New potent sialyltransferase inhibitors - Synthesis of donor and of transition-state analogues of sialyl donor CMP-Neu5Ac

Article abstract of DOI:10.1002/(SICI)1521-3765(19980615)4:6<1106::AID-CHEM1106>3.0.CO;2-7

Enzymatic sialyl transfer with CMP-Neu5Ac as donor can be inhibited by CDP. Therefore phosphonates 1a,b, 2 and 3 were synthesized as substrate analogues. With α(2-6)-sialyltransferase from rat liver (EC2.4.99.1) only moderate inhibition was found for these compounds. In order to obtain transition-state analogues of CMP-Neu5Ac different linkages between 2,3-dehydro-N-acetylneuraminol and CMP were generated, yielding 4, (R)-5 and (R)-6. Compound (R)-6, in which the CMP residue is attached to C-1 of 2,3-dehydro-N-acetylneuramin-1-yl phosphonate, exhibited excellent α(2-6)-sialyltransferase inhibition in the nanomolar range (K(i)=350 nM), resulting in a 130-fold higher affinity for the enzyme than CMP-Neu5Ac (K(M) = 46 υM).