A Series of Lithocholic Acid Olefin (C11-C12) Analogs as Sialyltransferase Inhibitors : Synthesis and Preliminary Bioactivity Studies

• Main Author: 陳曼芸
• Other Authors: 李文山
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/36905303055594242770

碩士 === 國立臺灣師範大學 === 化學系 === 100 === Aberrant expressions of sialyltransferases (STs) have been reported to positively correlate with many cancers. Therefore, we interest that the development of sialyltransferase inhibitors to modulate sialyltransferase activity and thus alleviate or inhibit physiological processes (e.g., alteration of sialylation in cell surface and sialylation of glycoproteins/glycolipids) caused by sialyltransferases. In this thesis, we initially designed a potential STs’ inhibitor containing an olefin moiety within C-ring (C-11/C-12) of the lithocholic acid as a parent skeleton (compound EY-22). Synthesis of EY-22 was carried out from deoxycholic acid as the starting material. First, both the carboxylic acid at C-24 and the hydroxyl group at C-3 of deoxycholic acid were selectively protected. The protected deoxycholic acid was esterified to yield the required mesylate ester (mesylation of the hydroxyl group at C-12), which was subsequently converted to the protected lithocholic acid with an olefin at C-11 by the method of demesylation. However, demesylation resulted in a mixture compounds with the presence of desired product and steroidal rearrangement compound in the ratio of 1:1. Efficient formation of demesylation product was obtained from modification of reaction conditions. The final product EY-22 was accomplished after removal of the remaining protecting groups. A series of EY-22 based derivative, EY-36、EY-37、EY-39、EY-43、EY-45 and EY-46 (containing Asp, Glu, NBD and 4-nitrobenzoic acid moieties), were successful prepared according to the procedure described previously. Interestingly, effective disruption of wound closure was observed for cells cultured in the presence of derivatives EY-36、EY-39 and EY-45 compared to deoxycholic acid and DX-5. Assays of sialyltransferase inhibition are underway.