title: Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 1.
abstract: In an attempt to search for clinically useful antitumor agents, we have discovered that a series of 1,7-disubstituted-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids possessed moderate cytotoxic activity. We investigated the structure-activity relationships in this series of compounds by changing N-1 and C-7 positions and the core ring structure itself and evaluated the synthesized compounds against several murine and human tumor cell lines. These modifications led us to the following findings. (1) The 2-thiazolyl group at the N-1 position of the naphthyridine structure is the best substituent for antitumor activity. (2) Regarding core ring structure, the naphthyridine derivative is the most active followed by pyridopyrimidine analogue. (3) At the C-7 position, aminopyrrolidine derivatives are more effective than other amines or thioether derivatives. Finally, the trans-3-amino-4-methoxypyrrolidinyl derivative (43j) and the 3-amino-3-methylpyrrolidinyl derivative (43f) as well as 3-aminopyrrolidinyl derivative (AT-3639, 1) were determined to be effective in in vitro and in vivo antitumor assays, and their activity was comparable to that of etoposide.
authors.affiliation: Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33-94, Suita, Osaka 564-0053, Japan. kyoji-tomita@dainippon-pharm.co.jp
authors.forename: Kyoji
authors.initials: K
authors.lastname: Tomita
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tsuzuki
authors.forename: Koh-ichiro
authors.initials: K
authors.lastname: Shibamori
authors.forename: Masanori
authors.initials: M
authors.lastname: Tashima
authors.forename: Fumie
authors.initials: F
authors.lastname: Kajikawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sato
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kashimoto
authors.forename: Katsumi
authors.initials: K
authors.lastname: Chiba
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009368:Neoplasm Transplantation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C469913:7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid; D000970:Antineoplastic Agents; D009287:Naphthyridines; D013844:Thiazoles