(S)-11-(tert-Butyl-dimethyl-silanyl)-4-ethyl-4-hydroxy-9-methoxymethoxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione | 905843-13-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 英文名称: (S)-11-(tert-Butyl-dimethyl-silanyl)-4-ethyl-4-hydroxy-9-methoxymethoxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione
• 英文别名: (19S)-10-[tert-butyl(dimethyl)silyl]-19-ethyl-19-hydroxy-7-(methoxymethoxy)-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
• CAS: 905843-13-2
• 化学式: C₂₈H₃₄N₂O₆Si
• 分子量: 522.673
• InChiKey: LASNJVZJRBKRIG-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.78
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  98.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-11-(tert-Butyl-dimethyl-silanyl)-4-ethyl-4-hydroxy-9-methoxymethoxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione 在 4-二甲氨基吡啶 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 Amino-acetic acid (S)-11-(tert-butyl-dimethyl-silanyl)-4-ethyl-9-hydroxy-3,13-dioxo-3,4,12,13-tetrahydro-1H-2-oxa-6,12a-diaza-dibenzo[b,h]fluoren-4-yl ester; compound with trifluoro-acetic acid
  参考文献：
  名称：

  A Versatile Prodrug Approach for Liposomal Core-Loading of Water-Insoluble Camptothecin Anticancer Drugs

  摘要：

  We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group).

  DOI：

  10.1021/ja0256212
• 作为产物：
  描述：

  氯甲基甲基醚 、 DB-67 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以84%的产率得到(S)-11-(tert-Butyl-dimethyl-silanyl)-4-ethyl-4-hydroxy-9-methoxymethoxy-1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione
  参考文献：
  名称：

  喜树碱的α-氨基酸酯前药活化的动力学和机理。

  摘要：

  NMR光谱法和定量动力学分析表明，抗肿瘤剂喜树碱的α-氨基酸酯前药和更有效的亲脂性硅酸盐酯类似物DB-67可通过非酶机制进行定量转化为其药理活性内酯。 pH 7.4优于直接水解。替代途径涉及在喜树碱E-环羰基上可逆的分子内亲核胺攻击，以生成内酰胺（I），然后进行第二次分子内反应，以生成双环半原酸酯（I'）。分离出中间体，并使用NMR光谱法显示其在DMSO中以半原酸酯为主导的明显平衡存在。在37°C下于水性缓冲液（pH 3.0和7.4）中监测喜树碱或含有α-NH（2）或α-NHCH（3）及其相应半甲酸酯的DB-67前药的转化率与时间的关系，动力学数据适合基于所提出机制的模型。结果表明，虽然前药在pH 3时相对稳定，但在生理条件下（pH 7.4），前药及其相应的半甲酸酯中间体都容易释放内酯。发现在体外使用人乳腺癌细胞系（MDA-MB-435S），甘氨酸酯及其半原酸酯比N-甲基甘氨酸或其相应的半

  DOI：

  10.1021/jm060016l

文献信息

• Highly lipophilic camptothecin intermediates and prodrugs and methods of preparation thereof
  申请人：University of Kentucky Research Foundation

  公开号：US07064206B1

  公开（公告）日：2006-06-20

  The present invention relates to novel, highly lipophilic silatecan intermediates and prodrugs of DB-67 and other silatecans.

  本发明涉及新颖的、高脂溶性的硅铂环素中间体和DB-67及其他硅铂环素的前药。
• Kinetics and Mechanisms of Activation of α-Amino Acid Ester Prodrugs of Camptothecins
  作者：Lin Song、Robert Bevins、Bradley D. Anderson

  DOI：10.1021/jm060016l

  日期：2006.7.1

  quantitative conversion to their pharmacologically active lactones via a nonenzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiortho ester (I'). The intermediates were isolated

  NMR光谱法和定量动力学分析表明，抗肿瘤剂喜树碱的α-氨基酸酯前药和更有效的亲脂性硅酸盐酯类似物DB-67可通过非酶机制进行定量转化为其药理活性内酯。 pH 7.4优于直接水解。替代途径涉及在喜树碱E-环羰基上可逆的分子内亲核胺攻击，以生成内酰胺（I），然后进行第二次分子内反应，以生成双环半原酸酯（I'）。分离出中间体，并使用NMR光谱法显示其在DMSO中以半原酸酯为主导的明显平衡存在。在37°C下于水性缓冲液（pH 3.0和7.4）中监测喜树碱或含有α-NH（2）或α-NHCH（3）及其相应半甲酸酯的DB-67前药的转化率与时间的关系，动力学数据适合基于所提出机制的模型。结果表明，虽然前药在pH 3时相对稳定，但在生理条件下（pH 7.4），前药及其相应的半甲酸酯中间体都容易释放内酯。发现在体外使用人乳腺癌细胞系（MDA-MB-435S），甘氨酸酯及其半原酸酯比N-甲基甘氨酸或其相应的半
• A Versatile Prodrug Approach for Liposomal Core-Loading of Water-Insoluble Camptothecin Anticancer Drugs
  作者：Xinli Liu、Bert C. Lynn、Junhong Zhang、Lin Song、David Bom、Wu Du、Dennis P. Curran、Thomas G. Burke

  DOI：10.1021/ja0256212

  日期：2002.7.1

  We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group).