Oligo-2'-fluoronucleotide N3'->P5' phosphoramidates

• US 5,684,143 A
• Filed: 02/21/1996
• Issued: 11/04/1997
• Est. Priority Date: 02/21/1996
• Status: Expired due to Term

• Current Assignee: Geron Corporation
• Original Assignee: Lynx Therapeutics, Inc. (Illumina Incorporated)
• Inventors: Gryaznov, Sergei, Schultz, Ronald G.
• Primary Examiner(s): Elliott, George C.
• Assistant Examiner(s): McGarry, Sean
• Application Number:
  US08/603,566
• Time in Patent Office: 622 Days
• Field of Search: 514/44, 536/23.1, 536/24.5, 536/25.1, 536/24.3, 435/6, 435/91.1, 435/172.1
• US Class Current: 536/23.1
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

A new class of oligonucleotide N3'"'"'→P5'"'"' phosphoramidates having 2'"'"' fluoro substituents are provided that have superior acid stability. The invention includes oligo-2'"'"'-fluoronucleotide N3'"'"'→P5'"'"' phosphoramidates, methods of synthesis, and duplexes and triplexes formed with DNA and RNA. Compounds of the invention are useful where the formation of stable and specific duplex and/or triplex structures is desired, including antisense and/or anti-gene pharmaceuticals, branched DNA components, DNA and/or RNA capture agents, components of DNA-based diagnostic assays, and the like.

Claims

1. A polynucleotide comprising an oligo-2'"'"'-fluoronucleoside N3'"'"'→

P5'"'"' phosphoramidate segment defined by the formula;

##STR4## wherein B is a purine or pyrimidine, n is an integer greater than 1, and R⁴ is hydrogen or a phosphate protecting group.

2. The polynucleotide of claim 1, wherein R⁴ is hydrogen or a phosphate protecting group selected from the group consisting of methyl, β

-cyanoethyl, or 4-nitrophenylethyl.

3. The polynucleotide of claim 1, wherein n is an integer between 2 and 30.

4. The polynucleotide of claim 3, wherein n is an integer between 2 and 20.

5. The polynucleotide of claim 1, wherein B is a pyrimidine.

6. The polynucleotide of claim 1 in a triplex comprising said polynucleotide and a target double-stranded DNA.

7. The polynucleotide of claim 1, wherein the oligo-2'"'"'-fluoronucleoside N3'"'"'→

P5'"'"' phosphoramidate segment is defined by the formula;

##STR5## wherein R¹ is hydroxyl or a 5'"'"'-hydroxyl protecting group.

8. The polynucleotide of claim 7, wherein R¹ is hydroxyl or a trityl group.

9. The polynucleotide of claim 7, wherein R⁴ is hydrogen or a phosphate protecting group selected from the group consisting of methyl, β

-cyanoethyl, or 4-nitrophenylethyl.

10. The polynucleotide of claim 7, wherein n is an integer between 2 and 30.

11. The polynucleotide of claim 10, wherein n is an integer between 2 and 20.

12. The polynucleotide of claim 7, wherein B is a pyrimidine.

13. The polynucleotide of claim 7 in a triplex comprising said polynucleotide and a target double-stranded DNA.

14. The polynucleotide of claim 7, wherein R¹ is hydroxyl, R⁴ is H, and n is an integer greater than 8.

15. The polynucleotide of claim 14, wherein n is an integer between 8 and 20.

16. The polynucleotide of claim 15, hybridized to double-stranded DNA to form a triplex.