Design, Synthesis And Biological Evaluation Of Chiral Novel Platinum Complexes

In recent years, platinum-based anti-tumor drugs have been regarded as the first-line drugs in the clinical treatment of malignant tumors due to a series of advantages, such as the unique mechanism of anti-tumor, strong anti-tumor activities and wide antitumor spectrum. But its clinical widespread side effects, drug resistance, cross resistance and the target is not clear and so on, have become the obstacles to limit its clinical application.The anti-tumor mechanism of dinuclear platinum complexes is different from that of the traditional platinum complexes. Dinuclear platinum complexes can avoid the clinical defects of the classical platinum anti-tumor drugs in a certain extent, therefore, it will demonstrate the higher anti-tumor activities than the mononuclear platinum complexes.Using supramolecular compounds as drug carriers to bind with platinum complexes to construct the supramolecular-platinum targeted drug delivery systems, which introduce the supramolecular advantages into the platinum anti-tumor drugs, will be expected to solve many problems of the classicl platinum drugs in clinical application. Cyclodextrin as the representative of the second generation of supramolecular compounds, has been used in the construction of supramolecular platinum targeted drug delivery systems.This paper is aimed for finding the novel platinum anti-tumor drugs which could display high efficiency and low toxicity. This work was done in the following two parts:The first part, combined with the advantages of the novel dinuclear platinum complexes and the DNA intercalators,7 novel dinuclear platinum complexes which with DNA intercalators were designed, synthesized and their anti-tumor activities in vitro were studied; The second part, combined with the advantages of supramolecular-platinum targeted drug delivery systems, we designed, synthesized a new kind of cyclodextrin-chiral diaminocyclohexane derivative and the structure was confirmed, which lay the foundation for designing the cyclodextrin-platinum derivative prodrugs which could target rectum or caecum.This thesis includes the following contents:1、 A novel two amine chiral tetradentate ligand HP with the benzene as DNA intercalator was designed and prepared, the structure of HP was characterized by elemental analysis, IR,1H NMR and electrospray ionization mass spectrometry.2、7 kinds of novel chiral dinuclear platinum complexes (D1-D7) were prepared with HP as the ligand and selected seven different leaving groups. Elemental analysis, IR,1H NMR and electrospray ionization mass spectrometry were used to determine the structures of dinuclear platinum complexes (D1-D7).3、 Four kinds of human tumor cell lines (human lung cancer cell line A549, human breast cancer cell line MCF-7, human liver cancer cell line HepG-2 and human colon cancer cell line HCT-116) and one normal human umbilical vein endothelial cell line HUVEC were selected for MTT assay to test the in vitro anti-tumor activities of dinuclear platinum complexes (D1-D7). The results showed that dinuclear platinum complexes (D1-D7) have certain selectivity on different tumor cells and they all showed low cytotoxic activities on normal cells, in addition, when response to the same kind of sensitive tumor cell lines, D7 showed the best anti-tumor activity.4、 A new kind of cyclodextrin-chiral diaminocyclohexane derivative was prepared, and the structure was characterized by the proton nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.