Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages

1. An oligomeric compound of the formula:

5′-(Nu 1 —L 1 ) n —Y—(L 2 -Nu 2 ) p —3′

wherein:

each Nu 1 and Nu 2 , independently, has the formula:

wherein

Bx is a heterocyclic base moiety;

Lx is hydrogen, a protecting group or a substituent group;

one of R 12 , R 13 and R 14 is hydroxyl, a protected hydroxyl, a covalent attachment to a solid support, a nucleoside, an oligonucleoside, a nucleotide, an oligonucleotide, a conjugate group or an optionally protected substituent group;

another of R 12 , R 13 and R 14 is hydrogen, hydroxyl, a protected hydroxyl or an optionally protected substituent group;

the remaining of R 12 , R 13 and R 14 , of Nu 1 , is L 1 ;

the remaining of R 12 , R 13 and R 14 , of Nu 2 , is L 2 ;

each L 1 and each L 2 is, independently, a phosphodiester, phosphorodithioate; chiral Sp phosphorothioate; phosphoramidate; thiophosphoramidate; phosphonate; methylene phosphonate; phosphotriesters; thionoalkylphosphonate; thionoalkylphosphotriester; boranophosphate; boranothiophosphate; thiodiester; thionocarbamate; siloxane; carbamate; sulfamate; morpholino sulfamide; sulfonamide; sulfide; sulfonate; N,N′-dimethylhvdrazine; thioformacetal; formacetal; thioketal; ketal; amine (—NH—CH 2 —CH 2 —); hydroxylamine; hydroxylimine; hydrazinyl; amide (—CH 2 —N(JJ)—C(O)—) and (—CH 2 —C(O)—N(JJ)—); oxime (—CH 2 —O—N═CH—); or alkylphosphorus (—C(JJ) 2 —P(═O)(OJJ)—C(JJ) 2 —C(JJ) 2 —) internucleoside linkage, wherein each JJ is, independently, hydrogen or C 1 to C 10 alkyl wherein at least one of L 1 and L 2 is other than phosphodiester;

Y has the formula:

wherein;

each Rp is a chiral Rp phosphorothioate internucleotide linkage; and

each n, m and p is, independently, from 1 to 100; where the sum of n, m and p is from 3 to about 200;

wherein the oligomeric compound comprises from 5 to about 50 nucleosides.

2. The oligomeric compound of claim 1 wherein at least one Nu 1 or at least one Nu 2 comprises a substituent group.

3. The oligomeric compound of claim 2 wherein at least one Nu 1 and at least one Nu 2 independently comprise a substituent group.

4. The oligomeric compound of claim 1 wherein each Nu 1 and each Nu 2 independently comprises a substituent group.

5. The oligomeric compound of claim 2 wherein said substituent group is covalently attached to the 2′, 3′ or 5′-position of said Nu 1 or Nu 2 .

6. The oligomeric compound of claim 5 wherein said substituent group is covalently attached to the 2′-position of said Nu 1 or Nu 2 .

7. The oligomeric compound of claim 1 wherein each of said substituent groups is, independently, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 20 aryl, O-alkyl, O-alkenyl, O-alkynyl, O-alkylamino, O-alkylalkoxy, O-alkylaminoalkyl, O-alkyl imidazole, thiol, S-alkyl, S-alkenyl, S-alkynyl, NH-alkyl, NH-alkenyl, NH-alkynyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, N-phthalimido, halogen keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, heterocycle, carbocycle, polyamine, polyamide, polyalkylene glycol, and polyether;

or each substituent group has one of formula I or II:

wherein:

Z 0 is O, S or NH;

J is a single bond, O or C(═O);

E is C 1 -C 10 alkyl, N(R 1 )(R 2 ), N(R 1 )(R 5 ), N═C(R 1 )(R 2 ), N═C(R 1 )(R 5 ) or has one of formula III or IV;

each R 6 , R 7 , R 8 , R 9 and R 10 is, independently, hydrogen, C(O)R 11 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, alkylsulfonyl, arylsulfonyl, a chemical functional group or a conjugate group, wherein the substituent groups are selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl;

or optionally, R 7 and R 8 , together form a phthalimido moiety with the nitrogen atom to which they are attached;

or optionally, R 9 and R 10 , together form a phthalimido moiety with the nitrogen atom to which they are attached;

each R 11 is, independently, substituted or unsubstituted C 1 -C 10 alkyl, trifluoromethyl, cyanoethyloxy, methoxy, ethoxy, t-butoxy, allyloxy, 9-fluorenylmethoxy, 2-(trimethylsilyl)ethoxy, 2,2,2-trichloroethoxy, benzyloxy, butyryl, iso-butyryl, phenyl or aryl;

R 5 is T-L,

T is a bond or a linking moiety;

L is a chemical functional group, a conjugate group or a solid support material;

each R 1 and R 2 is, independently, H, a nitrogen protecting group, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, wherein said substitution is OR 3 , SR 3 , NH 3 + , N(R 3 )(R 4 ), guanidino or acyl where said acyl is an acid amide or an ester;

or R 1 and R 2 , together, are a nitrogen protecting group or are joined in a ring structure that optionally includes an additional heteroatom selected from N and O;

or R 1 , T and L, together, are a chemical functional group;

each R 3 and R 4 is, independently, H, C 1 -C 10 alkyl, a nitrogen protecting group, or R 3 and R 4 , together, are a nitrogen protecting group;

or R 3 and R 4 are joined in a ring structure that optionally includes an additional heteroatom selected from N and O;

Z 4 is OX, SX, or N(X) 2 ;

each X is, independently, H, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C(═NH)N(H)R 5 , C(═O)N(H)R 5 or OC(═O)N(H)R 5 ;

R 5 is H or C 1 -C 8 alkyl;

Z 1 , Z 2 and Z 3 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;

Z 5 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(R 1 )(R 2 ) OR 1 , halo, SR 1 or CN;

each q 1 is, independently, an integer from 1 to 10;

each q 2 is, independently, 0 or 1;

q 3 is 0 or an integer from 1 to 10;

q 4 is an integer from 1 to 10;

q 5 is from 0, 1 or 2; and

provided that when q 3 is 0, q 4 is greater than 1.

8. The oligomeric compound of claim 1 wherein at least one R 14 is L 1 or L 2 .

9. The oligomeric compound of claim 1 wherein at least one R 14 is L 1 and at least one R 14 is L 2 .

10. The oligomeric compound of claim 1 comprising from 8 to about 30 nucleosides.

11. The oligomeric compound of claim 1 comprising from 15 to about 25 nucleosides.