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

Bioorg Med Chem Lett. 2016 May 1;26(9):2194-7. doi: 10.1016/j.bmcl.2016.03.070. Epub 2016 Mar 17.

Abstract

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 ∼10-fold improvement in activity.

Keywords: Conjugate; GalNAc; Nucleic acid; Synthesis.

MeSH terms

  • Acetylgalactosamine / analogs & derivatives*
  • Acetylgalactosamine / chemical synthesis*
  • Acetylgalactosamine / pharmacology
  • Animals
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Indicators and Reagents
  • Mice
  • Nitro Compounds / chemical synthesis*
  • Nitro Compounds / pharmacology
  • Oligonucleotides, Antisense / chemical synthesis*
  • Oligonucleotides, Antisense / pharmacology
  • Propionates / chemical synthesis*
  • Propionates / pharmacology
  • Scavenger Receptors, Class B / metabolism

Substances

  • Indicators and Reagents
  • Nitro Compounds
  • Oligonucleotides, Antisense
  • Propionates
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • nitromethanetrispropionic acid
  • Acetylgalactosamine