title: Synthesis of N-acetyl-D-galactosamine and folic acid conjugated ribozymes.
abstract: To evaluate potential improvement in tissue specific targeting and cellular uptake of therapeutic ribozymes, we have developed three new phosphoramidite reagents. These reagents can be used in automated solid-phase synthesis to produce oligonucleotide conjugates containing N-acetyl-D-galactosamine (targeting hepatocytes) and folic acid (targeting tumor). N-Acetyl-D-galactosamine was attached through a linker to both 2'-amino-2'-deoxyuridine and D-threoninol scaffolds, and these conjugates were converted to phosphoramidite building blocks. Incorporation of a D-threoninol-based monomer into ribozymes provided multiply labeled ribozyme conjugates. Attachment of the fully protected pteroic acid to the D-threoninol-6-aminocaproyl-L-glutamic acid construct afforded the folic acid conjugate, which was converted into the phosphoramidite and incorporated onto the 5'-end of the ribozyme.
authors.affiliation: Department of Chemistry & Biochemistry, Ribozyme Pharmaceuticals, Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA.
authors.forename: Jasenka
authors.initials: J
authors.lastname: Matulic-Adamic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Serebryany
authors.forename: Peter
authors.initials: P
authors.lastname: Haeberli
authors.forename: Victor R
authors.initials: VR
authors.lastname: Mokler
authors.forename: Leonid
authors.initials: L
authors.lastname: Beigelman
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D003432:Cross-Linking Reagents / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005492:Folic Acid / Q000737:chemistry; D009841:Oligonucleotides / Q000138:chemical synthesis; D009943:Organophosphorus Compounds / Q000737:chemistry; D016337:RNA, Catalytic / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; D016337:RNA, Catalytic; C434331:phosphoramidite; D005492:Folic Acid; D000116:Acetylgalactosamine