Design And Synthesis Of Glycoclusters Involved In The Hyperacute Rejection Of Xenotransplantation

Tissue and organ transplantations have become routine surgery to save human lives from organ failure. The majority of the clinically successful surgeries are of allotransplantation type, which is hampered by shortage of donated human organs . Therefore, Xenotransplantation, is the use of animals instead of humans as a source of organs, tissues and cells, present a practical solution to the shortage of donated human organs for transplantation. However, xenotransplantation has been hampered by xenograft discordance mainly caused by hyperacute rejection (HAR). Recent studies indicated that HAR can be triggered by the recongnition of naturally occurring human anti-Gal antibodies to carbohydrate epitopes bearing a Galal-3GalB terminus(termed a-Gal ) on the surface of xenograft cells. As a result, antibody-dependent cell-mediated cytotoxicity by human blood monocytes and macrophages along with the cascade of complement-mediated lysis of cells can destroy an organ in minutes to a few hours. In order to overcome HAR in pig-to-human xenotransplantation, several approaches have been proposed, one of which is to inhibit the binding of the a-Gal to anti-Gal using synthetic a-Gal. While the interaction between carbohydrate and protein is rather weak, and the multivalent interaction can increased the binding affinity greatly.Based on the above-mentioned, two kinds of target glycoclusters with different glycoterminus, flexible linkers and different scaffolds were designed, disaccharide glycocluster ( including TM1-TM7) and trisaccharide glycocluster(TM8-TM9) respectively , with the purpose of obtaining glycoclusters with high binding affinity to anti-Gal antibody and thus better inhibiting the HAR.According to the different structures of designed target compounds, , convergent and divergent strategies were chosen to synthesize the target compounds correspondingly . target compounds (TM1-TM7) were synthesized by divergent strategy which was realized by glycosylation of the flexible linker with the disaccharide glycoterminus and then coupled to the different scaffolds ( rigid and flexible ).with the bearing reactive moiety ( carboxylic group and amine groups) found in the linkers, and in this way can we avoid the trouble caused by simultaneous multistep glycosylation encountered in convergent strategy. In contrast, target compounds (TM8-TM9) were synthesized using convergent strategy that was furnished by direct simultaneous multistep glycosylation of the flexicible scaffolds with the trisaccharide glycoterminus.In this dissertation, A total of 60 compounds were synthesized, 20 of which are unreported with 8 target compounds included, most of the compounds were confirmed by IR, 1HNMR, 13CNMR, HMBC and HMQC; and screening of their bioactivities are under way.