HETEROCYCLES [h]-FUSED ONTO 4-OXOQUINOLINE-3-CARBOXYL-IC ACID,III.FACILE SYNTHESIS AND ANTITUMOR ACTIVITY OF MODEL HETEROCYCLES [a]-FUSED ONTO PYRIDO[2,3-f]QUINOXAL-INE-3-CARBOXYLIC ACIDS

摘要

Direct interaction between 7-chloro-1-cyclopropyl-6-fiuoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and each of(S)-proline,(2S,4R)-4-hydroxyproline and(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in hot aqueous ethanolic NaHCO3 yielded the corresponding optically pure N-(4-oxoquinolin-7-yl)-alpha-amino acids.The latter derivatives underwent reductive lactamization upon treatment with Na2S2O4 in aqueous ethanol to afford moderate yields of the respective pyrido[2,3-f]quinoxaline-3-carboxylic acid [fused]-to tetrahydropyrrolo[1,2-a]-,tetrahydrohydroxylpyrrolo[1,2-a]-and tetrahydroisoquin-olino[2,3-a]heterocyclics 10-12,respectively.The antitumor activity against four human tumor cell lines showed that 10-12 displayed high levels of cytotoxicity as compared with Cisplatin.Interestingly,these compounds were more potent against breast carcinoma cell lines(MCF-7 and T-47D)than the lymphoid origin tumor cell lines(Jurkat and BHL-89).In particular,the(S)-proline derivative 10 exhibited preferential cytotoxicity to adherent cells(IC_(50)= 0.5(mu M),indicative of better potential in blocking the growth of solid tumors rather than the disseminated ones.