title: 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.
authors.affiliation: Department of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hattori
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kohchi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Oikawa
authors.forename: Hitomi
authors.initials: H
authors.lastname: Suda
authors.forename: Masako
authors.initials: M
authors.lastname: Ura
authors.forename: Tohru
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Miwa
authors.forename: Mika
authors.initials: M
authors.lastname: Endoh
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Eda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanimura
authors.forename: Akira
authors.initials: A
authors.lastname: Kawashima
authors.forename: Ikuo
authors.initials: I
authors.lastname: Horii
authors.forename: Hideo
authors.initials: H
authors.lastname: Ishitsuka
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000069287:Capecitabine; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D042943:Dihydrouracil Dehydrogenase (NADP); D015195:Drug Design; D004355:Drug Stability; D004950:Esterases / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013939:Thymidine Phosphorylase / Q000378:metabolism; D014018:Tissue Distribution; D014498:Uracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C477084:2',3'-O-diacetyl-5'-deoxy-5-vinylcytidine; D011355:Prodrugs; D003841:Deoxycytidine; C022859:5-vinyluracil; D014498:Uracil; D000069287:Capecitabine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D004950:Esterases; D003564:Cytidine Deaminase; D005472:Fluorouracil