Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation

Abstract

Compositions comprising first and second oligomers are provided wherein at least a portion of the first oligomer is capable of hybridizing with at least a portion of the second oligomer, at least a portion of the first oligomer is complementary to and capable of hybridizing to a selected target nucleic acid, and at least one of the first or second oligomers includes a modification comprising a polycyclic sugar surrogate. Oligomer/protein compositions are also provided comprising an oligomer complementary to and capable of hybridizing to a selected target nucleic acid and at least one protein comprising at least a portion of an RNA-induced silencing complex (RISC), wherein at least one nucleoside of the oligomer has a polycyclic sugar surrogate modification.

1 . A nucleoside comprising a bicyclic sugar moiety having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 Q is CH 2  or C(═O);  
 R is H, a protecting group or C 1 -C 12  alkyl; and  
 T 1  and T 2  are each, independently, hydroxyl, a protected hydroxyl, a conjugate group, an activated phosphorus moiety or a covalent attachment to a support medium.  
 
   
   
       2 . The nucleoside of  claim 1  wherein Q is CH 2 .  
   
   
       3 . The nucleoside of  claim 1  wherein Q is C(═O).  
   
   
       4 . The nucleoside of  claim 1  wherein R is H.  
   
   
       5 . The nucleoside of  claim 1  wherein R is methyl.  
   
   
       6 . The nucleoside of  claim 1  having the configuration:  
     
       
         
         
             
             
         
       
     
     wherein 
 Bx is a heterocyclic base moiety;  
 Q is CH 2  or C(═O);  
 R is H, a protecting group or C 1 -C 12  alkyl; and  
 T 1  and T 2  are each independently, hydroxyl, a protected hydroxyl, a conjugate group, an activated phosphorus moiety or a covalent attachment to a support medium.  
 
   
   
       7 . An oligomeric compound comprising at least one nucleoside comprising a bicyclic sugar moiety having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 Bx is a heterocyclic base moiety;  
 Q is CH 2  or C(═O);  
 R is H, a protecting group or C 1 -C 12  alkyl; and  
 each of T 3  and T 4  is an internucleoside linkage connecting the nucleoside to the oligomeric compound or one of T 3  and T 4  is an internucleoside linkage connecting the nucleoside to the oligomeric compound and the other of the T 3  and T 4  is hydroxyl, a protected hydroxyl, a conjugate group, an activated phosphorus moiety, a covalent attachment to a support medium or an internucleoside linkage attached to a nucleoside, a nucleotide, a nucleoside mimic, an oligonucleoside, an oligonucleotide or an oligonucleotide mimic.  
 
   
   
       8 . The oligomeric compound of  claim 7  wherein each nucleoside comprising the bicyclic sugar moiety has the configuration:  
     
       
         
         
             
             
         
       
     
     wherein 
 Bx is a heterocyclic base moiety;  
 Q is CH 2  or C(═O);  
 R is H, a protecting group or C 1 -C 12  alkyl; and  
 each of T 3  and T 4  is an internucleoside linkage connecting the nucleoside to the oligomeric compound or one of T 3  and T 4  is an internucleoside linkage connecting the nucleoside to the oligomeric compound and the other of the T 3  and T 4  is hydroxyl, a protected hydroxyl, a conjugate group, an activated phosphorus moiety, a covalent attachment to a support medium or an internucleoside linkage attached to a nucleoside, a nucleotide, a nucleoside mimic, an oligonucleoside, an oligonucleotide or an oligonucleotide mimic.  
 
   
   
       9 . The oligomeric compound of  claim 7  comprising from about 10 to about 40 nucleosides.  
   
   
       10 . The oligomeric compound of  claim 7  comprising from about 18 to about 30 nucleosides.  
   
   
       11 . The oligomeric compound of  claim 7  comprising from about 21 to about 24 nucleosides.  
   
   
       12 . The oligomeric compound of  claim 7  comprising from about 15 to about 30 nucleosides.  
   
   
       13 . The oligomeric compound of  claim 7  comprising a plurality of nucleosides linked by internucleoside linking groups wherein each of the internucleoside linking groups is, independently, phosphodiester, phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl and other alkyl phosphonate, chiral phosphonate, phosphinate, phosphoramidate, thionophosphoramidate, thionoalkylphosphonate, thionoalkylphosphotriester, selenophosphate, boranophosphate or methylene(methylimino).  
   
   
       14 . The oligomeric compound of  claim 13  wherein each of the internucleoside linking groups is, independently, phosphodiester or phosphorothioate.  
   
   
       15 . The oligomeric compound of  claim 7  further comprising at least one nucleoside having formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 Bx is a heterocyclic base moiety;  
 J is H, hydroxyl, protected hydroxyl or a sugar substituent group; and  
 each of T 5  and T 6  is an internucleoside linkage connecting the nucleoside to the oligomeric compound or one of T 5  and T 6  is an internucleoside linkage connecting the nucleoside to the oligomeric compound and the other of the T 5  and T 6  is hydroxyl, a protected hydroxyl, a conjugate group, an activated phosphorus moiety, a covalent attachment to a support medium or an internucleoside linkage attached to a nucleoside, a nucleotide, a nucleoside mimic, an oligonucleoside, an oligonucleotide or an oligonucleotide mimic.  
 
   
   
       16 . The oligomeric compound of  claim 15  comprising a plurality of nucleosides having formula I wherein each J is, independently, H, hydroxyl, protected hydroxyl or a sugar substituent group.  
   
   
       17 . The oligomeric compound of  claim 15  wherein each sugar substituent group is, independently, alkyl, alkenyl, alkynyl, O-, S- or N-alkyl; O-, S- or N-alkenyl; O-, S,- or N-alkynyl; O-alkyl-O-alkyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O[(CH 2 ) n O] m CH 3 , OCH 2 C(═O)N(H)(CH 3 ), O(CH 2 ) n OCH 3 , O(CH 2 ) n NH 2 , O(CH 2 ) n CH 3 , O(CH 2 ) n ONH 2 , O(CH 2 ) n ON[(CH 2 ) n CH 3 ] 2 , SH, SCH 3 , OCN, F, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group or a reporter group; 
 wherein alkyl groups are C 1  to C 10  and are substituted or unsubstituted, alkenyl groups are C 2  to C 10  and are substituted or unsubstituted, and alkynyl groups are C 2  to C 10  and are substituted or unsubstituted and where n and m are each independently from 1 to about 10.    
   
   
       18 . The oligomeric compound of  claim 17  wherein each of the sugar substituents groups is, independently, OCH 2 C(═O)N(H)(CH 3 ), O—CH 2 CH 2 OCH 3 , O(CH 2 ) 2 ON(CH 3 ) 2 , O—(CH 2 ) 2 —O—(CH 2 ) 2 —N(CH 3 ) 2 , O—CH 3 , OCH 2 CH 2 CH 2 NH 2 , CH 2 —CH═CH 2 , O—CH 2 —CH═CH 2  or F.  
   
   
       19 . The oligomeric compound of  claim 15  wherein each of the sugar substituent groups independently, comprises formula II:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R d  is a single bond, O, S or C(═O);  
 R e  is C 1 -C 10  alkyl, N(R k )(R m ), N(R k )(R n ), N═C(R p )(R q ), N═C(R p )(R r ) or has formula IIIa;  
                     
 R p  and R q , are each independently hydrogen or C 1 -C 10  alkyl;  
 R r  is —R x —R y ;  
 each R s , R t , R u , and R v  is, independently, hydrogen, C(O)R w , 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 u  and R v , together form a phthalimido moiety with the nitrogen atom to which they are attached;  
 each R w  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 k  is hydrogen, a nitrogen protecting group or —R x —R y ;  
 R x  is a bond or a linking moiety;  
 R y  is a chemical functional group, a conjugate group or a solid support medium;  
 each R m  and R n  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 the substituent groups are selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, alkynyl;  
 or R m  and R n , together, are a nitrogen protecting group, are joined in a ring structure that optionally includes an additional heteroatom selected from N and O or are a chemical, functional group;  
 m a  is 1 to about 10;  
 each mb is, independently, 0 or 1;  
 mc is 0 or an integer from 1 to 10;  
 md is an integer from 1 to 10; and  
 provided that when mc is 0, md is greater than 1.  
 
   
   
       20 . A composition comprising a first oligomeric compound and a second oligomeric compound; 
 the first oligomeric compound is complementary to and capable of hybridizing with the second oligomeric compound;    the first oligomeric compound is complementary to and capable of hybridizing to a selected target nucleic acid,    wherein at least one of the first and the second oligomeric compounds comprises at least one nucleoside of  claim 1;  and    wherein the composition further comprises one or more optional overhangs, phosphate moieties, conjugate groups or oligomer terminal groups.    
   
   
       21 . The composition of  claim 20  wherein the first and the second oligomeric compounds are a complementary pair of siRNA oligomeric compounds.  
   
   
       22 . The composition of  claim 20  wherein the first and the second oligomeric compounds are an antisense/sense pair of oligomeric compounds.  
   
   
       23 . The composition of  claim 20  wherein each of the first and the second oligomeric compounds has from about 10 to about 40 nucleosides.  
   
   
       24 . The composition of  claim 20  wherein each of the first and the second oligomeric compounds has from about 18 to about 30 nucleosides.  
   
   
       25 . The composition of  claim 20  wherein each of the first and the second oligomeric compounds has from about 21 to about 24 nucle