O⁶-[(S)-(4-isopropenylcyclohex-1-enyl)methyl]guanine

• 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-[(S)-(4-isopropenylcyclohex-1-enyl)methyl]guanine
• 英文别名: O6-Substituted Guanine Deriv. 28；6-[[(4S)-4-prop-1-en-2-ylcyclohexen-1-yl]methoxy]-7H-purin-2-amine
• 化学式: C₁₅H₁₉N₅O
• 分子量: 285.349
• InChiKey: SPADJAXDGBDSFV-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  89.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (S)-(-)-紫苏醇 、 (2-氨基嘌呤-6-基)三甲基氯化铵 在 sodium hydride 作用下， 以 二甲基亚砜 为溶剂， 反应 1.0h， 以64%的产率得到O⁶-[(S)-(4-isopropenylcyclohex-1-enyl)methyl]guanine
  参考文献：
  名称：

  Resistance-Modifying Agents. 8. Inhibition of O⁶-Alkylguanine-DNA Alkyltransferase by O⁶-Alkenyl-, O⁶-Cycloalkenyl-, and O⁶-(2-Oxoalkyl)guanines and Potentiation of Temozolomide Cytotoxicity in Vitro by O⁶-(1-Cyclopentenylmethyl)guanine

  摘要：

  A series of O-6-allyl- and O-6-(2-oxoalkyl)guanines were synthesized and evaluated, in comp ari son with the corresponding O-6-alkylguanines, as potential inhibitors of the DNA-repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). Simple O-6-alkyl- and O-6-cycloalkylguanines were weak AGT inactivators compared with O-6-allylguanine (IC50 = 8.5 +/- 0.6 muM) With IC50 values ranging from 100 to 1000 muM. The introduction of substituents at C-2 of the allyl group of O-6-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O-6-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 muM) O-6-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC50 = 0.55 +/- 0.02 muM) and 1-cyclopentenylmethylguanine (IC50 = 0.39 +/- 0.04 muM) exhibiting potency approaching that of the benchmark AGT inhibitor O-6-benzylguanine (IC50 = 0.18 +/- 0.02 muM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC50 = 0.20 +/- 0.07 muM) and potentiated the cytotoxicity of the monomethylating antitumor agent Temozolomide by approximately 3- and 10-fold, respectively, in the HT29 and Colo205 tumor cell lines. The observation that four mutant AGT enzymes resistant to O-6-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O-6-substituent of each compound makes similar binding interactions within the active site of AGT.

  DOI：

  10.1021/jm000961o