Synthesis And Characterization Of Naphthalimide Derivatives Containing Sulfone Or Triazine

In this paper,we used naphthalimide which was a typical DNA intercalating agent as theparent,and we introduced the pharmacophores such as cholesterol,cyanuric chloride,and sulfone to modify them.Three series of D,S,and F including 14 new DNA anti-tumor drug molecules were designed and synthesized.Then the interaction between compounds and DNA was investigated by UV spectroscopy,fluorescence spectroscopy and CD spectroscopy.In order to explore its pharmaceutical value,anti-tumor activity tests in vitro were performed.The chapter was based on the novel structure of cholesterol and its derivatives in anti-tumor literature reports.Thus we used 4-bromo-1,8-naphthalene anhydride as raw material,and we designed and synthesized four structures containing cholesteryl ester structure and naphthalene structure of the drug molecules.We used MS,1HNMR and13 CNMR to verify the structure of the moleculars.Through the UV spectrum,fluorescent spectrum,circular dichroism spectrum and viscosity test,we can conclude that the series of compounds can be combined with DNA.(the compound D3 has a maximum binding constant of 1.85×104 M-1)The anti-tumor activity test in vitro indicated that the series of compounds can inhibit the proliferation of MCF-7,A549 and Hela tumor cells at micromolar concentrations.Among them,D3 had the strongest inhibitory potency,and the half inhibitory concentrations for the three tumor cells were 13.36 ?M,21.67 ?M and 23.15 ?M respectively.The cyanuric chloride tri-substituted reaction was designed as the original intention,and naphthalene anhydride structure was also introduced as the intercalation matrix.Six naphthalimide compounds with tri-substituted cyanuric chloride were designed and synthesized as DNA-targeting antitumor agents.The molecular structure was verified by MS,1HNMR and 13 CNMR.The UV,fluorescence,circular dichroism and viscosity tests before and after the interaction of the molecule with DNA indicated that the series of molecules can bind with DNA(the compound S5 has a maximum binding constant of 4.08×104M-1).The in vitro anti-tumor activity test showed that the series of compounds had a significant inhibitory effect on the proliferation of MCF-7,A549 and Hela tumor cells.Among them,compound S5 had the strongest inhibitory potency,and the half inhibitory concentrations for the three tumor cells were 27.23 ?M,11.94 ?M and 22.45 ?M respectively.Similarly,we used 4-bromo-1,8-naphthalic anhydride as the starting material.The thiomorpholine group was firstly introduced into the the naphthalimide precursor.And thenwe synthesized the new drug structure containing sulfone and amine nitrogen oxide with the controlled oxidation conditions,and two molecules of this type were obtained.In a similar manner,we introduced 2-mercaptobenzothiazole into 4-bromo-1,8-naphthalene anhydride and controlled the oxidation conditions to obtain naphthalimide oxide compounds containing both benzothiazole and sulfone.Two molecules of this type were synthesized.The molecular structure was verified by MS,1HNMR and 13 CNMR.Then we used UV,fluorescence,circular dichroism,viscosity testing to explore the mode of action of this series of compounds with DNA.(the compound F2 has a maximum binding constant of 3.54×104M-1)The MTT colorimetric method which was used to investigate the anti-tumor activity of the compounds indicating that the series of compounds can significantly inhibit the proliferation of tumor cells at the micromolar level.Among them,compound F2 had the strongest inhibitory potency,and the half inhibitory concentrations for the three tumor cells were 11.61 ?M,9.58 ?M,and 17.18 ?M,respectively.