Functionalized polymer hybrids
A method of synthesizing a polynucleotide composition includes attaching a compound including at least one initiator or at least one transfer agent for a reversible deactivation radical polymerization to an end of a nucleotide chain assembly immobilized upon a solid phase support during a solid phase synthesis of a polynucleotide so that the initiator or the transfer agent is attacked to the end of a nucleotide chain assembly in a manner which is stable under conditions of deprotection of the polynucleotide, and growing a polymer from the initiator of from a site of the chain transfer agent via the reversible deactivation radical polymerization to form the polynucleotide composition.
1. A method of synthesizing a polynucleotide composition comprising: attaching a compound comprising at least one initiator or at least one transfer agent for a reversible deactivation radical polymerization to an end of a nucleotide chain assembly immobilized upon a solid phase support during a solid phase synthesis of a polynucleotide so that the initiator or the transfer agent is attached to the end of a nucleotide chain assembly in a manner which is stable under conditions of deprotection of the polynucleotide, and growing a polymer from the initiator or from a site of the chain transfer agent via the reversible deactivation radical polymerization to form the polynucleotide composition.
2. The method of claim 1 wherein the initiator or the chain transfer agent is attached to the end of a nucleotide chain assembly in a manner which is stable under conditions of detachment of the polynucleotide from the solid phase support.
3. The method of claim 2 wherein the polymer is grown from the polynucleotide while the polynucleotide is attached to the solid phase support or after the polynucleotide is detached from the solid phase support.
4. The method of claim 3 wherein the polynucleotide is a ribonucleic acid (RNA), a deoxyribonucleic acid (DNA), a DNA/RNA hybrid, or a derivative thereof.
5. The method of claim 3 wherein the compound is attached to the nucleotide chain assembly at an intermediate position within the polynucleotide or at the terminus of the polynucleotide.
6. The method of claim 3 wherein the compound comprising the initiator or the transfer agent has the formula R 1 -L-(R 2 —) n —R 3 , wherein R 1 comprises a group adapted to react with the end of the nucleotide chain assembly, L is a base stable spacer group, wherein R 2 is a base stable linking group, wherein n is 0 or an integer in the range of 1 to 20, and R 3 is a residue of an initiator or a residue of a chain transfer agent for a reversible deactivation radical polymerization.
7. The method of claim 6 wherein L is selected from the group consisting of
wherein T is selected from the group O, S, —C(O)NH—or —NHC(O)—, p is an integer between 1 and 18 and q is an integer between 1 and 18.
8. The method of claim 7 wherein R 2 is selected from the group consisting of
wherein R′ is selected from the group of H, alkyl and aryl.
9. The method of claim 8 wherein R 1 comprises a phosphoramidite group, an azide group, an alkyne group, an N-hydroxysuccinimide ester group, a maleimide group, a dibromomaleimide group or a thiol group.
10. The method of claim 8 wherein R 1 comprises a phosphoramidite group.
11. The method of claim 10 wherein the phosphoramidite group has the formula
wherein R 4 is (CH 2 ) r CN, wherein r is an integer in the range of 1-5, and R 5 and R 6 are each independently selected from the group consisting of methyl, ethyl, propyl, pentyl, hexyl or heptyl.
12. The method of claim 10 wherein R 3 has the formula:
wherein X is a homolytically cleavable group or a group activated by degenerative radical exchange;
R 11 , R 12 are each independently selected from the group consisting of a homolytically cleavable group, a group activated by degenerative radical exchange, H, C 1 -C 20 alkyl, C 3 -C 8 cycloalkyl, C(═Y)R 15 , C(═Y)NR 16 R 17 , COCl, OH, CN, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, oxiranyl, glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, C 1 -C 6 alkyl in which from 1 to all of the hydrogen atoms are replaced with halogen and C 1 -C 6 alkyl substituted with from 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkoxy, aryl, heterocyclyl, C(═Y)R 15 , C(═Y)NR 16 R 17 , oxiranyl and glycidyl,
wherein R 15 is C 1 -C 20 alkyl, C 1 -C 20 alkoxy, aryloxy or heterocyclyloxy, and R 16 and R 17 are independently H, or C 1 -C 20 alkyl, or R 16 and R 17 may be joined together to form an alkylene group of from 2 to 5 carbon atoms, wherein Y is NR 18 or O and R 18 is H, straight or branched C 1 -C 20 alkyl or aryl.
13. The method of claim 12 wherein X is selected from the group consisting of Cl, Br, I, nitroxyl, organotellurium, organostibine, organobismuthine, and —S—C(═S)—Z, wherein Z is selected from the group consisting of alkyl, alkoxy, alkylthio, aryl, and heteroaryl.
14. The method of claim 3 wherein the initiator of the transfer agent is bound to a phosphoramidite via the base stable linking group which is selected from the group consisting of
wherein where R′ is selected from the group consisting of H, alkyl and aryl, and the phosphoramidite is reacted with a free hydroxyl group of the end of the nucleotide chain assembly.
15. The method of claim 3 further comprising removal of the polynucleotide from the solid support and deprotection of the polynucleotide.
16. The method of claim 1 wherein the polymer is grown from the initiator or from the site of the transfer agent under aqueous conditions or in the presence of a polar solvent and the polymer is hydrophilic or water soluble, or the polymer is grown from the initiator or from the site of the transfer agent under non-aqueous conditions and the polymer is hydrophobic or water insoluble.
17. The method of claim 4 wherein the compound is attached at a 2′-position, a 5′-position or a 3′- position.
18. The method of claim 1 wherein the at least one initiator or the at least one transfer agent participates in an ATRP reaction, a RAFT reaction, a concurrent ATRP/RAFT reaction or a NMP reaction.
19. The method of claim 18 wherein the initiator for ATRP is adapted to initiate a controlled ATRP in the presence of a catalyst complex formed with an excess of ligand under polymerization conditions wherein the polynucleotide is stable.
20. A composition having the formula R 1 -L-(R 2 —) n —R 3 , wherein R 1 is a phosphoramidite, L is a base stable spacer group, wherein R 2 is a base stable linking group, wherein n is 0 or an integer in the range of 1 to 20, and R 3 is a residue of an initiator or a chain transfer agent for a reversible deactivation radical polymerization.
21. The composition of claim 20 wherein L is selected from the group consisting of
wherein T is selected from the group O, S, —C(O)NH—or —NHC(O)—, p is an integer between 1 and 18 and q is an integer between 1 and 18.
22. The composition of claim 20 wherein R 2 is selected from the group consisting of
wherein where R′ is selected from the group consisting of H, alkyl and aryl.
23. A method of forming a composition for growth of a polymer via reversible deactivation radical polymerization therefrom, comprising: attaching at least one initiator or at least one transfer agent for a reversible deactivation radical polymerization to a first compound by reacting a second compound with the first compound, the second compound having the formula R 1 -L-(R 2 —) n —R 3 , wherein R 1 is a phosphoramidite, L is a base stable spacer group, R 2 is a base stable linking group, wherein n is 0 or an integer in the range of 1 to 20, and R 3 is a residue of an initiator or a residue of a transfer agent for a reversible deactivation radical polymerization.