Synthesis,Characterization And Antitumor Mechanism Investigation Of Tricarbonyl Rhenium(Ⅰ)/Polypyridine Ruthenium(Ⅱ)-Daminozide Conjugates

Platinum-based anticancer drugs have been widely used as chemotherapy agents in clinical settings.However,due to their inherent properties,platinum-based drugs exhibit significant toxic side effects and are prone to inducing drug resistance,which limits their long-term clinical utility.Currently,other types of metal-based anticancer compounds have shown promise in overcoming these limitations.Numerous studies have shown that ruthenium and rhenium complexes have unique anticancer mechanisms,which do not target the same pathways as platinum-based drugs and therefore avoid the problem of drug resistance.Furthermore,their antitumor activity often exceeds that of cisplatin.Ruthenium-based anticancer compounds,such as NAMI-A and KP1019,have entered clinical trials,providing new effective options for cancer treatment.Research has shown that one important reason for cisplatin resistance is its targeting of nuclear DNA,which highlights the necessity of searching for alternative targets beyond DNA.JMJD(Jumonji domain containing lysine demethylases)is overexpressed in tumor tissue and plays a key role in catalyzing histone demethylation,thereby promoting transcriptional expression of cancer-related genes,which in turn promotes cancer cell proliferation,metastasis,angiogenesis,and drug resistance.Therefore,one current focus of anticancer drug research is to develop drugs with JMJD demethylase inhibitory activity.Metal complexes bind to small molecules are widely used in developing enzyme inhibitors due to their tunable three-dimensional structures,which can improve binding affinity and selectivity with enzymes,as well as the ability to covalently interact with protein residues,ultimately achieving multiple anticancer mechanisms.Additionally,in recent years,daminozide,used as a plant growth regulator,has been found to possess certain JMJD inhibitory activity,thereby inhibiting cancer cell growth.This provides an effective pathway for the development of more effective and less toxic anticancer drugs.Based on the research background above,a series of rhenium(Ⅰ)or ruthenium(Ⅱ)complexes bonded to daminozide were designed and synthesized,and explored their anti-tumor activity and mechanisms of action.This thesis includes the following three chapters:Chapter 1: Introduces the research progress of rhenium(Ⅰ)and ruthenium(Ⅱ)complexes,as well as the research progress of histone demethylase and apoptosisrelated progress.Chapter 2: Two rhenium(Ⅰ)complexes,Re-1 and Re-2,were designed and synthesized.The study showed that complex Re-2 mainly localized to the mitochondria and caused a series of mitochondrial damage-related events.In addition,Re-2 could further inhibit JMJD activity,induce cell cycle arrest at G2/M phase,and inhibit cell migration and colony formation.Our research shows that these rhenium(Ⅰ)complexes are promising anti-cancer agents with dual functions(including JMJD inhibition and mitochondria-mediated cell apoptosis).Chapter 3: Two ruthenium(Ⅱ)complexes,Ru-1 and Ru-2,were designed and synthesized.MTT assay data showed that Ru-2 has a significant inhibitory effect on tumor cells,and compared with the clinical chemotherapy drug cisplatin,Ru-2 showed higher cytotoxicity against the tested tumor cell lines.Further mechanism studies showed that Ru-2 can inhibit JMJD activity,induce tumor cell apoptosis,including several key events: increasing intracellular reactive oxygen species levels,decreasing mitochondrial membrane potential,and inhibiting tumor cell migration and colony formation.