title: [Synthesis and anti-proliferative activity of fluoroquinolone C-3 fused heterocyclic α,β-unsaturated ketones derived from ciprofloxacin].
abstract: To discover novel antitumor fluoroquinolone lead compounds from a rational modification for antibacterial fluoroquinolones, a fused heterocyclic ketone corresponding to thiazolo[2,3- b][1,2,4]triazolone used as a bioisosteric replacement of the C-3 carboxylic acid group of ciprofloxacin 1, and further modification by a Claisen condensation reaction with substituted benzaldehydes formed novel fluoroquinolone C-3 fuse heterocyclic α, β-unsaturated ketones as the title compounds (6a-6r), separately. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS, and the in vitro anti-proliferative activity against human hepatoma Hep-3B cells, pancreatic Capan-1 cells and leukemia HL60 cells was evaluated by a MTT assay. The preliminary results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. In particular, compounds carrying an electron-withdrawing carboxyl (6k, 6m) or sulfonamide substituent (6q, 6r) attached to benzene ring were comparable to or better than constractive drug doxorubicin against Capan-1 cells. As such, it suggests that it is favorable for a fused heterocyclic α, β-unsaturated ketone scaffold instead of the C-3 carboxylic acid group to improve the antitumor activity of fluoroquinolones.
authors.forename: Taol
authors.initials: T
authors.lastname: Li
authors.forename: Zhou
authors.initials: Z
authors.lastname: Gao Liu
authors.forename: Yu-suo
authors.initials: YS
authors.lastname: Xie
authors.forename: Yan-fei
authors.initials: YF
authors.lastname: Feng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yan
authors.forename: Shu-min
authors.initials: SM
authors.lastname: Wu
authors.forename: Li-li
authors.initials: LL
authors.lastname: Ni
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Wen-long
authors.initials: WL
authors.lastname: Huang
authors.forename: Guo-qiang
authors.initials: GQ
authors.lastname: Hu
mesh_terms: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002939:Ciprofloxacin / Q000031:analogs & derivatives*; D024841:Fluoroquinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D024841:Fluoroquinolones; D007659:Ketones; D002939:Ciprofloxacin