Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling
AssigneeIsis Pharmaceuticals, Inc.
InventorsYogesh S. Sanghvi, Phillip D. Cook
Life of this patent
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Abstract
Methods for preparing oligonucleotide analogs which have improved nuclease resistance and improved cellular uptake are provided. In preferred embodiments, the methods involve reductive coupling of 3'- and 4'-substituted or 4'- and 3'-substituted nucleosidic synthons.
Claims20
A method for forming between adjacent sugar moieties a covalent linkage having structure CH.dbd.N--R.sub.A --CH.sub.2, CH.sub.2 --R.sub.A --N.dbd.CH, or R.sub.A --N.dbd.CH--CH.sub.2 where R.sub.A is O or NR.sub.1, comprising the steps of:
- (a) providing synthons having structure:
- ##STR4## (b) contacting said synthons for a time and under reaction conditions effective to form said covalent linkage;
- wherein:
- Z.sub.1 and Y.sub.2 are selected such that
- (i) Z.sub.1 is C(O)H and Y.sub.2 is CH.sub.2 R.sub.A NH.sub.2 ;
- or
- (ii) Z.sub.1 is CH.sub.2 R.sub.A NH.sub.2 and Y.sub.2 is C(O)H;
- or
- (iii) Z.sub.1 is R.sub.A NH.sub.2 and Y.sub.2 is H(O)CCH.sub.2 ;
- R.sub.1 is H or alkyl having 1 to about 10 carbon atoms;
- B.sub.X1 and B.sub.X2 are, independently, nucleosidic bases;
- Q.sub.1 and Q.sub.2 are O;
- and
- X.sub.1 and X.sub.2 are, independently, H;
- OH;
- F;
- or O-alkyl having 1 to about 10 carbon atoms.
A method for forming between adjacent sugar moieties a covalent linkage having structure CH.sub.2 --NR.sub.1 --R.sub.A --CH.sub.2, CH.sub.2 --R.sub.A --NR.sub.1 --CH.sub.2, R.sub.A --NR.sub.1 --CH.sub.2 --CH.sub.2 where R.sub.A is O or NR.sub.2, comprising the steps of:
- (a) providing synthons having structures:
- ##STR5## (b) contacting said synthons for a time and under reaction conditions effective to form an intermediate linkage;
- and
- (c) reducing said intermediate linkage to form said covalent linkage;
- wherein:
- Z.sub.1 and Y.sub.2 are selected such that
- (i) Z.sub.1 is C(O)H and Y.sub.2 is CH.sub.2 R.sub.A NH.sub.2 ;
- or
- (ii) Z.sub.1 is CH.sub.2 R.sub.A NH.sub.2 and Y.sub.2 is C(O)H;
- or
- (iii) Z.sub.1 is R.sub.A NH.sub.2 and Y.sub.2 is H(O)CCH.sub.2 ;
- R.sub.1 and R.sub.2 are, independently, H or alkyl having 1 to about 10 carbon atoms;
- B.sub.X1 and B.sub.X2 are, independently, nucleosidic bases;
- Q.sub.1 and Q.sub.2 are O;
- and
- X.sub.1 and X.sub.2 are, independently, H;
- OH;
- F;
- or O-alkyl having 1 to about 10 carbon atoms.
Dependencies are inferred from the claim text.