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

  • Bioorg Med Chem Lett. 2003 Mar 10;13(5):867-72. doi: 10.1016/s0960-894x(02)01082-x.
Kazuo Hattori  1 ,  Yasunori Kohchi ,  Nobuhiro Oikawa ,  Hitomi Suda ,  Masako Ura ,  Tohru Ishikawa ,  Masanori Miwa ,  Mika Endoh ,  Hiroyuki Eda ,  Hiromi Tanimura ,  Akira Kawashima ,  Ikuo Horii ,  Hideo Ishitsuka ,  Nobuo Shimma
Affiliations
  • 1. Department of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
PMID: 12617910 DOI: 10.1016/s0960-894x(02)01082-x
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.

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