Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine.

Abstract

A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.

Cite this paper

@article{Hattori2003DesignAS, title={Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine.}, author={Kazuo Hattori and Yasunori Kohchi and Nobuhiro Oikawa and Hitomi Suda and Masako Ura and Tohru Ishikawa and Masanori Miwa and Mika Endoh and Hiroyuki Eda and Hiromi Tanimura and Akira Kawashima and Ikuo Horii and Hideo Ishitsuka and Nobuo Shimma}, journal={Bioorganic & medicinal chemistry letters}, year={2003}, volume={13 5}, pages={867-72} }