Synthesis, Structures And Antitumor Activities Of Oxamide-bridged Polynuclear Complexes Based On DNA Interactions

Studies on the design and exploitation of new metal complexes with antitumor activities were always hot spots in the filed of inorganic medicinal chemistry, since the discovery of the anticancer activities of cis-platin and its successful application in clinic. Investigation of the interaction between metal complexes and DNA could obtain important information about the novel antitumor or anticancer drugs design and the mechanism of action of drugs. In order to explore new effective anticancer drugs that could selectively inhibit tumor cells, in this dissertation, eleven polynuclear complexes with two dissymmetrical N,N′-disubstituted oxamides or their mononuclear complexes as the ligands have been designed and synthesized, their crystal structures, DNA-binding properties and antitumor activities also have been studied systematically. The detail contents include several aspects as follows:1. Synthesis and structures of bridging polynuclear complexes: eleven polynuclear complexes have been synthesized by choosing N-(2-carboxylatophenyl)-N′-[3-(dimethylamino) -propyl]oxamidate (H₃dmapob), N-benzoato-N′-[3-(dimethylamino)propyl]oxamido (H₃pdmapo), or mononuclear complexes (Na[Cu(dmapob)], Na[Cu(pdmapo)]) as the bridging ligands, including: three binuclear complexes [Cu₂(dmapob)(NO₂-phen)(H₂O)](ClO₄)·(H₂O) (1), [Cu₂(dmapob) -(dabt)(CH₃OH)](ClO₄) (2), [Ni₂(dmapob)(dabt)(CH₃OH)₂](ClO₄)·0.25CH₃OH (3); four tetra -nuclear complexes [Cu₂(dmapob)(phen)]₂(ClO₄)₂·(CH₃OH) (4), [Cu₂(dmapob)(dmbt)]₂(ClO₄)₂ (5), [Cu₂(dmapob)(Me2bpy)]₂(ClO₄)₂·2H₂O (6), [Cu₂(dmapob)(Me2bpy)]₂(pic)₂·6H₂O (7); one one-dimensional complex {[Cu₂(dmapob)(dabt)]NO₃·0.6H₂O}_n (8); and three binuclear complexes [Cu₂(pdmapo)(phen)(H₂O)](NO₃) (9), [Ni₂(pdmapo)(phen)₂](ClO₄) (10), [Cu(pdmapo)(H₂O)Ni -(bpy)₂](ClO₄) (11). Their structures have been characterized by elemental analyses, IR and single-crystal X-ray diffraction. The influence factors of the crystal structures of these complexes, and the effects of hydrogen bonds andπ-πstacking interactions on the crystal structures and supramolecular structures of these complexes were also discussed.2. Interactions of complexes with DNA: the DNA-binding properties of the eleven complexes have been studied by the electronic and fluorescence spectra, electrochemical measurements and viscosity measurements. Besides, the influences of the types of metal ions, terminal ligands and counter-ions on the interactions between complexes with HS-DNA were also investigated. The results reveal that all of the eleven complexes interact with HS-DNA via the intercalation mode, and according to the difference of the metal ions, terminal ligands and counter-ions, the bonding strength of these complexes with HS-DNA follow the order: (1) > (2) > (3); (4) > (5) > (6) > (7); (9) > (10) > (11).3. In vitro antitumor activities of complexes: The in vitro antitumor activities of complexes (1)-(11) against two cancer cell lines: human hepatocellular carcinoma cell line SMMC-7721 and human lung adenocarcinoma cell line A549 were tested by SRB method, the results indicate that except complex (8), other ten complexes have a certain cytotoxicities against SMMC-7721 and A549 cell lines, with IC₅₀ values less than 100μg/mL, respectively. Especially, complexes (3) and (11) show the strongest in vitro antitumor activities against the two cancer cell lines in these complexes, and the IC₅₀ values are in the ranges of 30⁶0 ng/mL.The researches of this dissertation enrich the content of oxamide-bridged polynuclear complexes, supply the chemical basis to explore novel bridging polynuclear complexes with high activity, low toxicity and antitumor activities, and could be the valuable references for studying the relationship between structures and properties of complexes.