A Comparative Study On The Interaction Of The Chiral Ruthenium(Ⅱ) Complexes With DNA And Their Antitumor Activities

In this thesis, a pair of ruthenium（II）-based enantiomers Δ-[Ru（bpy）₂PBIP]²⁺ andΛ-[Ru（bpy）₂PBIP]²⁺（bpy = 2,2’-bipyridine, PBIP = 4-bromophenyl imidazo [5,6-f]phenanthroline） have been designed and synthesized. The systematic comparative studies on the interactions of the two enantiomers with calf thymus DNA（CT DNA） and their cytotoxicity, and the apoptosis mechanism of Cervical cancer cell Hela induced by them have been carried out by use of spectroscopic methods, biophysical methods, cell biological methods, along with computer molecular simulation technology. Concretely, this thesis mainly consists of the following aspects:（1） The harmfulness of malignant tumor, as well as the current situation and existing problems in research of anti-cancer drugs have been summarized. The research progress and application of polypyridyl ruthenium（II） complexes, and the research methods of the interactions between metal complexes and nucleic acid have been introduced. On the basis of the summarizations and introductions, the contents of this thesis and the significance of this studies were presented.（2） A new polypyridyl ligand PBIP and the corresponding ruthenium（II） polypyridyl complex enantiomers Δ, Λ- [Ru（bpy）₂PBIP]²⁺ have been designed and synthesized. Both the ligand and the chiral complexes have been characterized by mass spectrometry, NMR spectrometry.（3） The binding behaviors of both the two enantiomers to CT DNA have been investigated systematically and comparatively by spectroscopic methods（UV-visible spectroscopy, fluorescence spectroscopy, circular dichroism method） and biophysical methods（equilibrium dialysis, viscosity experiments）. Experimental results show that both the chiral complexes Δ, Λ- [Ru（bpy）₂PBIP]²⁺ can bind to CT DNA through intercalation, and that ?enantiomer binds to CT DNA more strongly than Λ-enantiomer does.（4） The anti-tumor activity of Δ and Λ-[Ru（bpy）₂PBIP] ²⁺ and the apoptosis mechanism of Hela induced by the experiments of molecular biology and cell biology（cytotoxicity assay,flow cytometry, etc.）. MTT experimental results indicate that the Δ form is more toxic to Hela tumor cells than its Λ form. Flow cytometry results show that the Δ form induces Cervical cancer cell Hela tumor cell apoptosis more efficiently than its Λ form does. In addition, west blot results suggest that the both the two enantiomers may induce the tumor cell apoptosis through the simultaneous activation of both the ectogenic and endogenic apoptosis pathways.This study should be useful and helpful to the design of the potential anti-tumor drugs targeted to nucleic acid.