| Autor: |
Tsuzuki Y; Chemistry Research Laboratories, Dainippon Pharmaceutical Co. Ltd., Enoki 33-94, Suita, Osaka 564-0053, Japan. yasunori_tuduki@dainippon-pharm.co.jp, Tomita K, Shibamori K, Sato Y, Kashimoto S, Chiba K |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2004 Apr 08; Vol. 47 (8), pp. 2097-109. |
| DOI: |
10.1021/jm0304966 |
| Abstrakt: |
We have previously reported that a series of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids possess moderate cytotoxic activity. In a further attempt to find clinically useful antitumor agents, we investigated the structure-activity relationships (SARs) of a new series of compounds obtained by changing the C-6 position of the fluorine atom in addition to the C-5 and C-7 positions and evaluating their cytotoxic activity against several murine and human tumor cell lines. Our results showed that the 6-unsubstituted 1,8-naphthyridine structure had the most potent cytotoxic activity against murine P388 leukemia twice that of the 6-fluoro analogue. In addition, introduction of an amino group at the C-5 position did not have any substantial effect on the cytotoxic activity, while both the 5-chloro and 5-trifluoromethyl groups decreased the cytotoxic activity by 5- to 10-fold. Moreover, aminopyrrolidine derivatives at the C-7 position showed more potent cytotoxic activity than other amines or carbon derivatives. Among the 7-(3-aminopyrrolidinyl) derivatives, the trans-3-methoxy-4-methylaminopyrrolidinyl derivative (27l) was determined to have potent cytotoxic activity in both in vitro and in vivo assays and high water solubility. Finally, the (S,S)-isomer (AG-7352, 3) of 27l, with a cytotoxic activity against human tumor cell lines more potent than that of etoposide, was selected for further development. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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