Enzymatic activation of indolequinone-substituted 5-fluorodeoxyuridine prodrugs in hypoxic cells.

Abstract

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.

• Authors: Yota Jiho, Ryohsuke Kurihara, Kiyohiko Kawai, Hisatsugu Yamada, Yoshihiro Uto, Kazuhito Tanabe
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 29 Issue 11 Pg. 1304-1307 (06 01 2019) ISSN: 1464-3405 [Electronic] England
• PMID: 30975626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Ltd.

Chemical References

• Indolequinones
• Prodrugs
• Floxuridine
• NADP
• NADPH-Ferrihemoprotein Reductase

Topics

• Cell Hypoxia (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Floxuridine (chemistry, metabolism, pharmacology)
• Humans
• Indolequinones (chemistry, metabolism, pharmacology)
• Molecular Structure
• NADP (metabolism)
• NADPH-Ferrihemoprotein Reductase (metabolism)
• Prodrugs (chemistry, metabolism, pharmacology)
• Structure-Activity Relationship