Synthesis, DNA Binding And In Vitro Antitumor Activity Of Bis-naphthalene Compounds With Different Diamine Linkers

DNA, the carrier of genetic information, is closely related with a variety of viral infections, cancers and certain genetic diseases. In tumor cells, the small molecules which were designed and synthesized as the target of DNA can be closely interaction with the double helix structure of DNA. They interfere with DNA replication, inhibit the tumor cells growth and result in tumor cells death. Therefore, it has important significance in developing anticancer drugs to study the binding ability between small molecules and DNA duplex.In this paper, some novel bis-naphalenyl compounds with different diamine linkers were synthesized and characterized by 1H NMR, 13 C NMR and HR-MS. The DNA binding abilities of the compounds were studied by using flourescence titration, DNA thermal denaturation experiments, viscosity titration and NMR studies. The cytotoxicity activity of the compounds was evaluated by MTT assay in vitro.First, bis-naphalenyl compound 7 was synthesized to study the influence of peptide linker. The viscosity of titration techniques, fluorescence titration experiments used to study interaction between compound 7 and DNA. It was found that the compound 7 exhibit partial intercalating binding mode. Flourescence titration experiments shown that the binding constant between compound 7 and DNA was a middle-level. The cytotoxicity activities of the compound were evaluated by MTT assay in vitro. According to the results of MTT assay, the IC50 values of the compound 7 was not as the control drug(5-Fluorouracil).Secondly, a series of bis-naphalenyl compounds 9a-e were synthesized. The diamine linkers were changed to vary the length and flexibility of these compounds. The viscosity of titration techniques, fluorescence titration experiments and NMR studies used to study interaction between compounds 9a-e and DNA. It was found that the bis-naphalenyl compounds exhibit partial intercalating binding mode and the binding constants of compounds were in the same order of magnitude. The cytotoxicity activities of the compounds were evaluated by MTT assay in vitro. According to the results of MTT assay, bis-naphalenyl compound 9c with hexamethylenediamine linker, and 9d with p-xylylenediamine linker were found to be more toxic against BGC823 cells. The IC50 values of the two compounds were similar to that of the control drug(5-Fluorouracil) on BGC823 cells. Compared with the results on BGC823 cells, better results were found on SW480 cells. The IC50 values of compounds 9c and 9d were smaller than that of the control drug(5-Fluorouracil). The IC50 values of 9c, 9d, and 5-Fluorouracil were 52.01, 66.09, and 230.11 M, respectively.Finally, a series of bis-naphthalimide derivatives 13a-e were synthesized. Their DNA binding abilities were studied by UV titration experiments, fluorescence titration experiments, the viscosity of titration techniques. According to the results above, we found that the binding constants of the compounds were decreasing with the length increasing in the linker. But the results of anti-tumor activity in vitro were less significant. The sequence selectivity of the compound 13 a was studied by UV titration experiment. Then we found that the compound 13 a prefered to binding with AT base pairs. The cytotoxicity activities of the compounds were evaluated by MTT assay in vitro. According to the results of MTT assay, the IC50 values of the compounds was not as the control drug(5-Fluorouracil).