The Study Of Osthole And Ruthenium(?),Iridium(?) Polypyridyl Complexes On Antitumor Activity

At present,there is still a major medical problem for the therapy of malignant tumors in the world,with the progress of science and technology,scientists continue to seek new anticancer drugs and have in-depth study on its mechanism of anti-tumor,in order to triumph over human malignant tumor.The Chinese medicine8 has a profound history,with its low toxicity and mild side effect8 has attracted much attention.In the new era,applied new scientific methods and technology in developing new pharmacological properties of traditional Chinese medicine,has become a hot spot.Osthole,as traditional Chinese medicine,has a variety of therapeutic effects,what's more,though the inexplicit mechanism,in the latest study8it's reported that osthole has unique anti-tumor effect,therefore this paper has done a study on the anti-tumor mechanism of osthole in gastric cancer cells.Meanwhile,in the exploration of diversified antitumor drugs,the metal complexes8 be in a very important position,have made many breakthroughs,but its application still has limitations,hence8 in order to develop the targeted,high efficiency and low toxicity of transition metal complexes for antitumor drugs8 we still need to continuously study on it.So in this study,we have synthesized two new iridium(III)complexes and a series of ruthenium(II)complexes to study on the anti-tumor mechanism of them and made some discussion.All of the antitumor drugs in this paper,osthole is Chinese medicine monomer.Ruthenium(II)and iridium(III)complexes have been designed and synthesized in the laboratory and characterized by elemental analysis,ESI-MS,1H NMR and 13 C NMR and so on.In this thesis,we investigated the antitumor activity and anti-tumor mechanisms of the selected drugs from nine main aspects: cytotoxicity,apoptosis,reactive oxygen species,mitochondrial membrane potential changes,DNA damage,cell cycle distribution,invasion,autophagy and apoptotic protein expression.The experimental results show that osthole and the designed metal complex exhibit good antitumor activity.The morphological changes and apoptotic levels of apoptotic cells were observed through AO/EB,Hoechst 33258 and Annexin V/PI staining assay.ROS experiments showed that the intracellular levels of reactive oxygen species increased after the treament of osthole,ruthenium(II)or iridium(III)complexes respectively,meanwhile,the mitochondrial membrane potential decreased can be found in the mitochondrial membrane potential experiment.The antitumor drugs8 studied in this paper8 have a blocking effect on the cell cycle,meanwhile it is found that osthole and one kind of the iridium(III)complexes can cause DNA damage and form tailing in comet assay. In addition8 except of the ruthenium(II)complexes,osthole and the iridium(III)complexes can cause cell autophagy.In the study of invasion,osthole and the metal complexes were capable to inhibit the ability of invasion of the corresponding selected tumor cells.Finally,the expression of the apoptotic protein indicated that osthole and the metal complexes can increase in the expression levels of Bax and Bak and suppressed the expression of the anti-apoptotic protein Bcl-2 and Bcl-x,which can further lead to the activation of caspase cascade.In conclusion,osthole and the metal complexes may induce apoptosis of tumor cells through ROS-mediated mitochondrial apoptosis pathway.