1 0 0 0 OA Synthesis of 5-Fluorouracil Derivatives Containing an Inhibitor of 5-Fluorouracil Degradation
- 著者
- 廣橋 満 木戸 勝 山本 栄仁 小島 裕 實川 浩一郎 藤井 節郎
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.41, no.9, pp.1498-1506, 1993-09-15 (Released:2008-03-31)
- 参考文献数
- 23
- 被引用文献数
- 6 10
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 crystallo-graphic 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.
- 著者
- 滝川 浩郷 森 謙治 木戸 勝 Albizati K. F. Faulkner D. J.
- 出版者
- 天然有機化合物討論会実行委員会
- 雑誌
- 天然有機化合物討論会講演要旨集
- 巻号頁・発行日
- vol.34, pp.707-714, 1992
In 1985, limatulone (1a and 1b) was isolated from the intertidal limpet Collisella limatula, and found to inhibit fish and crab predation. It is the most potent fish feeding inhibitor and is about an order of magnitude more effective than polygodial. Although the natural limatulone was optically inactive, it was not clear whether it was a meso-compound (1a) or a racemate (1b). We therefore decided to confirm the structure by a total synthesis. The known 3, which was obtained from the starting material (2) in 4 steps, was alkylated with BrCH_2CO_2Et to give 4a. The corresponding acid 4b was employed for the lactone-ring formation to give a stereoisomeric mixture of lactones 5a and 5b. After separation, lactone 5a was converted to the coupling-partners 10 and 11 via 6, respectively. The carbanion derived from 11 was alkylated with 10 to give a complex mixture, which was desulfonylated with Na-Hg to give a mixture of 12a and 12b. This was converted to a separable mixture of 13a and 13b. Fortunately, the structure of the less polar isomer could be solved by an X-ray analysis. An aldehyde 15a, which was prepared from 13a in 3steps, was treated with ClCH_2Li to give bis-epoxide 16a. Epoxide-opening of 16a by a Grignard reagent gave 17a. Swern oxidation of 17a to 18a was followed by removal of the EE protective groups to give meso-limatulone (1a), (overall yield: 0.62% from 2 in 24 steps). Similarly, (±)-13b was converted to (±)-limatulone (1b), (overall yield: 0.39% from 2 in 24 steps). The ^1H-NMR spectrum of the reported limatulone was identical to that of (±)-limatulone (1b). To our surprise, however, another fraction from the HPLC of Collisella limatula showed the ^1H-NMR spectrum superimposable on that of meso-limatulone (1a). Accordingly, Collisella limatula produces both meso-1a and (±)-1b.