Synthesis of 5-fluorouracil derivatives containing an inhibitor of 5- fluorouracil degradation

Article abstract of DOI:10.1248/cpb.41.1498

The reactivities of 5-fluorouracil (5-FUra) degradation inhibitors, 2,4- (2) and 2,6-dihydroxypyridines (3), were investigated. Acylation of 2 and 2,4-bis(trimethylsilyloxy)pyridines with equimolar amounts of acid chlorides preferentially occurred at the 4-OH and 2-OH positions, respectively, and the structure of monobenzoylated 5-chloro-2,4-dihydroxypyridine (2b) was determined as 4-benzoyloxy-5-chloro-2-pyridone (5b) by X-ray crystallographic analysis. Compounds 2 and 3, as well as the N-2-tetrahydrofuryl (11), N- alkyl (12), and N-carbamoyl (14) derivatives of 2, exhibit dynamic keto-enol tautomerism. The acyl derivatives of these pyridines are labile and are thought to be active esters. Monoacyl ester derivatives of these pyridines were combined with 5-FUra analogs to develop novel antitumor agents containing an inhibitor of 5-FUra degradation. One of them, 3-[3-(6- benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5- fluorouracil (BOF-A2) (22b), was the most effective and is currently undergoing late phase-II clinical trials.

Full text of DOI:10.1248/cpb.41.1498

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service