Design And Synthesis Of Novel Podophyllotoxin Sulfonylureas And Kinsenoside Derivatives

This thesis described herein involves the two main parts as follow.1. Design, Synthesis and Antitumor Activity Studies of Novel Podophyllotoxin Sulfonylureas DerivativesIn the 1950’s, sulfonylureas was firstly used as the oral hypoglycemic agents in clinical. With the in-depth study on this kind of compounds, it is focused by scientists for the broad-spectrum antitumor activity. Sulfonylureas localizes in mitochondria and make it damage on morphology to kill the tumor cells.Podophyllotoxin is a kind of naturally lignan isolated from the plants. It has been known for approximately 1000 years from its first application in folk medicines to its most recent development in podophyllotoxin derivatives as valuable antitumor agents. Its powerful cytotoxic properties have been attributed by the inhibition of tubulin polymerization and arrest the division process of cells in M phase. Its analogues. Etoposide. Teniposide. and Etopophos are now widely used in clinical cancer chemotherapy. The mechanism of these three drugs is different from that of podophyllotoxin. They act as topoisomerase-Ⅱ inhibitors to induce of DNA single-strand and double-strand breaks, and arrest the division process of cells in S and G2 phase.Design and synthesis of the target compounds, is a combination of the structural characteristics of these two kinds of compounds. not only retains the structure of the podophyllotoxin, also introduces the functional group of the sulfonylurea in the C-4 position of podophyllotoxin active site, in order to find out the efficiency and low toxicity antitumor agents. In this experiment, the target compounds were prepared by three 4β-amino podophyllotoxin derivatives and sulfonyl carbamic acid ethyl esters. These novel sulfonylureas derivatives of podophyllotoxin were screened for their cytotoxicity against four human tumor cell lines, including A549, DU145, KB and KBvin. The results show that the target compounds exhibits antitumor activity. Among them, the compounds 8c and 8e exhibit the best antitumor activity, whose activities are higher than Etoposide.2. Design and Synthesis of Glycosides Kinsenoside AnaloguesKinsenoside as a kind of glycosides is isolated from Anoeclochilus koshunensis (Orehidaeeae, Anoectochilus BI.). Goodyeroside A, the epimer of Kinsenoside, was discovered and isolated from Goodyera R. Br. (Orehidaeeae). The plants of Anoectochilus BI. and Goodyera R. Br. have important medicinal value, such as antidiabetic. bronchitis, nephritis, el al. The studies show Kinsenoside and Goodyeroside A have a high level of antihyperlipemia, decreasing triglyceride levels, antidiabetic, or hepatoprotective effects. The separation of these compounds is difficult for their multi-hydroxy characteristics, it is beneficial to find out a synthetic or semi-synthetic route for the later research in clinical.In this experiment. D-glucose. D-galactose, D-xylose was the starting material. The hydroxyl groups of the glycosyl were protected successively with acetyl group and benzyl group. C-1 of the glycosyl was selectively protected by thioglycoside, and then selectively deprotectd to expose the hydroxyl groups. The glycosides were synthesized by C-1 hydroxyl and y-butyrolactone, and finally Pd-C catalytic hydrogenation to get Kinsenoside and its analogous.