The Study On Synthesis And Antitumor Activity Of New Typle Ruthenium(?)Polypyridyl Complex

At present,there are three main types of cancer treatment,chemotherapy,radiotherapy and surgical treatment.Among them,chemical treatment is most commonly used,after comprehensive consideration,chemotherapy has become the first choice for more and more patients.Further development of chemical treatment depends on the research of chemotherapy drugs.Nowadays,there are many kinds of chemotherapeutic drugs used in clinic,but most of them have some disadvantages such as poor water solubility,strong side effects and poor selectivity.Because of the excellent antitumor activity and the small side effects,ruthenium(II)polypyridyl complexes has been paid more and more attention by researchers.This paper aims to develop better and more effective antitumor drugs with the guidance of the principle of rational design for anticancer drugs,the whole work is listed as below:1.Under the guidance of the principle of rational drug design,four new complexes were synthesized.Based on the four complexes,we synthesized fifteen ruthenium(II)polypyridyl complexes and these complexes were characterized by elemental analysis,ESI-MS,1H NMR and 13 C NMR.2.Study on antitumor activity of the synthesized ruthenium(II)polypyridyl complexes.MTT assay was used to screen the antitumor activity of the complexes,and it was found that these complexes have good activity toward specific tumor cells.AO/EB and endocytosis assay showed that the complexes could be uptake into the cell successfully,and the apoptotic morphological features were observed.Single cell gel electrophoresis was used to analyze the effects of complexes on the DNA damage,and it was found that these complexes could cause DNA damage and fragmentation.Quantitative analysis of cell cycle and apoptosis by flow cytometry showed that these complexes could lead to significant cell cycle arrest and induce different degree of cell apoptosis.The changes of intracellular reactive oxygen species(ROS)and mitochondrial membrane potential,as well as the autophagy were analyzed qualitatively by fluorescence microscopy and flow cytometry(FCM).The results showed that these complexes could increase the levels of reactive oxygen species and decrease the mitochondrial membrane potential,what is more,some complexes can induce autophagy.The boyden chamber invasion assay was carried out to investigate the invasiveness of tumor cells,and the complexes could inhibit the cell invasion.Finally,western blot was used to study the signal pathway of apoptosis mechanism,the results show that these complexes can suppressed the expression of the anti-apoptotic protein Bcl-2 and Bcl-x,whereas the increase in the expression levels of Bax and Bak was observed.Owing to these changes,the release of the apoptotic factors in mitochondria occurred,leading to the activation of caspase cascade.Taking all these results together,we conclude that these ruthenium(II)polypyridyl complexes can induce apoptosis through a ROS-mediated mitochondrial dysfunction pathway.