Oligonucleotides comprising a non-phosphate backbone linkage
View Patent ↗One aspect of the present invention relates to a ribonucleoside substituted with a phosphonamidite group at the 3′-position. In certain embodiments, the phosphonamidite is an alkyl phosphonamidite. Another aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one non-phosphate linkage. Representative non-phosphate linkages include phosphonate, hydroxylamine, hydroxylhydrazinyl, amide, and carbamate linkages. In certain embodiments, the non-phosphate linkage is a phosphonate linkage. In certain embodiments, a non-phosphate linkage occurs in only one strand. In certain embodiments, a non-phosphate linkage occurs in both strands. In certain embodiments, a ligand is bound to one of the oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, a ligand is bound to both of the oligonucleotide strands comprising the double-stranded oligonucleotide. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-phosphate linkage. Representative non-phosphate linkages include phosphonate, hydroxylamine, hydroxylhydrazinyl, amide, and carbamate linkages. In certain embodiments, the non-phosphate linkage is a phosphonate linkage. In certain embodiments, a ligand is bound to the oligonucleotide strand. In certain embodiments, the oligonucleotide comprises at least one modified sugar moiety.
1. A compound represented by formula I:
wherein
R 1 is optionally substituted aralkyl, —Si(R 7 ) 3 , —C(O)R 4 , —CO 2 R 4 , or —C(O)(NR 8 )R 4 ;
R 2 represents independently for each occurrence H, alkyl, or halogen;
R 3 , R 4 , and R 7 each represent independently for each occurrence alkyl, aryl, or aralkyl;
R 5 is —Si(R 7 ) 3 , —C(O)R 4 , —CO 2 R 4 , or —C(O)(NR 8 )R 4 ;
R 8 represents independently for each occurrence H, alkyl, aryl, or aralkyl;
R 9 represents independently for each occurrence H or alkyl; and
the stereochemical configuration at any stereocenter of a compound represented by I is R, S, or a mixture of these configurations.
2. The compound of claim 1 , wherein R 5 is Si(R 7 ) 3 , and R 3 , R 4 , and R 7 are alkyl.
3. The compound of claim 1 , wherein R 5 is Si(R 7 ) 3 , and R 3 , R 4 , and R 7 are alkyl; R 1 is optionally substituted dimethoxytrityl; and R 6 is
4. The compound of claim 1 , wherein R 2 is H, R 3 is methyl, R 4 is isopropyl, R 5 is Si(CH 3 ) 2 -tert-butyl, R 1 is optionally substituted dimethoxytrityl, and R 6 is
5. The compound of claim 1 , wherein R 2 is H, R 3 is methyl, R 4 is isopropyl, R 5 is Si(CH 3 ) 2 —
6. A compound represented by formula Ia:
wherein
R 1 is optionally substituted aralkyl, —Si(R 7 ) 3 , —C(O)R 4 , —CO 2 R 4 , or —C(O)(NR 8 )R 4 ;
R 2 represents independently for each occurrence H, alkyl, or halogen;
R 3 , R 4 , and R 7 each represent independently for each occurrence alkyl, aryl, or aralkyl;
R 5 is —Si(R 7 ) 3 , —C(O)R 4 , —CO 2 R 4 , or —C(O)(NR 8 )R 4 ;
R 8 represents independently for each occurrence H, alkyl, aryl, or aralkyl; and
R 9 represents independently for each occurrence H or alkyl.
7. The compound of claim 6 , wherein R 5 is Si(R 7 ) 3 , and R 3 , R 4 , and R 7 are alkyl.
8. The compound of claim 6 , wherein R 5 is Si(R 7 ) 3 , and R 3 , R 4 , and R 7 are alkyl; R 1 is optionally substituted dimethoxytrityl; and R 6 is
9. The compound of claim 6 , wherein R 2 is H, R 3 is methyl, R 4 is isopropyl, R 5 is Si(CH 3 ) 2 -tert-butyl, R 1 is optionally substituted dimethoxytrityl, and R 6 is
10. The compound of claim 6 , wherein R 2 is H, R 3 is methyl, R 4 is isopropyl, R 5 is Si(CH 3 ) 2 —