Design,Synthesis And Anti-tumor Biological Activity Evaluation Of Novel Platinum Complexes

Platinum anticancer drugs have been widely used in various solid tumors because of their unique mechanism of action and excellent antitumor activity.They have become the first-line of chemotherapy for clinical treatment.Although patients have a high sensitivity to platinum drugs,serious side effects and drug resistance are almost the clinical drawbacks of all platinum drugs during treatment.In order to improve these deficiencies,designing novel platinum antitumor drugs and constructing platinum drug targeting drug delivery systems are important options for the study of new platinum anticancer drugs.On the basis of the classical structure-activity relationship of traditional mononuclear platinum drugs,the group that has potential anti-tumor effects can be selected to synergistically add platinum functional units to exert dual-function anti-tumor activity.Due to the advantages of non-toxicity,non-immunogenicity,large drug loading,and EPR effect of tumors,gold nanoparticles have become one of the common drug carriers for platinum-based drug delivery system design.In this dissertation,we design the small molecule platinum antitumor drugs with synergistic interactions as the starting point,and use five different carboxylate ions as leaving groups to design a new class of platinum antitumor complexes.Analytical means confirmed its structure and conducted a preliminary study of its antitumor activity.In addition,a hydrophilic PEG chain was designed and synthesized,and lipoic acid-modified gold nanoparticles were prepared and its structure was confirmed,which laid the foundation for the design of gold nanoparticle-based delivery systems of antitumor platinum drugs.The specific content includes the following sections:1.Five kinds of carboxylic acids such as chloroacetic acid,dichloroacetic acid,chloropropionic acid,2-chloropropionic acid and 3-chloropropionic acid were chosenas leaving groups to prepare five novel platinum with classical configurations.Complexes P1-P5 were characterized by NMR,high resolution mass spectrometry and infrared analysis.2.Four types of human tumor cell lines(HEPG-2 human hepatoma cell line,MCF-7 human breast cancer cell line,A549 human lung cancer cell line,HCT116 human colon cancer cell line)were selected for determination in vitro anticancer activity of novel mononuclear platinum complexes P1-P5 by MTT assay.The results showed that P1-P5 all had certain antitumor activity against these tumor cells.Among them,the cytotoxicity of P2 against three of the tumor cell lines exceeded that of the positive control group carboplatin.Moreover,the water solubility of the mononuclear platinum complex P1-P5 is better than carboplatin and oxaliplatin.3.The hydrophilic PEG chain between the lipoic acid-modified gold nanoparticles,the passive target group and the platinum drug active center was successfully prepared,and structure confirmed by transmission electron microscopy,ultraviolet spectroscopy,and nuclear magnetic resonance spectroscopy.