2′ Modified oligonucleotides

• US 6,911,540 B2
• Filed: 06/27/2002
• Issued: 06/28/2005
• Est. Priority Date: 10/24/1989
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Buhr, Chris A., Matteucci, Mark
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): OWENS JR, HOWARD V
• Application Number:
  US10/186,058
• Publication Number:
  US 20030036649A1
• Time in Patent Office: 1,097 Days
• Field of Search: 536/23.1, 536/22.1, 536/25.3, 536/25.34, 536/25.6, 536/26.26, 536/26.7, 536/25.33, 536/25.5
• US Class Current: 536/23.1
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• 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
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3517 Marker; Tag
• CPC Class Codes: C12N 2310/3527 Other alkyl chain
• CPC Class Codes: C12N 2310/353 linked to the nucleic acid via an atom other than carbon
• CPC Class Codes: C12N 2310/3535 Nitrogen

Abstract

Oligomers which have substituents on the 2′ position are resistant to oligonucleases and furthermore can be derivatized to deliver reagents or drugs, to carry label, or to provide other properties.

Claims

1. A mixed sequence oligonucleotide having the formula:

or a salt thereof, wherein;

each B independently is a protected or unprotected purine or pyrimidine base in the β

-anomeric configuration;

W₃ and W₄ are each independently H, PO₃<sup>−

2</sup>, a protecting group, or an intermediate moiety in the formation of an internucleotide link which when reacted with the appropriate —

OH results in Z;

n is an integer of 1-200;

each Z is independently P(O)O, P(O)S or P(O)N(R)₂;

each R is independently H or alkyl (C_1-6);

each A is H,OH, O—

Pr wherein Pr is a protecting group, or X-Y wherein X-Y is O-(unsubstituted alkyl (C_2-20)), S-(unsubstituted alkyl (C_1-20)), or NH-(unsubstituted alkyl (C_1-20)); and

at least one A is X-Y.

2. The oligonucleotide of claim 1 wherein W₃ and W₄ are H.

3. The oligonucleotide of claim 1 wherein at least one W₃ or W₄ is a group reactive to link hydroxyl groups.

4. The oligonucleotide of claim 1 wherein at least one Z is P(O)S or P(O)N(R)₂.

5. The oligonucleotide of claim 1 wherein at least one Z is P(O)N(R)₂.

6. The oligonucleotide of claim 1 wherein at least one Z is P(O)S.

7. The oligonucleotide of claim 1 wherein X-Y is O-(unsubstituted alkyl (C_2-6)), S-(unsubstituted alkyl (C_2-6)), or NH-(unsubstituted alkyl (C_2-6)).

8. The oligonucleotide of claim 1 wherein B is a conventional purine or pyrimidine.

9. The oligonucleotide of claim 8 wherein B is adenine, thymine, cytosine, guanine or uracil.

10. The oligonucleotide of claim 1 wherein at least one A is H.

11. The oligonucleotide of claim 1 wherein at least one A is OH.

12. The oligonucleotide of claim 1 wherein X-Y is O-(unsubstituted alkyl (C_2-6)).

13. The oligonucleotide of claim 1 wherein X-Y is S-(unsubstituted alkyl (C_2-6)).

14. The oligonucleotide of claim 1 wherein X-Y is NH-(unsubstituted alkyl (C_2-6)).