10-[4-(2,3,4-tri-O-acetyl-6-O-methyl-β-D-glucuronyloxy)-3-nitrobenzyloxy]camptothecin | 1018932-85-8

• 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: 10-[4-(2,3,4-tri-O-acetyl-6-O-methyl-β-D-glucuronyloxy)-3-nitrobenzyloxy]camptothecin
• 英文别名: methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-[4-[[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-7-yl]oxymethyl]-2-nitrophenoxy]oxane-2-carboxylate
• CAS: 1018932-85-8
• 化学式: C₄₀H₃₇N₃O₁₇
• 分子量: 831.744
• InChiKey: CIACUVVFJZXSJK-FHWMFMEKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  60
• 可旋转键数：
  14
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  258
• 氢给体数：
  1
• 氢受体数：
  18

反应信息

• 作为反应物：
  描述：

  10-[4-(2,3,4-tri-O-acetyl-6-O-methyl-β-D-glucuronyloxy)-3-nitrobenzyloxy]camptothecin 在 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以46%的产率得到10-[4-(6-O-methyl-β-D-glucuronyloxy)-3-nitrobenzyloxy]camptothecin
  参考文献：
  名称：

  Benzyl Ether-Linked Glucuronide Derivative of 10-Hydroxycamptothecin Designed for Selective Camptothecin-Based Anticancer Therapy

  摘要：

  A beta-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin (7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10- to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of beta-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli beta-glucuronidase had a quite low K-m of 0.18 mu M for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human beta-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.

  DOI：

  10.1021/jm701151c
• 作为产物：
  描述：

  methyl 1-O-(4-methanesulfonyloxymethyl-2-nitrophenyl)-2,3,4-tri-O-acetyl-β-D-glucopyranuronate 、 10-羟基喜树碱 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以47%的产率得到10-[4-(2,3,4-tri-O-acetyl-6-O-methyl-β-D-glucuronyloxy)-3-nitrobenzyloxy]camptothecin
  参考文献：
  名称：

  Benzyl Ether-Linked Glucuronide Derivative of 10-Hydroxycamptothecin Designed for Selective Camptothecin-Based Anticancer Therapy

  摘要：

  A beta-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin (7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10- to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of beta-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli beta-glucuronidase had a quite low K-m of 0.18 mu M for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human beta-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.

  DOI：

  10.1021/jm701151c