.0 °C(Predicted)
• 密度：
  1.44±0.1 g/cm3(Predicted)

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：
  0.08
• 拓扑面积：
  63.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  O⁶-benzyl-2-fluorohypoxanthine 、 DL-丙氨酸 在 palladium on activated charcoal ammonium hydroxide 、 氢气 、 potassium carbonate 作用下， 生成 ammonium (+/-)-2-(6,9-dihydro-6-oxo-1H-purin-2-ylamino)propionate
  参考文献：
  名称：

  Ochs, Stefan; Severin, Theodor, Liebigs Annalen der Chemie, 1994, # 8, p. 851 - 854

  摘要：

  DOI：
• 作为产物：
  描述：

  O-6-苄基鸟嘌呤 在 tetrafluoroboric acid 、 sodium nitrite 作用下， 以 水 为溶剂， 反应 1.25h， 以50%的产率得到O⁶-benzyl-2-fluorohypoxanthine
  参考文献：
  名称：

  嘌呤衍生的一氧化氮用于双价核酸非共价旋转标记碱性位点。

  摘要：

  制备了一系列基于嘌呤的自旋标记物，用于通过氢键结合至相对链上的孤儿碱基以及与侧翼碱基的π堆积相互作用，对双链核酸的无碱基位点进行非共价自旋标记。1,1,3,3-四甲基异吲哚-2-基氧基和2,2,6,6-四甲基哌啶-1-基氧基（TEMPO）与嘌呤的C2或C6位共轭，产生鸟嘌呤，腺嘌呤或2,6-二氨基嘌呤。源自异吲哚啉的自旋标记物显示出与RNA双链体中无碱基位点的广泛或完全结合，而来自TEMPO的自旋标记物显示出有限的结合。腺嘌呤衍生的自旋标签（5）分别与胸腺嘧啶和尿嘧啶配对时，在低温下完全结合到DNA和RNA双链体中的无碱基位点，从而补充了先前描述的鸟嘌呤衍生的自旋标记Ǵ，该标记有效地与相反的胞嘧啶结合。化合物ǵ也显示结合在DNA-RNA杂交脱碱基位点，无论是在DNA或所述RNA链。Ǵ与RNA的无碱基位点结合后，仅显示出较小的侧翼序列效应。当脱碱基位点被放置在靠近RNA双链体的端部时，自旋标记的亲和力ǵ降低;

  DOI：

  10.1002/chem.201705410

文献信息

• 8-Substituted O6-Benzylguanine, Substituted 6(4)-(Benzyloxy)pyrimidine, and Related Derivatives as Inactivators of Human O6-Alkylguanine-DNA Alkyltransferase
  作者：Mi-Young Chae、Kristin Swenn、Sreenivas Kanugula、M. Eileen Dolan、Anthony E. Pegg、Robert C. Moschel

  DOI：10.1021/jm00002a018

  日期：1995.1

  Several 8-substituted O6-benzylguanines, 2- and/or 8-substituted 6-(benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(benzyloxy)-s-triazine were tested for their ability to inactivate the human DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT, alkyltransferase). Two types of compounds were identified as being significantly more effective than O6-benzylguanine (the prototype

  测试了几种8-取代的O6-苄基鸟嘌呤，2-和/或8-取代的6-（苄氧基）嘌呤，取代的6（4）-（苄氧基）嘧啶和6-（苄氧基）-s-三嗪的能力。使人类DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（AGT，烷基转移酶）失活。已鉴定出两种类型的化合物在使人HT29结肠肿瘤细胞提取物中的AGT失活方面比O6-苄基鸟嘌呤（原型低分子量灭活剂）明显更有效。它们是在8位带有吸电子基团的8-取代的O6-苄基鸟嘌呤（例如8-氮杂-O6-苄基鸟嘌呤和O6-苄基-8-溴鸟嘌呤）和5-取代的2,4-二氨基-6-（苄氧基）在5位带有吸电子基团的嘧啶（例如2,4-二氨基-6-（苄氧基）-5-亚硝基和2，4-二氨基-6-（苄氧基）-5-硝基嘧啶）。在完整的HT29结肠肿瘤细胞中，后者的衍生物在灭活AGT方面比O6-苄基鸟嘌呤更有效。如果这些类型的嘌呤和嘧啶没有表现出不希望的毒性，则它们可以优于O6-苄基鸟嘌呤作为用
• Reaction of 2′-deoxyguanosine with glucose
  作者：S. Ochs、T. Severin

  DOI：10.1016/0008-6215(94)00254-d

  日期：1995.1

  Abstract Glucose reacts with 2′-deoxyguanosine under physiological conditions to give the diastereomeric purine substituted trihydroxy-α-amino hexanoic acids 4 as main products. Hydrolysis of 4 leads to the guanine derivatives 6 which have been synthesized by an independent route.

  摘要葡萄糖在生理条件下与2'-脱氧鸟苷反应，以非对映异构嘌呤取代的三羟基-α-氨基己酸4为主要产物。4的水解产生鸟嘌呤衍生物6，其通过独立的途径合成。
• Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines
  申请人：The United States of America as represented by the Department of Health

  公开号：US05525606A1

  公开（公告）日：1996-06-11

  The present invention provides 8-substituted O.sup.6 -benzylguanines of the formula ##STR1## wherein R.sub.1, R.sub.2, and R.sub.3 are as defined in the specification, and 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O.sup.6 -benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.

  本发明提供了式子如下的8-取代O.sup.6-苄基鸟嘌呤：##STR1##其中R.sub.1，R.sub.2和R.sub.3如规范中定义的，以及4（6）-取代的2-氨基-5-硝基-6（4）-苄氧基嘧啶，以及已发现有效的AGT失活剂的4（6）-取代2-氨基-5-亚硝基-6（4）-苄氧基嘧啶衍生物，以及包含这些衍生物和药用可接受载体的制药组合物。本发明还提供了一种增强哺乳动物体内肿瘤细胞化疗治疗的方法，该方法使用一种抗肿瘤烷基化剂，该烷基化剂在鸟嘌呤的O.sup.6-位置引起细胞毒性损伤，通过向哺乳动物体内投与上述衍生物，2,4-二氨基-6-苄氧基-s-三嗪，5-取代的2,4-二氨基-6-苄氧基嘧啶，或8-氮杂-O.sup.6-苄基鸟嘌呤的有效量，并向哺乳动物体内投与引起鸟嘌呤的O.sup.6-位置细胞毒性损伤的抗肿瘤烷基化剂的有效量。
• Substituted benzyloxypyrimidines and their inactivation of O.sup.6
  申请人：The United States of America as represented by the Department of Health

  公开号：US05753668A1

  公开（公告）日：1998-05-19

  The present invention provides certain novel nitro or nitroso substituted benzyloxy pyrimidines useful as AGT inactivators. An example of such a pyrimidine is a compound of the formula ##STR1## wherein R.sub.1, is NO.sub.2 or NO, and R.sub.2 is hydrogen, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkythio, trifluoromethoxy, oxymethanesulfonyl, oxytrifluoromethanesulfonyl, or C.sub.1 -C.sub.4 oxyacyl. The present invention further provides pharmaceutical compositions comprising these compounds, and a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.

  本发明提供了某些新型的硝基或亚硝基取代的苄氧基嘧啶，可用作AGT失活剂。这样的嘧啶的一个例子是式子##STR1##中的化合物，其中R.sub.1是NO.sub.2或NO，R.sub.2是氢、卤素、C.sub.1-C.sub.4烷基、C.sub.1-C.sub.4羟基烷基、硫醇、C.sub.1-C.sub.4烷硫基、三氟甲氧基、氧甲烷磺酰基、氧三氟甲烷磺酰基或C.sub.1-C.sub.4氧酰基。本发明还提供了包含这些化合物的药物组合物，以及一种增强哺乳动物中肿瘤细胞的化疗治疗的方法，该方法使用一种抗肿瘤烷基化剂，在鸟嘌呤的O.sup.6位引起细胞毒性损伤。
• Pharmaceutical composition comprising 2,4-diamino-6-benzyloxy-s-triazine and inactivation of O6-alkylguanine-DNA-alkyltransferase
  申请人：The United States of America as represented by the Department of Health and Human Services

  公开号：US06303604B1

  公开（公告）日：2001-10-16

  The present invention provides 8-substituted O6-benzylguanine, 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of quanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O6-benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine.

  本发明提供了8-取代的O6-苄基鸟嘌呤，4(6)-取代的2-氨基-5-硝基-6(4)-苄氧基嘧啶和4(6)-取代的2-氨基-5-亚硝基-6(4)-苄氧基嘧啶衍生物，发现它们是有效的AGT失活剂，以及包含这些衍生物和药学上可接受的载体的制药组合物。本发明还提供了一种增强哺乳动物体内抗肿瘤烷基化剂治疗肿瘤细胞的方法，该烷基化剂在鸟嘌呤的O6位引起细胞毒性损伤，通过向哺乳动物体内投与上述衍生物、2,4-二氨基-6-苄氧基-s-三嗪、5-取代的2,4-二氨基-6-苄氧基嘧啶或8-氮杂-O6-苄基鸟嘌呤的有效量，并向哺乳动物体内投与一种在鸟嘌呤的O6位引起细胞毒性损伤的抗肿瘤烷基化剂的有效量。