title: A convenient synthesis of 5'-triantennary N-acetyl-galactosamine clusters based on nitromethanetrispropionic acid.
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.
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States. Electronic address: mmigawa@ionisph.com.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Migawa
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vasquez
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: W Brad
authors.initials: WB
authors.lastname: Wan
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Kinberger
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Østergaard
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.affiliation: Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
mesh_terms: D000116:Acetylgalactosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007202:Indicators and Reagents; D051379:Mice; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis* / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology; D051122:Scavenger Receptors, Class B / Q000378:metabolism
chemical_list: D007202:Indicators and Reagents; D009574:Nitro Compounds; D016376:Oligonucleotides, Antisense; D011422:Propionates; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C000621354:nitromethanetrispropionic acid; D000116:Acetylgalactosamine
keywords: Conjugate; GalNAc; Nucleic acid; Synthesis