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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/21739


    標題: 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
    貢獻者: 藥學系         
    日期: 2008-03
    上傳時間: 2009-10-13 10:53:01 (UTC+8)
    摘要: A β-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 β-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli β-glucuronidase had a quite low Km of 0.18 µM 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 β-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.
    關聯: Journal. Medicinal Chemistry 51(6):p.1740-1746
    Appears in Collections:[藥學系(所)] 期刊論文

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