RNA mimetics: oligoribonucleotide N3'-->P5' phosphoramidates.
The synthesis and properties of novel RNA mimetics, oligoribonucleotide N3'-->P5' phosphoramidates, are described. These oligonucleotides contain 3'-aminoribonucleosides connected via N3'-->P5' phosphoramidate linkages, replacing the native RNA O3'-->P5' phosphodiester counterparts. The key monomers 2'-t-butyldimethylsilyl-3'-(monomethoxytrityl)-amino-5'-phospho ramidi tes were synthesized and used to prepare the oligonucleotide phosphoramidates using a solid phase methodology based on the phosphoramidite transfer reaction. Oligoribophosphoramidates are very resistant to enzymatic hydrolysis by snake venom phosphodiesterase. These compounds form stable duplexes with complementary natural phosphodiester DNA and RNA strands, as well as with 2'-deoxy N3'-->P5' phosphoramidates. The increase in melting temperature, Delta T m, was 5-14 degrees C relative to the 2'-deoxy phosphoramidates for decanucleotides. Also, the thermal stability of the ribophosphoramidatehomoduplex was noticeably higher (Delta T m +9.5 degrees C) than that for the isosequential 2'-deoxy phosphoramidate complex. Furthermore, the oligopyrimidine ribo N3'-->P5' phosphoramidate formed an extremely stable triplex with an oligopurine/oligopyrimidine DNA duplex with Delta T m +14.3 degrees C relative to the 2'-deoxy N3'-->P5' phosphoramidate counterpart. The properties of the oligoribonucleotide N3'-->P5' phosphoramidates indicate that these compounds can be used as hydrolytically stable structural and functional RNA mimetics.
Gryaznov
S M
SM
Lynx Therapeutics Inc., 3832 Bay Center Place, Hayward, CA 94545, USA. sgryaznov@geron.com
Winter
H
H
D001483:Base Sequence; D007202:Indicators and Reagents; D018716:Molecular Mimicry; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D009943:Organophosphorus Compounds; D011089:Polydeoxyribonucleotides / Q000737:chemistry; D011131:Polyribonucleotides / Q000737:chemistry; D012313:RNA
D007202:Indicators and Reagents; D009843:Oligoribonucleotides; D009943:Organophosphorus Compounds; D011089:Polydeoxyribonucleotides; D011131:Polyribonucleotides; D012313:RNA