9-aminocamptothecin-N-(benzyloxycarbamate)-β-D-glucuronide

• 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: 9-aminocamptothecin-N-(benzyloxycarbamate)-β-D-glucuronide
• 英文别名: N-[9-(β-D-glucuronyl)benzyloxycarbonyl]aminocamptothecin；9-amino-camptothecin-glucuronide；(2S,3S,4S,5R,6S)-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),2,4(9),5,7,10,15(20)-heptaen-8-yl]carbamoyloxymethyl]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
• 化学式: C₃₄H₃₁N₃O₁₃
• 分子量: 689.632
• InChiKey: PMAYIZIIHIVPPX-JBYBKPQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  50
• 可旋转键数：
  8
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  235
• 氢给体数：
  6
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  9-aminocamptothecin-N-(benzyloxycarbamate)-β-D-glucuronide 在 phosphate buffer 、 Escherichia coli β-glucuronidase 作用下， 生成 10-羟基喜树碱
  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

文献信息

• Benzyl Ether-Linked Glucuronide Derivative of 10-Hydroxycamptothecin Designed for Selective Camptothecin-Based Anticancer Therapy
  作者：Yu-Ling Leu、Chien-Shu Chen、Yih-Jang Wu、Ji-Wang Chern

  DOI：10.1021/jm701151c

  日期：2008.3.1

  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.