Synthesis, Structure And Cytotoxicity Of Oximide-bridged Polynuclear Copper(Ⅱ) Complexes With DNA-binding Properties

Studies on transition-metal complexes with DNA are of great interest to get information about drug design and tools of molecular biology. Because of the important role of copper(II) played in the body, recently, many copper(II) complexes have been synthesized and their DNA-binding properties studied, and numerous copper(II) complexes have been shown to possess anticancer, anticarcinogenic, and antimutagenic effects both in vitro and in vivo. Oxamides are good candidates as the bridging ligand in forming polynuclear complexes because their coordinating ability toward transition–metal ions can be modified and tuned by changing the nature of the amide. Compared with the extensively researches in symmetrical N,N′-bis (substituted)oxamide polynuclear systems, only few dissymmetrical N,N′-bis-(substituted)oxamide polynuclear complexes have been reported due to the difficulties in their synthesis. However, the fact that those complexes bridged by dissymmetrical N,N′-bis(substituted)oxamides have shown predominant properties prompted us to design and synthesize new polynuclear complexes with dissymmetrical N,N′-bis(substituted)oxamides. Two novel dissymmetrical oxamide ligands and their polynuclear complexes were synthesized and characterized by means of X-ray single crystal diffraction, elemental analysis and IR. The interaction of the ligands and complexes with herring sperm DNA (HS-DNA) has been investigated by electronic absorption titration, fluorescence titration, electrochemical titration and viscosity measurements, and the cytotoxicity activities against SMMC-7721 and A549 were studied in vitro.This thesis consists of four sections as follows: Two novel dissymmetrical N,N′-bis(substituent)oxamide ligands were synthesized: N-phenolato-N′-[2-(dimethylamino)ethyl]oxamide (H₃pdmaeox) andN-benzoato-N′- (2-methylamino-propyl)oxamide (H₃dmaepox) were synthesized and characterized by IR, elemental analyses and X-ray single crystal diffraction. Five oximade-briged polynuclear complexes were synthesized: Varing polynuclear complexes with different end-capped ligand, counter ion and solvent were synthesized. A new dicopper(II) complex, [Cu₂(pdmaeox)(bpy)(H₂O)](pic)·H₂O (2), bridged by H₃pdmaeox (1); four tetracopper(II) complexes, [Cu₄(maepox)₂(bpy)₂](ClO₄)₂·(CH₃OH)₂ (4), [Cu₄(maepox)₂(phen)₂](ClO₄)₂·- (CH₃OH)₂ (5), [Cu₄(maepox)₂(phen)₂(H₂O)₂](pic)₂ (6), and [Cu₄(maepox)₂(me₂bpy)₂- (H₂O)₂](pic)₂·(CH₃CH₂OH)₂ (7), bridged by H₃dmaepox (3) were synthesized and characterized by IR, elemental analyses and X-ray single crystal diffraction.The interaction of the compounds above with herring sperm DNA (HS-DNA) has been investigated: The DNA interaction properties were investigated by electronic absorption titration, fluorescence titration, electrochemical titration and viscosity measurements. The results reveal that the interaction mode of ligand (1) and (3), complexes (4), (5) and (6) with HS-DNA might be intercalate. The interaction mode of complexes (2) and (7) might be electrostatic binding. The result of DNA interaction of ligand (1) and it's related complex (2) indicated that the DNA interaction mode of complex might different from it's complex, which was conformed by ligand (3) and related complex. Our research suggests that bridging ligand,end-capped ligand and counter iron might affect the affinity and interaction mode of complex with DNA.The cytotoxicities of the compounds with SMMC-7721 and A549 are examined by SRB assay in vitro: The results suggest that the two ligands display no cytotoxicities, but all compounds exhibit varying degree cytotoxicities against SMMC-7721 and A549. In particular, complex (5) shows the strongest activities with IC50 values 26 and 35 ng/mL in the two human tumor cell lines, respectively.