A convenient synthesis of 5′-triantennary N-acetyl-galactosamine clusters based on nitromethanetrispropionic acid

A convenient method for the synthesis of several triantennary GalNAc clusters based on a nitromethanetrispropionic acid core was developed. The synthetic approach involves pentafluorophenolic ester intermediates which can be used in a one-pot, seven reaction procedure to quickly prepare a variety of triantennary GalNAc conjugated ASOs. The GalNAc clusters were conjugated to the 5'-end of an antisense oligonucleotide and evaluated for activity in primary mouse hepatocytes where they showed similar to 10-fold improvement in activity. (C) 2016 Elsevier Ltd. All rights reserved.