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US 5,378,825 AGranted
Backbone modified oligonucleotide analogs
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhilip D. Cook, Yogesh S. Sanghvi
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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.
Claims13
A method for synthesizing a compound having the structure:
- ##STR9## wherein:
- B.sub.x is a nucleosidic base;
- Q is O;
- X is H, OH, F, or O-alkyl;
- L.sub.1 and L.sub.4 are CH.sub.2 ;
- and
- L.sub.2 and L.sub.3 are, independently, P(O)R.sub.4, O, or NR.sub.3, provided that L.sub.2 and L.sub.3 are not both O;
- or
- L.sub.1, L.sub.2, L.sub.3 and L.sub.4, together, comprise a --CH.dbd.N--NH--CH.sub.2 -- or --CH.sub.2 --O--N.dbd.CH-- moiety;
- R.sub.3 is H or lower alkyl;
- and
- R.sub.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.sub.1 and E.sub.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.
15 more elements
Dependencies are inferred from the claim text.