Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine.
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.
Hattori
Kazuo
K
Department of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Kohchi
Yasunori
Y
Oikawa
Nobuhiro
N
Suda
Hitomi
H
Ura
Masako
M
Ishikawa
Tohru
T
Miwa
Masanori
M
Endoh
Mika
M
Eda
Hiroyuki
H
Tanimura
Hiromi
H
Kawashima
Akira
A
Horii
Ikuo
I
Ishitsuka
Hideo
H
Shimma
Nobuo
N
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
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