Synthesis And Activity Of Ferrocene Appended Naphthalimide Derivatives

The ferrocene derivatives are one of the famous kind of organometallic compounds,which have beings attracted more and more attention in the development of new drugs due to its excellent physical and chemical properties..The conjugation of ferrocene with organic drug molecules significantly improve the activity of drug molecules,especially in generation of reactive oxygen species?ROS?,the regulation of redox capacity and the improvement of lipophilicity,Herein,we combine ferrocene groups with traditional DNA intercalators naphthalimide to improve the properties of the DNA intercalating agent,promote the production of ROS,and further enhance the anticancer efficacy of the DNA intercalating agent.In this paper,we mainly studied the synthesis of ferrocene appended bis-naphthalimide derivatives,interaction with DNA duplexes and biological activity.First,we synthesized mononaphthalimide appended ferrocene derivatives,Then the DNA binding and anticancer activity of the synthesized compounds were sfudied.All of the results revealed that the conjugation of ferrocene was able to change the binding ability of synthesized compound with DNA and improve the anticancer activity.The flexible chain length play an important role in enhancing the anticancer activity of the compounds.And it was found that ferrocene appended bis-naphthalimide derivative exhibited better activity than that of Amonafide.Based on the above results,we synthesized a series of bis-naphthalimide appended ferrocene derivatives with different chain lengths,and studied the binding mode and ability with DNA by a series of titration experiments.The anti-tumor activity and its possible mechanism of anticancer was studied in vitro.The results showed that the compounds were partially inserted into the base pairs of DNA,When the chain length between the bisnaphthalimides was more than 10 carbon atoms,the compound exhibited the strongest binding ability to DNA.It was also found that and the compound 11a,11f showed the best anticancer activity against HepG2 cells than any other synthesized compounds,The IC₅₀ values were 0.40?mol/L and 2.75?mol/L,for the two compounds,respectively.According to the results,all of the Compounds were well taken up into cells and significantly increase intracellular ROS levels.