Syntheses, Structures And Anticancer Activities Of Functional Molecules Based On DNA Interactions

Design, synthesis, structure and property of functional molecules based on DNA interactions have gotten extended interests for their playing an important role in the design, synthesis and mechanism of drug.To search for effective antitumor functional molecules and obtain information for the design of new DNA targeting non-platinum metallic antitumor compounds,the syntheses,structures,antitumor and antibacterial activities of polynuclear complexes, which were bridged by N,N'-bis(substituent)-oxamide ligands,and natural organic substances were studied systematically in this dissertation. This dissertation consists of four sections as follows:1.Synthesis and structures of polynuclear complexes.N,N'-bis(substituent)-oxamides have played a key role in designing polymetallic systems because their coordinating ability. It has been shown that some complexes bridged by N,N'-bis(substituent)oxamides exhibited antitumor activity. Herein, four binuclear complexes, four tetranuclear complexes and five polymer-metal complexes bridged by symmetrical and dissymmetrical N,N'-bis(substituent)oxamides and one binuclear cobalt complex bidged both byμ-peroxo andμ-hydroxyl have been synthesized and characterized by elemental analysis, molar conductivity measurement, IR and electronic spectral studies and single crystal X-ray diffraction. The crystal structure analyses showed that hydrogen-bonding andπ-πstacking played an important role in the formation of supermolecular structures in these complexes.A 2-D polymer-metal complex [Cu2(heae)(N3)2]n bidged both by N,N'-bis(substituent)oxamide and azido groups was first found, in which azido groups echibited onlyμ-1,1 bridging mode. And in the structure of another polymer-metal complex{Mn[Cu(bhyox)]2}n·2nH2O, in which Mn2+ linked the tertranuclear copper units into 1-D structure,is first reported in the complexes bridged by N,N'-bis(substituent)oxamide with hydroxy group.2. The cytotoxic and antibacterial activities of the functional molecules.The cytotoxic and antibacterial activities of the complexes and the natural organic substance,tephrosin and rotenone were examined by SRB method and microdilution broth method, respectively.The results showed that the complexes bridged by the N,N'-bis(substituent)oxamide containing hydroxyl group and the complex bidged byμ-peroxo exhibited potent cytotoxic effects against P388 and BEL 7404 with the lowest IC50 value of 8.1μM. Tephrosin and rotenone exhibited potent cytotoxic effects against HCT8HCT8,BEL7402 and A2780 with the lowest IC50 value of 0.1μM. Most complexes displayed antibacterial activities.These investigations have opened vast perspectives of polynuclear complexes in the fields of biology.3.DNA-binding and cleavage properties of the complexes.The DNA-binding properties of the N,N'-bis(substituent)oxamide ligands, complexes, tephrosin and rotenone, were explored by using absorption and emission spectral, electrochemical methods and viscometry. The results show that the interaction modes of most complexes are intercalation. The effects of metal ions,and the structures of ligands on DNA interactions with the complexes were also studied. The DNA cleavage properties of the complexes were monitored by agarose gel electrophoresis.The results indicate that three tertranuclear copper(Ⅱ) complexes bridged by dissymmetrical N,N'-bis(substituent)oxamide can cleavage pBR322 DNA directly and the lowest effective concentration was 12.5μM. The possible mechanism of the DNA cleavage property of the three complexes may be through hydrolysis of the DNA phosphate esters in solutions.4.Inhibitory activity of complexes against DNA topoisomeraseⅠ.Overcome the limitations of the structure of camptothecin, two complexes, [Cu2(heae)(Me2phen)2](ClO4)2·H2O and [Cu4(bhyox)2(phen)2](ClO4)2, with inhibitory activity against DNA topoisomerase I are first reported. The IC50 values of the two complexes were 8.8μM and 13.2μM, respectively, which are lower than that of hydroxycamptothecin (OPT).From these researches, a new idea of the design of inhibitory agent against DNA topoisomeraseⅠcan be obtained.