Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages

• US 5,434,257 A
• Filed: 10/26/1993
• Issued: 07/18/1995
• Est. Priority Date: 06/01/1992
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: Gilead Sciences Inc.
• Inventors: Matteucci, Mark D., Cao, Xiaodong
• Primary Examiner(s): Ziska, Suzanne E.
• Assistant Examiner(s): CAMPELL, BRUCE R
• Application Number:
  US08/142,785
• Time in Patent Office: 630 Days
• Field of Search: 536/22.1, 536/23.1, 536/24.3, 536/24.33, 536/24.5, 536/25.1, 536/25.2, 536/25.3, 514/43, 514/44, 424/9
• US Class Current: 536/24.3
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• 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 2310/319 linked by 2'-5' linkages, i.e. having a free 3'-position
• CPC Class Codes: C12Q 1/68 involving nucleic acids

Abstract

Oligonucleotide analogs having one or more substitute linkages of the formula 2'"'"'/3'"'"'--S--CH₂ --CH═5'"'"' or 2'"'"'/3'"'"'--O--CH₂ --CH═5'"'"' between adjacent nucleomonomers are disclosed. The substitute linkage replace the usual phosphodiester linkage found in unmodified nucleic acids. The oligonucleotide analogs are easy to synthesize, stable in vivo, resistant to endogenous nucleases and are able to hybridize to target nucleic acid sequences in a sequence specific manner.

Claims

1. An oligomer comprising at least one substitute linkage between the 3'"'"' and 5'"'"' or 2'"'"' and 5'"'"' position of adjacent nucleomonomers, said substitute linkage having the formula 2'"'"'--O--CH₂ --CH═

5'"'"' or 3'"'"'--O--CH₂ --CH═

5'"'"' or 3'"'"'--S--CH₂ --CH═

5'"'"'.

2. The oligomer of claim 1 which is a dimer, trimer or tetramer.

3. The oligomer of claim 1 comprising a detectable label.

9. A nucleic acid complex comprising the oligomer of claim 1 and a nucleic acid molecule having a sequence complementary to the sequence of said oligomer.

4. An oligomer of the formula I or Ia:

##STR10## wherein;

X is S, O, CH₂, CHF or CF₂ ;

X¹ is O or S;

R¹ independently is H, OH, an oligomer or a blocking group;

R² independently is --O--alkyl,--S--alkyl, H, OH, OCH₃, SCH₃, OCH₂ CHCH₂, OC₃ H₇, SCH₂ CHCH₂, or a halogen;

B is independently a base; and

n is 0-100.

5. The oligomer of claim 4 wherein B is independently adenine, guanine, thymine, cytosine, 5-methylcytosine, 5-(1-propynyl)cytosine, 5-(1-propynyl)uracil, 7-deaza-7-methylguanine, 7-deaza-7-methyladenine, 7-deaza-7-(1-propynyl)guanine, 7-deaza-7-(1-propynyl)adenine, phenothiazine tricyclic cytidine, phenoxazine tricyclic cytidine, benzene tricyclic cytidine or 2-pyridine tricyclic cytidine.

6. The oligomer of claim 4 wherein R¹ is H-phosphonate, methylphosphonamidite, β

-cyanoethylphosphoramidite or alkylphosphoramidite.

7. The oligomer of claim 4 wherein R¹ is OH,--PO₃, DMTO or MMTO.

8. The oligomer of claim 4 which is a dimer, trimer or tetramer.