Cancer is a major extensive health problem which is the second leading cause of mortality in developed countries and most frightening disease in humans. DNA, as the carriers of genetic information of the living body, is not only the basis of biological growth, development, reproduction and other important life activities, but also closely related with tumor, viral infection and genetic diseases. The DNA is becoming one of the most promising biological targets of developing antitumor agents to constrain tumor cell growth.

The structure of precursor 1,8-naphthalimide was used as parent compound, and the triazole pharmacophore and benzothiazole was linked to naphthalene at 4 site by Click reaction. Based on this, we synthesized a series of novel “non-fused” naphthalimide derivatives first. Their structures were proved by TOF MS and ¹HNMR. Then we used UV-vis spectra, Fluorescence spectra, CD spectra and viscosity assay to discuss their action modes on DNA. Finally we employed MTT assay to further evaluate their antitumor activities.

The UV-vis spectra, fluorescence spectra, CD spectra and viscosity assay showed that the compounds could intercalate into DNA. The changes of UV-Vis spectra and enhancement of fluorescence intensity proved that the compounds could intercalate into the DNA effectively. CD spectra results indicated that M3 could turn the conformation of DNA from B to A-like, M4 could change the B-DNA to C-DNA, and M5, M6 stabilized the B-DNA. According to the bioactivities assays, the compounds exhibited efficient toxicity against tumor cells in vitro, in particular M3 and M4, whose IC₅₀ values against MCF-7 cells and Hela cells were 0.35μM, 0.12 μM and 0.66 μM, 0.19 μM, respectively. Moreover, both of them had better selectivity against MCF-7 cells and Hela cells than 7721 cells. When two nitrogen atoms of the side chain of the compounds separated by two carbon atoms, it showed significant inhibitory activity, such as M1, whose IC₅₀ values against MCF-7 cells, Hela cells and 7721 cells were 2.33 μM, 0.35 μM and 0.49 μM, respectively.Fig. 1 CD spectra of naphthalimide derivatives

Introducing various flexible side chains amine has great impact on biological activities of naphthalimide derivatives. It has vast importance to expand and develop new and efficient antitumor drugs of naphthalimide. It’s an effective way to improve the efficacy of antitumor activity by introducing the structure of triazole and benzothiazole to naphthalimide in the para position.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21576043), supported by “the Fundamental Research Funds for the Central Universities”.