Studies On Synthesis And Antitumor Activity Of Fluoroquinolone C-3Sym-triazole Thioether Schiff Base Derivatives

Objective: To design and synthetize series of fluoroquinolone C-3s-triazole thioetherschiff-bases compounds,for searching the novel approach and method of structural modification.Preliminary screening these compounds, preliminary investigating the mechanisms of their antitumoreffects, providing a theoretical gist for the application development for this class compounds.Methods: C-3carboxyl group of ciprofloxacin was replaced with (4-aryl-methylene amino)-[1,2,4] triazole thioether to form cyclopropyl fluoroquinolone C-3s-triazole thioether schiff-basederivatives, and C-3carboxyl group of levofloxacin was replaced with (4-aryl-methylene amino)-[1,2,4]triazole thioether to form1,8-(2-methyl ethoxyene) fluoroquinolone C-3s-triazole thioether schiff-basederivatives by utilizing the principles of bioisosterism. The structures of new compounds werecharacterized by MS. The effects of these new compounds on tumour cells proliferation were examinedusing MTT assay.Cell apoptosis was determined using Hoechst33258fluorescence staining.Proteinexpression of caspase-3and p53was detected with Western blot analysis.Results: We devised and synthesized three series of compounds, including12ciprofloxacin C-3triazole thioether Schiff-bases derivatives,12N-AC ciprofloxacin C-3triazole thioether Schiff-basesderivatives and12levofloxacin C-3triazole thioether Schiff-bases derivatives, The structures wereconfirmed by MS.Treatment with levofloxacin C-3triazole thioether Schiff-bases derivatives dramaticallyinhibited the proliferation of the tumour cells,treatment with M15﹑M18﹑M19and M20,the IC50values at24h in human hepatocarcinoma SMMC-7721cells were22.15﹑5.8﹑23.58and21.64μmol/L,respectively. Treatment with ciprofloxacin C-3triazole thioether Schiff-bases derivatives and N-ACciprofloxacin C-3triazole thioether Schiff-bases derivatives inhibited the proliferation of the tumour cellsless obviously. To investigate the mechanism of action of M20further,treatment with M20potentlyinhibited the proliferation of the cancer cell. M20significantly increased the protein expression of p53andCaspase-3.Conclusions: Levofloxacin C-3triazole thioether Schiff-bases derivatives dramatically inhibitedthe proliferation of the tumor cells.The cell-killing effect of levofloxacin C-3triazole thioether Schiff-basesderivatives on the tumor cells relates to inducing apoptosis.