The Antitumor Mechanism Of Phenanthroimidazole Derivatives And Ruthenium(Ⅱ) Complexes

Hepatocellular carcinoma(HCC)is one of the most common malignancy tumors with a high mortality rate,which becomes an important global health issue.Chemotherapy is an important means of cancer treatment.However,since no effective chemotherapy is available,the prognosis of advanced HCC patients is dismal.Therefore,it is necessary to find new effective medications for HCC.Development of pharmacologically effective agents with few side effects or little toxicity has become a goal for the researchers.In this paper,a series of imidazo[4,5f][1,10]phenanthroline derivatives 1-6 and two ruthenium(II)complexes have been designed and synthesized by microwave-assisted synthesis technology.The antitumor activity and their molecular mechanism are carried out as following:(1)A series of imidazo[4,5f][1,10]phenanthroline derivatives 1-6 were synthesized by using 1,10-phenanthroline as raw material.The structure of the phenanthroimidazole derivates were characterized by ESI-MS,1H-NMR and 13 C NMR.(2)MTT assay was used to demonstrated that the complexes have dose-dependent cytotoxic activity against a panel of human cancer cell lines,especially the complex 6 for Hep G2 cell lines.Moreover,compound 6 induced apoptosis was detected by flow cytometric analysis.The morphological changes observed under the inverted phase contrast microscope.A large numbers of cytoplasmic vacuoles were found in the cytoplasm,and the vacuoles became larger and denser with the increase of the concentration of compound 6.Transmission electron microscopy(TEM)was performed to furture observed the ultrastructural changes of Hep G2 cells treated with compound 6.To test autophagy at molecular level,the expression of LC3-II and Beclin1 were detected by western blot.(3)DNA ladder,flow cytometric analysis and Western Blot were employed to study the anti-tumor mechanism induced by compound 6.The results showed that compound 6 induced cell cycle arrest in G2/M phase.At the same time,compound 6treatment caused DNA damage,as shown by ladders in the DNA ladder analysis and upregulating the γ-H2 AX protein expression.The interaction between compound 6and DNA was further confirmed by several spectroscopy methods,and the results showed that compound 6 can bind with DNA.(4)Two ruthenium(II)complexes have been synthesized and their antitumor activity were demonstrated by MTT assay.The further studies show that both complexes can bind to CT-DNA.In conclusion,these complexes can be used as a promising inhibitor in chemotherapy,and their DNA binding behavior play a key role.