Carbohydrate or 2' -modified oligonucleotides having alternating internucleoside linkages

An oligonucleotide having the Formula:

• 18
• wherein:
• each B is a nucleobase;
• X1 is S;
• X2 is O;
• each R1, is, independently, H, hydroxyl, C1-C20 alkyl, C3-C20 alkenyl, C2-C20 alkynyl, halogen, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
• or R1 is a group of formula Z—R22—(R23)v;
• Z is O, S, NH, or N—R22—(R23)v;
• R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
• R23 is hydrogen, amino, halogen., hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides;
• v is from 0 to about 10;
• or R1 has the formula:
• 19
• y1 is 0 or 1;
• y2 is independently 0 to 10;
• y3 is 1 to 10;
• E is C1-C10 alkyl, N (Q1) (Q2) or N═C (Q1) (Q2);
• each Q1 and Q2 is, independently, H, C1-C10 alkyl, substituted alkyl, dialkylaminoalkyl, a nitrogen protecting group, a tethered or untethered conjugate group, a linker to a solid support;
• or Q1 and Q2, together, are joined in a nitrogen protecting group or a ring structure that can include at least one additional heteroatom selected from N and O;
• or R1 has one of formula I or II:
• 20
• wherein
• Z0 is O, S, or NH;
• q1 is from 0 to 10;
• q2 is from 1 to 10;
• q3 is 0 or 1;
• q4 is, 0, 1 or 2;
• Z4 is OM1, SM1, or N(M1)2;
• each M1 is, independently, H, C1-C8 alkyl, C1-C8 haloalkyl, C(═NH)N(H)M2, C(═O)N(H)M2 or OC(═O)N(H)M2;
• M2 is H or C1-C8 alkyl;
• Z1, Z2 and Z3 comprise a ring system having from about 4 to about 7 carbon atoms, or having from about 3 to about 6 carbon atoms and 1 or 2 hetero atoms wherein said hetero atoms are selected from oxygen, nitrogen and sulfur, and wherein said ring system is aliphatic, unsaturated aliphatic, aromatic, or saturated or unsaturated heterocyclic;
• and
• Z5 is alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, aryl having 6 to about 14 carbon atoms, N(Q1) (Q2), OQ1, halo, SQ1 or CN;
• n is from 2 to 50;
• and
• m is 0 or 1;
• R2 is H, a hydroxyl protecting group, or an oligonucleotide;
• and
• R3 is OH, an oligonucleotide, or a linker connected to a solid support.

A compound having the Formula:

• (5′) W1—W3—W3 (3′)
• wherein:
• W1 has the Formula:
• 21
• wherein:
• each B is a nucleobase;
• one of X1 or X2 is O, and the other of X1 or X2 is S;
• each R1, is, independently, H, hydroxyl, C1-C20 alkyl, C3-C20 alkenyl, C2-C20 alkynyl, halogen, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;
• or R1 is a group of formula Z—R22—(R23)v;
• Z is O, S, NH, or N—R22—(R23)v;
• R22 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
• R23 is hydrogen, amino, halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides;
• v is from 0 to about 10;
• or R1 has the formula:
• 22
• y1 is 0 or 1;
• y2 is independently 0 to 10;
• y3 is 1 to 10;
• E is C1-C10 alkyl, N(Q1) (Q2) or N═C(Q1) (Q2);
• each Q1 and Q2 is, independently, H, C1-C10 alkyl, substituted alkyl, dialkylaminoalkyrl, a nitrogen protecting group, a tethered or untethered conjugate group, a linker to a solid support;
• or Q1 and Q2, together, are joined in a nitrogen protecting group or a ring structure that can include at least one additional heteroatom selected from N and O;
• or R1 has one of formula I or II:
• 23
• wherein
• Z0 is O, S, or NH;
• q1 is from 0 to 10;
• q2 is from 1 to 10;
• q3 is 0 or 1;
• q4 is, 0, 1 or 2;
• Z4 is OM1, SM1, or N(M,)2;
• each M1 is, independently, H, C1-C8 alkyl, C1-C8 haloalkyl, C(═NH)N(H)M2, C(═O)N(H)M2 or OC(═O)N(H)M2;
• M2 is H or C1-C8 alkyl;
• Z1, Z2 and Z3 comprise a ring system. having from about 4 to about 7 carbon atoms, or having from about 3 to about 6 carbon atoms and 1 or 2 hetero atoms wherein said hetero atoms are selected from oxygen, nitrogen and sulfur, and wherein said ring system is aliphatic, unsaturated aliphatic, aromatic, or saturated or unsaturated heterocyclic;
• and
• Z5 is alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, aryl having 6 to about 14 carbon atoms, N(Q1)(Q2), OQ1, halo, SQ1 or CN;
• n is from 2 to 50;
• and
• m is 0 or 1;
• R2 is H, a hydroxyl protecting group, or an oligonucleotide;
• W3 has the Formula:
• 24
• wherein R3 is OH, an oligonucleotide, or a linker connected to a solid support;
• and
• W2 is a plurality of covalently bound nucleosides linked by phosphodiester or phosphorothioate linkages.