| Summary: | 碩士 === 國立臺灣大學 === 藥學研究所 === 99 === Saponin, a naturally occurring glycoside with diversities of structures and bioactivities, can be structurally divided into 2 major types-triterpenoidal and steroidal glycosides. The common features of steroidal spirostan saponins are hemolytic and cytotoxic where the sugar units are often required for function in vivo, but their roles at the molecular level are not well-understood. Due to the complexity of structures and limited availability of homogeneous saponins, development of practical methods for modification of the carbohydrate domain of natural products may lead to a better understanding of the structure activity relationships (SAR) of saponins and have better chance to identify new therapeutics.
Dioscin (diosgeninyl 3b-O-(2,4-di-O-a-L-rhamnopyranosyl-b-D-glucoside)), one of the most common steroidal spirostane saponins found in rhizome of Dioscoreaceae, exhibits potent antitumor activities. Thus, in order to study the SAR of dioscin, a series of analogues were designed and synthesized by the protection strategy. Glucose, as a common core structure of dioscin, was chosen and orthogonal protected to 3,6-di-O-benzyl-4-O-levulinoyl-2-O-(2-nitrophenylacetyl)-D-glucopyranosyl trichloroacetimidate 141. Compound 141 was then subjected to glycosylate with 6b-O-acteyl-chlorogenin 145 to give compound 164 which was selectively deprotected, glycosylated with various glycosyl donors, and global deprotected to obtain a library of dioscin analogues.
The effect of these analogues on human prostate carcinoma (PC-3) was studied via SRB assay, and the results showed that the compound had no inhibition of growth at 10 uM level. Only 97 and 104 with 2''-O- L-fucosyl and L-rhamnosyl, respectively, displayed weak cytotoxicities at a dose of 30 uM (still with GI50 ＞30 uM). Current study demonstrated that these dioscin analogues were not cytotoxic toward PC-3. Further studies of these derivatives for other cancer cell lines will be performed.
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