Synthesis, Characterization And Biological Evaluation Of Novel Dinuclear Platinum(Ⅱ) Complexes Containing DNA Intercalator

As one of the most important antitumor drugs with unique antitumor mechanism, broad antitumor spectrum and high antitumor activity, platinum-based antitumor drugs have been widely used in treatment of various malignancies. But all these platinum-based antitumor drugs that have been approved around the world have the similar structure and display the same side effects and resistance. Polynuclear platinum complexes, a class of non-classical platinum-based antitumor drugs with pharmacological profiles, different from that of currently used mononuclear platinum antitumor drugs. These complexes have more than one platinum centers and contain polyamine linkers. They bind to DNA in a manner different from that of classical platinum-based antitumor drugs and produce characteristic long-range inter-and intrastrand DNA cross-links. It is believed that polynuclear platinum complexes have the potential to overcome the problem of resistance and thereby much attention has focused on the design of polynuclear platinum-based complexes.Oxaliplatin is the most important representation of the third gernarition platinum-based antitumor drugs. It is also the first platinum-based drug with chiral ligand. The key to success of Oxaliplatin is trans-1R,2R-cyclohexane-1,2-diamine.DNA intercalators are a class of aromatic compounds which can insert into the groove and bases of DNA. This intercalation mode results in a conformational change of DNA, which plays a role of antitumor agent. The discovery of DNA intercalators establishes the foundation for the design of DNA targeted antitumor drugs. Several intercalators are used for the treatment of ovarian and breast cancer as well as acute leukemia.DNA is the common target of platinum-based drugs and DNA intercalators, so we designed and synthesized a novel chiral tetradentate ligand with DNA intercalator and trans-1R,2R-cyclohexane-1,2-diamine. Then we prepared seven novel dinuclear platinum complexes with chiral tetradentate ligand as carrier. Their structures were charactered by elemental analysis, IR,’H-NMR,13C-NMR and ES-MS. The solubility of seven novel dinuclear platinum complexes was tested. Their in vitro cytotoxicity have been evaluated by MTT assay using HepG-2, A549, HCT-116 and MCF-7 cell lines. Results indicated that the synthesized dinuclear platinum complexes have certain selective cytotoxicities against different tumor cell lines and the activity of the complex containing hydroxy is better than carboplatin.