Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy
Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy
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DOI：
10.1021/jm701151c
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发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Chern, Ji-Wang
中科院分区：
文献类型：
--
作者：
Leu, Yu-Ling;Chen, Chien-Shu;Chern, Ji-Wang
β-葡萄糖醛酸酶激活的前药方法被应用于 10-羟基喜树碱，这是一种喜树生物碱，具有良好的抗肿瘤活性，但水溶性较差。我们合成了 10-羟基喜树碱 (7) 的葡萄糖醛酸前药，其中葡萄糖醛酸通过自毁 3-硝基苄基醚接头连接到 10-羟基喜树碱的 10-OH 基团。化合物7在pH 4.0的水溶液中的溶解度是10-羟基喜树碱的80倍，并且在人血浆中稳定。前药 7 对四种人类肿瘤细胞系的毒性比母体药物低 10 至 15 倍。在存在 β-葡萄糖醛酸酶的情况下，前药 7 可以被激活，在肿瘤细胞中引发与母体药物相似的细胞毒性。酶动力学研究表明，大肠杆菌β-葡萄糖醛酸酶对化合物7的K-m相当低，为0.18μM，并且对7的催化效率比对6（9-氨基喜树碱的葡萄糖醛酸苷前药）高520倍。分子模型研究预测，化合物 7 与人 β-葡萄糖醛酸酶的结合亲和力高于化合物 6。前药 7 可能可用于通过前药单一疗法 (PMT) 或抗体导向的酶前药疗法 (ADEPT) 策略进行选择性癌症化疗。
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.