Modular synthesis of heparanase substrates

다국어 초록 (Multilingual Abstract)

Heparanase, preferentially expressed in many tumor cells, is an endoβDglucuronidase that cleaves specific sites of heparan sulfate. Elevated levels of heparanase expression correlate with tumor vasculatrity, metastatic potiential, and reduced postoperative survival of cancer patients. Consequencely, heparanase detection is considered a tool for cancer discovery. A library of 20 welldefined Tetra1 analogs were prepared in a convergent “2+2” glycosidation manner utilizing a relatively small number of protected disaccharide donors and acceptors. Among three different donors prepared for the fullprotected tetrasaccharide, trifluoroacetimidate donor was most suitable for the preservation and glycosidation reaction, and in each glycosylation, the yield was good and the major anomer was obtained. After coupling these 12 glycosydic reactions, the observation indicate that the coupling ratio is not only relating to the structure and exact nature of acceptors, but also correlated to the structure and size of donors. Key features of the approach include the use of Bz esters or PMB ethers for those hydroxyls that need sulfation, regioselective opening of the 4,6-O-benzylidene acetal for 4OBn that don’t need sulfation and 6OH that need oxidation, an anomeric TBS group for glycosyl donor synthesis, and benzyl ethers just as permanent protecting groups. The HS oligosaccharides will be employed to probe structural features of HS for cleavage of heparanase.