| Oligosaccharides and glycoconjugates play a crucial role in a multitude of important biological processes. The study indicated that as glycoconjugates natural oligosaccharide saponins are one of potent active drugs, which are clinically recognized for their antitumor, antifungal, cardiovascular and cytotoxic activities. This dissertation is focusing on the structure design, chemical synthesis and bioactivity study of active saponin derivatives.In this dissertation, at first, a series of glycosylated chloramphenicol derivatives were designed and synthesized. Their antibacterial activities were investigated in vivo and vitro. The results showed that the water-solubility of the glycosylated analogues has been remarkable improved compared to the original chloramphenicol, and the toxicity and the side effects have been deeply compressed. In the presence of corresponding glycosidase, the antibacterial activities can be resumed completely, indicating that a free primary hydroxyl group of chlorampheniol is critical to its bioactivity. This investigation may open a new field in the design and synthesis of chloramphenicol-like prodrugs.Then, a series of saponin analogues were designed and synthesized as the major work in this dissertation. Our previous study indicates that natural saponin (diosgenyl α-L-rhamnopyranosyl- (1→2) - [β-D-xylopyranosyl- (1→3) ] -β-D-galactopyranoside) shows promising cytotoxic activity towards human hepatocellular carcinoma BEL-7402 with an IC50 of < 6μg.mL-1. In order to explore the Structure-activity relationships, a series of natural saponins analogues containing 3-; 2, 3- branched sugar moieties were designed and synthesized and the cytotoxic activity was examined using Acid phosphatase assay. The results showed that compound 9, 24,29, 58 have promising cytotoxic activity towards human hepatocellular carcinomaBEL-7402 with an IC50 of approximately 3ugmL"', IC90 of approximately 6(igmL"!. Among of them, compound 9 is known good anticancer drug by other research group, compound 24, 29, 58 are new-designed saponin analogues. We find: 1) All of the active compounds need contain 2, 3- branched sugar moieties (2, 4- branched compound has no activity) and the diosgenyl itself has no activity towards human hepatocellular carcinoma BEL-7402 cells, So we proved that sugar moieties are essential components for their activities. 2) In the structure of trisaccharide moieties, the C-2 position of galactose all linked a-L-rhamnopyranosyl. If we got rid of the rhamnose moiety (such as compound 49, 52) or substituted other glycosyl moieties (such as compound 19) for it, the activities of saponin analogues have been deeply compressed or diminished, Which showed that the rhamnose moiety of saponins analogues plays a crucial role in inhibiting the growth of human hepatocellular carcinoma BEL-7402. 3) Of all the saponin analogues, all compounds that non reductive ends linked with monosaccharide of galactose-type (such as galactose, fucose and arabinose) show good activities, especially compound 58 (the C-3 position of galactose coupling galactosyl) which has the best activity, indicating that the terminal galactose has important meaning to anticancer bioactivities of this sort of saponin. It is told that which is related to the binding of galectin. The detailed mechanism is currently under investigation. |
