Nucleic acid prodrugs and methods of use thereof

An oligonucleotide composition comprising a plurality of oligonucleotides of the following structure:

• wherein:
• each X-phosphonate independently has an Rp or Sp configuration;
• R1 is —OH, or —ORa;
• Ra is a blocking group;
• each instance of R2 is independently hydrogen, —OH, -halogen, or —ORb, wherein Rb is a blocking group;
• each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase, wherein each modified nucleobase is independently adenine, cytosine, guanine, thymine or uracil, modified by one or more modifications:
• (1) a nucleobase is modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
• (2) one or more atoms of a nucleobase are independently replaced with a different atom selected from carbon, nitrogen or sulfur;
• (3) one or more double bonds in a nucleobase are independently hydrogenated;
• or
• (4) one or more aryl or heteroaryl rings are independently inserted into a nucleobase;
• or is independently selected from uracil, thymine, adenine, cytosine, and guanine having their respective amino groups protected by acyl groups, 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pseudoisocytosine, pseudouracil, 8-substituted purines, xanthine, hypoxanthine;
• or a modified nucleobase is a group selected from one of the following groups:
• (1)
• (2) corrin or porphyrin, each optionally modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
• (3) phenanthrene, pyrene, stillbene, isoxanthine, isozanthopterin, terphenyl, terthiophene, benzoterthiophene, coumarin, lumazine, tethered stillbene, benzo-uracil, or naphtho-uracil, each optionally modified by one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
• (4) 3-nitropyrrole, 5-bromouracil, 5-iodouracil, or 2,6-diaminopurine, or a nucleobase of 4-acetylcytidine;
• 5-(carboxyhydroxylmethyl)uridine;
• 2′-O-methylcytidine;
• 5-carboxymethylaminomethyl-2-thiouridine;
• 5-carboxymethylaminomethyluridine;
• dihydrouridine;
• 2′-O-methylpseudouridine;
• beta,D-galactosylqueosine;
• 2′-O-methylguanosine;
• N6-isopentenyladenosine;
• 1-methyladenosine;
• 1-methylpseudouridine;
• 1-methylguanosine;
• 1-methylinosine;
• 2,2-dimethylguanosine;
• 2-methyladenosine;
• 2-methylguanosine;
• N7-methylguanosine;
• 3-methyl-cytidine;
• 5-methylcytidine;
• N6-methyladenosine;
• 7-methylguanosine;
• 5-methylaminoethyluridine;
• 5-methoxyaminomethyl-2-thiouridine;
• beta,D-mannosylqueosine;
• 5-methoxycarbonylmethyluridine;
• 5-methoxyuridine;
• 2-methylthio-N6-isopentenyladenosine;
• N-((9-beta,D-ribofuranosyl-2-methylthiopurine-6-yl)carbamoyl)threonine;
• N-((9-beta,D-ribofuranosylpurine-6-yl)-N-methylcarbamoyl)threonine;
• uridine-5-oxyacetic acid methylester;
• uridine-5-oxyacetic acid (v);
• pseudouridine;
• queosine;
• 2-thiocytidine;
• 5-methyl-2-thiouridine;
• 2-thiouridine;
• 4-thiouridine;
• 5-methyluridine;
• 2′-O-methyl-5-methyluridine;
• or 2′-O-methyluridine;
• and
• (5) heteroaryl or heterocyclyl optionally substituted with one or more groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof;
• at least one X moiety is selected from —OCH2CH2S—S(O)2R10, OCH2CH2S—SCH2CH2OH, —OCH2CH2CO2H,
• wherein:
• R8 is a linear or branched alkyl, aryl, aralkyl, or aryloxylalkyl group having 1 to 15 carbon atoms,
• R9 is an alkyl group having 1 to 4 carbon atoms;
• R10 is an alkyl group having 1 to 4 carbon atoms;
• R11 is alkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl;
• R12 is hydrogen or alkyl;
• R3 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid;
• n is an integer of 10 to about 200;
• and
• the composition is stereodefined.