Synthesis of N-acetyl-D-galactosamine and folic acid conjugated ribozymes.
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.
Matulic-Adamic
Jasenka
J
Department of Chemistry & Biochemistry, Ribozyme Pharmaceuticals, Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA.
Serebryany
Vladimir
V
Haeberli
Peter
P
Mokler
Victor R
VR
Beigelman
Leonid
L
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
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009841:Oligonucleotides; D009943:Organophosphorus Compounds; D016337:RNA, Catalytic; C434331:phosphoramidite; D005492:Folic Acid; D000116:Acetylgalactosamine