Oligo-2′-Fluoro-2′-Deoxynucleotide N3′→P5′ Phosphoramidates: Synthesis and Properties

摘要

Uniformly modified oligodeoxyribonucleotide N3′→P5′ phosphoramidates containing 2′-fluoro-2′-deoxy-pyrimidine nucleosides were synthesized using an efficient interphase amidite transfer reaction. The 3′-amino group of solid phase-supported 2′-fluoro-2′-deoxynucleoside was used as an acceptor and 5′-diisopropylamino phosphoramidite as a donor of a phosphoramidite group in the tetrazole-catalyzed exchange reaction. Subsequent oxidation with aqueous iodine resulted in formation of an internucleoside phosphoramidate diester. The prepared oligo-2′-fluoro-nucleotide N3′→P5′ phosphoramidates form extremely stable duplexes with complementary nucleic acids: relative to isosequential phosphodiester oligomers, the melting temperature T_m of their duplexes with DNA or RNA was increased ～4 or 5°C per modification respectively. Moreover, these compounds are highly resistant to enzymatic hydrolysis by snake venom phosphodiesterase and they are 4–5 times more stable in acidic media (pH 2.2–5.3) than the parent oligo-2′-deoxynucleotide N3′→P5′ phosphoramidates. The described properties of the oligo-2′-fluoronucleotide N3′→P5′ phosphoramidates suggest that they may have good potential for diagnostic and antisense therapeutic applications.