The Anticancer Activity Of Osmium And Ruthenium Complexes Bearing N,O Aryl Ligands Induced Endoplasmic Reticulum Stress In Vitro

Cancer is one of the common fatal diseases,chemotherapy is a major clinical treatment.At present,platinum anticancer drugs such as cisplatin are the first-line drugs used in the clinical treatment of cancer.However,limited by drug resistance and side effects,researchers have turned their attention to new metal-based anticancer drugs.Nowadays,some new metal-based anticancer drugs including ruthenium,osmium,iridium and gold complexes,etc.,which mostly show distinct pharmacological activities and anticancer mechanisms from traditional platinum anticancer drugs.This thesis contains two subjects:（1）two nitrido osmium（VI）complexes containing benzoimidazole or benzothiazole ligands,（2）osmium（III）and ruthenium（III）complexes with schiff base,pyridine and triphenyl phosphine liands.In the first chapter,we studied the synthesis and antitumor activity of the osmium（VI）having benzoimidazole or benzothiazole ligand.The stability of the complexes in solution was tested by UV-Vis spectrophotometer,and in vitro anticancer activities of the complexes were determined by MTT assay.The anticancer mechanism of the complexes was determined by means of flow cytometry and western blotting.MTT assay showed that the IC₅₀ was was similar to that of cisplatin in vitro,which could inhibit the proliferation of tumor cells.The cell cycle data indicated that Os N-PBS could induce cell arrest in the S phase and G2/M phase.In addition,the experimental data also showed that Os N-PBS could induce cell starvation and decrease intracellular ATP,induce endoplasmic reticulum stress and autophagy to inhibit cell proliferation.In the second chapter,the anticancer activities of osmium（III）and ruthenium（III）containing schiff base,pyridine and triphenyl phosphine liands were studied.By means of flow cytometry,DNA electrophoresis,and western blotting,we evaluated their different antitumor mechanism.It was showed that[Ru^Ⅲ（NHPPh₃）（salen）（py）]⁺can cause cell cycle arrest and induce necroptosis and apoptosis,while[Os^Ⅲ（NHPPh₃）（salen）（py）]⁺can induce apoptosis and cause DNA fragmentation.Through comparism,it was showed that[Ru^Ⅲ（NHPPh₃）（salen）（py）]⁺has stronger cytotoxicity than[Os^Ⅲ（NHPPh₃）（salen）（py）]⁺.