Enzymatic activation of indolequinone-substituted 5-fluorodeoxyuridine prodrugs in hypoxic cells.
Enzymatic activation of indolequinone-substituted 5-fluorodeoxyuridine prodrugs in hypoxic cells.
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DOI：
10.1016/j.bmcl.2019.04.003
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发表时间：
2019-06
影响因子：
2.7
通讯作者：
Yota Jiho;Ryohsuke Kurihara;K. Kawai;H. Yamada;Y. Uto;K. Tanabe
中科院分区：
文献类型：
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作者：
Yota Jiho;Ryohsuke Kurihara;K. Kawai;H. Yamada;Y. Uto;K. Tanabe
在各种酶中，催化单电子还原的还原酶参与缺氧下功能化合物或物质的选择性激活，这是实体瘤众所周知的病理生理特征之一。酶促单电子还原已被认为是一种有用的反应，可应用于肿瘤缺氧靶向药物的设计。在本报告中，我们描述了带有吲哚醌单元（IQ-FdUrd）的5-氟脱氧尿苷（FdUrd）前药的酶促反应，吲哚醌单元是还原酶的底物。细胞色素NADPH P450还原酶处理后，IQ-FdUrd在缺氧条件下被激活释放FdUrd。我们还证实 IQ-FdUrd 在缺氧肿瘤细胞中表现出选择性细胞毒性。
Among the various enzymes, reductases that catalyze one-electron reduction are involved in the selective activation of functional compounds or materials in hypoxia, which is one of the well-known pathophysiological characteristics of solid tumors. Enzymatic one-electron reduction has been recognized as a useful reaction that can be applied in the design of tumor hypoxia-targeting drugs. In this report, we characterized the enzymatic reaction of 5-fluorodeoxyuridine (FdUrd) prodrug bearing an indolequinone unit (IQ-FdUrd), which is a substrate of reductases. IQ-FdUrd was activated to release FdUrd under hypoxic conditions after treatment with cytochrome NADPH P450 reductase. We also confirmed that IQ-FdUrd showed selective cytotoxicity in hypoxic tumor cells.