Effect Of Ancillary Ligands On The Interaction Of Ruthenium (?) Polypyridine Complexes With Biomacromolecules

In the field of cancer medicine,many researchers are looking for metal complexes with higher efficacy and lower side effects that can replace platinum complexes as anticancer drugs.Among them,aryl ruthenium complexes have been regarded as the potential excellent anticancer agents due to their targeting to tumor cells,high antitumor activity with low toxicity.In this thesis,Three ruthenium?II?polypyridyl complexes([Ru?bpy?₂CCPIP]²⁺,[Ru?phen?₂CCPIP]²⁺and[Ru?dmp?₂CCPIP]²⁺)with the same intercalative ligand CCPIP?CCPIP=2-?2,4-Dichlorobenzene?imidazo[5,6-f]phenanthroline?but different ancillary ligands,were designed and synthesized,and characterized by mass spectrometry?MS?,elemental analysis?EA?and nuclear magnetic resonance?NMR?.Multiple spectroscopic methods including UV-Vis spectrometry,fluorescence and circular dichroism spectroscopies,along with biophysical research methods such as viscosity measurement and computer molecular simulation techniques were applied for the comparative studies on the interactions of the three complexes with human serum albumin?HSA?and calf thymus deoxyribonucleic acid?CT DNA?,respectively.The experimental results of the interactions between the complexes and HSA showed that all the three complexes quenched the fluorescence of HSA with a static quenching mode,and the quenching ability of[Ru?phen?₂CCPIP]²⁺is stronger than the two others.Circular dichroism spectra indicated that the interactions between complexes and HSA led to changes in the secondary structure of HSA.The calculated binding constants and the number of binding sites of the complexes to HSA demonstrated that[Ru?phen?₂CCPIP]²⁺binds to HSA more avidly than[Ru?bpy?₂CCPIP]²⁺and[Ru?dmp?₂CCPIP]²⁺does,and that there is just one binding site existed for complexes to HSA.The thermodynamic analysis further suggested that the interactions of the three ruthenium?II?polypyridyl complexes with HSA are spontaneous processes and the main forces stabilizing the Ru-HSA complexes are hydrogen bonds or vant der Waals forces.Studies on the interaction of complexes with DNA showed that[Ru?bpy?₂CCPIP]²⁺and[Ru?phen?₂CCPIP]²⁺can interact with DNA through an intercalative mode,and[Ru?phen?₂CCPIP]²⁺binds to DNA more strongly than[Ru?bpy?₂CCPIP]²⁺does,while[Ru?dmp?₂CCPIP]²⁺can only partially insert into DNA base pairs.Circular dichroism spectral experiments indicated that all these three complexes bind to DNA stereoselectively to some extent.All above experimental results were better explained by hydrophobic interaction,steric hindrance of the ancillary ligands and density functional theory?DFT?calculations.The computer simulations were performed to investigate the interaction mode of the three ruthenium?II?polypyridyl complexes with HSA and CT-DNA respectively.The docking results confirmed the above experimental results and also showed that[Ru?phen?₂CCPIP]²⁺binds to both HSA and CT DNA more strongly.The main force between the complexes and HSA is van der Waals force,the DNA-binding mode for both[Ru?bpy?₂CCPIP]²⁺and[Ru?phen?₂CCPIP]²⁺isintercalation,and[Ru?dmp?₂CCPIP]²⁺can just partially insert into DNA.All of the above studies suggested that the interaction of complex[Ru?phen?₂CCPIP]²⁺with phen?phen=1,10-phenanthroline?as ancillary ligands with whether the carrier protein HSA or CT DNA is much stronger.The reason may be that the ancillary ligand phen has better hydrophobicity and planarity with less steric hindrance,resulting in a stonger binding capacity to biomacromolecules.These research works could provide some basic information for the study of the structure-activity relationship of metal complexes,as well as the design and development of metal ruthenium complexes as anticancer drugs.