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US 5,969,118 AGranted
Backbone modified oligonucleotide analogs and preparation thereof through radical coupling
AssigneeIsis Pharmaceuticals, Inc.
InventorsYogesh S. Sanghvi, Phillip Dan Cook
Life of this patent
Estimating the term…
Abstract
Methods for preparing oligonucleotide analogs which have improved nuclease resistance and improved cellular uptake are provided. In preferred embodiments, the methods involve radical coupling of 3'- and 5'-substituted or 5'- and 3'-subutituted nucleosidic synthons.
Claims12
A compound having structure:
- ##STR8## wherein:
- Z.sub.1 is CH.sub.2 --R.sub.B, R.sub.B, CH.sub.2 --R.sub.A N.dbd.CH.sub.2, or R.sub.A N.dbd.CH.sub.2, provided that Z.sub.1 is not R.sub.A N.dbd.CH.sub.2 when X.sub.1 is H or OH, and Z.sub.1 is not R.sub.B when R.sub.B is OC(O)O--C.sub.6 H.sub.5 ;
- R.sub.A is O or NH;
- R.sub.B is a radical generating group selected from I, OC(O)O--C.sub.6 H.sub.5, OC(O)S--C.sub.6 H.sub.5, Se--C.sub.6 H.sub.5, O--C(S)O--C.sub.6 F.sub.5, O--C(S)O--C.sub.6 Cl.sub.5, O--C(S)O--(2,4,6--C.sub.6 Cl.sub.3), NO.sub.2, C(S)S--Me, C(S)O--(p--CH.sub.4 F), bis-dimethylglyoximato-pyridine cobalt, O--C(S)C.sub.6 H.sub.5, O--C(S)SCH.sub.3, O--C(S)-imidazole, and C(O)O-pyridin-2-thione;
- Y.sub.1 is H, hydroxymethyl, a nucleoside, a nucleotide, an oligonucleotide, an oligonucleoside, or a hydroxyl-protected or amine-protected derivative thereof;
- B.sub.X1 is a nucleosidic base;
- Q.sub.1 is O, S, CH.sub.2, CHF or CF.sub.2 ;
- and
- X.sub.1 is H, OH, C.sub.1 to C.sub.10 lower alkyl, substituted lower alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF.sub.3, OCF.sub.3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SOCH.sub.3, SO.sub.2 CH.sub.3, ONO.sub.2, NO.sub.2, N.sub.3, NH.sub.2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino or substituted silyl.
6 more elements
A compound having structure:
- ##STR9## wherein:
- Y.sub.2 is CH.sub.2 --R.sub.B, R.sub.B, CH.sub.2 --R.sub.A N.dbd.CH.sub.2, or R.sub.A N.dbd.CH.sub.2 ;
- R.sub.A is O or NH;
- R.sub.B is a radical generating group selected from I, OC(O)O--C.sub.6 H.sub.5, OC(O)S--C.sub.6 H.sub.5, Se--C.sub.6 H.sub.5, O--(S)O--C.sub.6 F.sub.5, O--(S)O--C.sub.6 Cl.sub.5, O--(S)O--(2,4,6--C.sub.6 Cl.sub.3), Br, NO.sub.2, Cl, C(S)S--Me, C(S)O--(p--CH.sub.4 F), bis-dimethylglyoximato-pyridine cobalt, O(S)C.sub.6 H.sub.5, O(S)SCH.sub.3, O(S)-imidazole, and C(O)O-pyridin-2-thione;
- Z.sub.2 is H, hydroxyl, a nucleoside, a nucleotide, an oligonucleotide, an oligonucleoside, or a hydroxyl-protected or amine-protected derivative thereof;
- B.sub.X2 is a nucleosidic base;
- Q.sub.2 is O, S, CH.sub.2, CHF or CF.sub.2 ;
- and
- X.sub.2 is H, OH, C.sub.1 to C.sub.10 lower alkyl, substituted lower alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF.sub.3, OCF.sub.3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SOCH.sub.3, SO.sub.2 CH.sub.3, ONO.sub.2, NO.sub.2, N.sub.3, NH.sub.2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino or substituted silyl;
- provided that R.sub.B is not I, Br, or Cl when Z.sub.2 is hydroxyl, Q.sub.2 is O, and X.sub.2 is H or OH.
7 more elements
Dependencies are inferred from the claim text.