| There are many anticancer drugs in clinic, such as alkylating agent, anti metabolism drugs, antitumor antibiotics, hormones and metal platinum. Although they all work somehow in cancer treatment, generally they may have poor selectivity, immunosuppressive treatment, low efficiency, drug resistance, or the disadvantages of inhibiting the growth of normal cells. Most of them can not meet the needs of clinical medicine. At present, most common solid tumors such as liver cancer, lung cancer, colon cancer and pancreatic cancer still lack effective drugs, so the development of new high efficiency, high selectivity, low toxicity of anti-cancer drugs is urgently needed. The drugs which consist of quinoline compounds have become one of the most common anticancer drugs in clinic. Quinoline compounds are an important class of nitrogen-containing aromatic heterocyclic compounds. The special structure gives quinoline compounds excellent activities in anti-tumor, anti-inflammatory, anti-hypertension and sterilization etc. They play an important role in medicine and pesticide, which are critical in agricultural production and human health. 1,2-dihydroquinolines as an important class of the quinoline compounds, which have rich functional groups and chiral center, have attracted more and more attention in recent years. Based on the current situation of the research and development of 1,2-dihydroquinolines, in this paper we designed and synthesized a series of new quinoline derivatives by the allylation of 1,2-dihydroquinolines, explored the preparation conditions of target compounds, and selected the compounds with good antitumor activity. In addition, we incorporated the compounds into cationic liposomes and studied their antitumor activity.We summerized our main works as follows:1. The synthesis and characterization of 1,2-dihydroquinolines First of all, a series of chloride compounds are obtained by the reflux reaction between corresponding acid and thionyl; a series of quinoline Reissert products, ?-cyano 1,2-dihydroquinolinse, are obtained by the acyl chloride reacting with quinoline and three methyl silane; ?-cyano 1,2-dihydroquinolines and MBH carbonate react to generate a series of allylation products. In this paper, we totally synthesized 21 compounds. The structures of the 21 compounds were characterized by 1H NMR, nuclear magnetic resonance, and mass spectra. In the study of the reaction of Reissert with MBH, it was found that there was a lot of side reactions in the Lewis base catalysis, and the product was difficult to separate. Therefore, we explore the preparation conditions of the reaction products, including temperature, the relative amount of reagents, catalysts, solvents and nitrogen protection groups, etc. We screen the optimum conditions for the preparation of organic synthesis. Finally, a possible reaction mechanism for the formation of 1,2-dihydroquinolines is proposed by us.2. The detection of physical and chemical properties of compounds and the screening of antitumor activity In this chapter, we take the synthesized 21 kinds of 1,2-dihydroquinolines as candidates to screen the compound with best antitumor activity by MTT cell inhibition test. Two types of human hepatocellular carcinoma, Hep G2 and SMMC cells, were selected for the study. All the tested compounds show good anticancer effect at higher concentrations. IC50 experimental results show that 2-cyano-2- Ethyl(2-)-(methoxycarbonyl)- Quinoline-1(2H)-carboxylat(allyl)(compound 3n) has strong inhibitory effect on tumor cells and weak inhibitory effect on normal cells. Thereby, we chose this compound as an anti-tumor drug in following research. The physical and chemical properties of the compound were detected. The results showed that the compound was very difficult to dissolve in water, and the solubility of the compound was good, which is difficult to be directly administered.3. The establishment of the drug delivery system of liposomes and cationic liposomes In order to improve the absorption of compound 3n, the preparation of liposome was selected. In this paper, we take egg yolk lecithin(EPC), D cholesterol(Chol), and two oil phosphatidylcholine(DOTAP) lipid as source materials, use ethanol injection method to prepare two kinds of liposome, liposomes(Cp3n-n Lip) and cationic liposome(Cp3n-c Lip), respectively. Based on 3n compound, the drug loaded Cp3n-n Lip and Cp3n-c Lip are prepared. At the same time, the physical and chemical properties of liposomes were investigated and the drug loading was optimized. The results showed that the optimized preparation conditions for the liposomes were 10%. The diameters of neutral liposome and cationic liposome particles were around 120 nm and around 112 nm, respctively. There are no significant difference in size. The electric potential of neutral lipid was about-6.45 m V, and of cationic liposome was about 41.23 m V. There is a big difference.4. The evaluation of liposomes and cationic liposomes in vitro In this paper, the prepared drug delivery systems of liposome and cationic liposome were evaluated in vitro. The study showed that the two drug loading systems both can maintain good stability in the serum environment by serum stability test and release test in vitro. And the study also showed that the drug delivery system could achieve a certain slow-released effect. The transfection efficiency of Cp3n-c Lip was significantly higher than that of Cp3n-n Lip in two cell lines by flow cytometry and confocal laser scanning. The results showed that cationic liposome could improve the uptake efficiency of tumor cells in the tumor cells. MTT test results showed that in Hep G2 and SMMC cells, the inhibitory effect of Cp3n-c Lip on cells was stronger than that of Cp3n-n Lip.In summary, we take 1,2-dihydroquinolines as the study object. we not only optimize the experimental methods and preparation conditions of organic synthesis, but also explore the anticancer activity of these compounds. Due to many chiral structures of ?-substituted 1,2-dihydroquinolines and isomers by-products, it is very difficult to prepare and purify the organic synthesis products. Therefore, we optimize the synthesis method and the preparation conditions, and successfully synthesized 21 kinds of ?-substituted 1,2-dihydroquinolines. Next, we have screened the 21 compounds for anti-cancer activity in vitro. Finally we find the 3n compounds with highest anti-cancer activity. It is very difficult to deliver the drug due to that the compound is very difficult to dissolve in water. Thereby we develop the compound and liposome complex. The encapsulation of drug by cationic liposome can overcome the disadvantages of poor solubility and low bioavailability, which can prolong the cycle time and the effect of tumor targeting. By exploring the anticancer effect of cationic liposome complex of 1,2-dihydroquinolines, it can lay a solid foundation for further research work in vivo. |
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