Synthesis of Bisubstrate and Donor Analogues of Sialyltransferase and Their Inhibitory Activities

摘要

Sialyltransferases(STs)are involved in the biosynthesis of glycoconjugates with important biological activities.Most STs utilize cytidine-5'-monophospho-N-acetylneuraminic acid(CMP-Neu5Ac)as a common donor substrate.A bisubstrate analogue containing the donor substrate(CMP-Neu5Ac mimic)and the acceptor substrate(galactose)was synthesized.Four donor analogues having the partial structure of the bisubstrate analogue were also synthesized to support study of the structure-activity relationship.Each analogue contains an ethylene group in place of the exocyclic anomeric oxygen of CMP-Neu5Ac.The bisubstrate analogue exhibited only weak inhibitory activity to rat recombinant alpha-2,3-and alpha-2,6-ST(IC_(50)= 1.3,2.4 mM).Conversion of the C-1 carboxylate of the Neu5Ac moiety to carboxyamide,hydroxymethyl,or methylene phosphate each resulted in a reduction in inhibitory activity.Among the synthesized analogues,cytidin-5'-yl sialylethylphos-phonate(4)was the most potent inhibitor against rat recombinant alpha-2,3-and alpha-2,6-ST(IC_(50)= 0.047,0.34 mM).