Backbone modified oligonucleotide analogs

{
  "publication_number": "US5378825A",
  "country": "US",
  "kind": "A",
  "title": "Backbone modified oligonucleotide analogs",
  "abstract": "Therapeutic oligonucleotide analogs which have improved nuclease resistance and improved cellular uptake are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in wild type oligomers with four atom linking groups forms unique di- and poly- nucleosides and nucleotides useful in regulating RNA expression and in therapeutics. Methods of synthesis and use are also disclosed.",
  "claims": [
    "1. A method for synthesizing a compound having the structure: ##STR9## wherein: B x is a nucleosidic base; Q is O; X is H, OH, F, or O-alkyl; L 1 and L 4 are CH 2; and L 2 and L 3 are, independently, P(O)R 4, O, or NR 3, provided that L 2 and L 3 are not both O; or L 1, L 2, L 3 and L 4, together, comprise a --CH═N--NH--CH 2 -- or --CH 2 --O--N═CH-- moiety; R 3 is H or lower alkyl; and R 4 is OH; comprising the steps of: providing a first moiety comprising the structure: ##STR10## and a second moiety comprising the structure: ##STR11## wherein E 1 and E 2 are the same or different and are halomethyl, trifluoromethyl sulfonylmethyl, p-methyl-benzene sulfonylmethyl, or formyl; and coupling said first and second moleties with a linking group through said electrophilic reactive groups to form said compound.",
    "2. The method of claim 1 wherein the electrophilic reactive group of the first moiety is C-formyl.",
    "3. The method of claim 1 wherein the electrophilic reactive group of the second moiety is C-formyl.",
    "4. The method of claim 1 wherein said linking group is hydrazine or hydroxylamine.",
    "5. The method of claim 1 wherein L 1, L 2, L 3 and L 4, together, are --CH 2 --NR 3 --NR 3 --CH 2 --.",
    "6. The method of claim 1 wherein L 1, L 2, L 3 and L 4, together, are --CH 2 --NR 3 --O--CH 2 --.",
    "7. The method of claim 1 wherein L 1, L 2, L 3 and L 4, together, are --CH 2 --O--NR 3 --CH 2 --.",
    "8. The method of claim 1 wherein L 1, L 2, L 3 and L 4, together, are --CH 2 O--P(O)R 4 --CH 2 --.",
    "9. The method of claim 1 wherein L 1, L 2, L 3 and L 4, together, are --CH 2 --P(O)R 4 --O--CH 2 --.",
    "10. The method of claim 1 wherein at least one of E 1 or E 2 is halomethyl.",
    "11. The method of claim 1 wherein at least one of E 1 or E 2 is trifluoromethyl sulfonylmethyl.",
    "12. The method of claim 1 wherein at least one of E 1 or E 2 is p-methyl-benzene sulfonylmethyl.",
    "13. The method of claim 1 wherein an least one of E 1 or E 2 is formyl."
  ],
  "description_excerpt": "This invention relates to the design, synthesis and application of nuclease resistant oligonucleotide analogs for therapeutics, diagnostics and as research reagents. Oligonucleotide analogs are provided that have modified linkages which replace phosphorodiester bonds which normally serve as inter-sugar linkages in wild type nucleic acids. Such analogs are resistant to nuclease degradation and are capable of modulating the activity of DNA and RNA.\n\nIt is well known that most of the bodily states in mammals including most disease states, are affected by proteins. Such proteins, either acting directly or through their enzymatic functions, contribute in major proportion to many diseases in animals and man.\n\nClassical therapeutics has generally focused upon interactions with such proteins in an effort to moderate their disease causing or disease potentiating functions. Recently, however, attempts have been made to moderate the actual production of such proteins by interactions with the molecules, i.e. intracellular RNA, that direct their synthesis. These interactions have involved the hybridization of complementary \"antisense\" oligonucleotides or certain analogs thereof to RNA. Hybridization is the sequence-specific hydrogen bonding of oligonucleotides or oligonucleotie analogs to RNA or single stranded DNA. By interfering with the production of proteins, it has been hoped to effect therapeutic results with maximum effect and minimal side effects. In the same way, oligonucleotide analogs may modulate the production of proteins by an organism.",
  "cpc": [
    "C07D 405/04",
    "A61K 47/549",
    "A61K 47/59",
    "A61P 37/04",
    "A61P 43/00",
    "C07D 405/14",
    "C07F 7/1804",
    "C07H 11/00",
    "C07H 19/04",
    "C07H 19/06",
    "C07H 19/10",
    "C07H 19/16",
    "C07H 21/00"
  ],
  "ipc": [
    "A61K 31/70",
    "A61K 31/7088",
    "A61K 47/48",
    "A61K 48/00",
    "A61P 37/04",
    "A61P 43/00",
    "C07D 239/54",
    "C07D 405/04",
    "C07D 405/14",
    "C07D 473/00",
    "C07F 7/18",
    "C07H 19/04",
    "C07H 19/06",
    "C07H 19/10",
    "C07H 19/16",
    "C07H 21/00",
    "C12Q 1/68"
  ],
  "assignees": [
    "Isis Pharmaceuticals Inc"
  ],
  "inventors": [
    "Philip D. Cook",
    "Yogesh S. Sanghvi"
  ],
  "filing_date": "1991-05-21",
  "publication_date": "1995-01-03",
  "grant_date": "1995-01-03",
  "priority_date": "1990-07-27",
  "application_number": "US-70361991-A",
  "family_id": "24826111",
  "cited_by_count": 1024,
  "citations": [
    "WO1989011486A1",
    "WO1989012060A1",
    "WO1992002534A2",
    "WO1992005186A1"
  ]
}