Conformationally-preorganized, MiniPEG-containing gamma-peptide nucleic acids
The present invention relates to γ-PNA monomers according to Formula I where substituent groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , B and P are defined as set forth in the specification. The invention also provides methodology for synthesizing compounds according to Formula I and methodology for synthesizing PNA oligomers that incorporate one or more Formula I monomers.
1. A PNA oligomer of at least two monomer subunits in length that comprises an amine terminus and a carboxy terminus and that comprises at least one gamma PNA monomer subunit, wherein said gamma PNA monomer subunit has the formula XII;
wherein,
X is selected from the group consisting of adenine, cytosine, guanine, thymine, uracil, modified nucleobases, fluorophores and aromatic ligands;
Y comprises the amine terminus of the PNA oligomer and optionally one or more additional linked PNA monomer subunits;
Z comprises the carboxy terminus of the PNA oligomer and optionally one or more additional linked PNA monomer subunits,
provided that at least one of Y or Z comprises at least one additional PNA monomer subunit;
each of R 1 and R 2 is independently selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxylalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, C3-Cs)aryl(C 1 -C 6 )alkylene, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene,
provided that at least one of R 1 and R 2 is selected from the group consisting of
each of R 3 and R 4 is independently selected from the group consisting of hydrogen (H),
R 5 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxylalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;
P 2 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
P 3 selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;
n is an integer from 1 to 10, inclusive;
x is an integer from 1 to 10, inclusive; and
y is an integer from 1 to 9, inclusive.
2. The PNA oligomer of claim 1 , wherein said gamma PNA monomer subunit has the formula XIII
wherein R 1 is selected from the group consisting of:
3. The PNA oligomer of claim 2 , wherein said gamma PNA monomer subunit has the formula XXIII
wherein
n is 1,
x is an integer from 1 to 10, inclusive and
R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl.
4. The PNA oligomer of claim 3 , wherein x is an integer from 1 to 4 inclusive, and R 8 is selected from the group consisting of hydrogen (H), methyl, and t-butyl.
5. The PNA oligomer of claim 1 , wherein said gamma PNA monomer subunit has the formula XIV
wherein R 2 is selected from the group consisting of:
6. The PNA oligomer of claim 5 , wherein said gamma PNA monomer subunit has the formula XXIV
wherein
n is 1,
x is an integer from 1 to 10, inclusive,
and R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl and t-butyl.
7. The PNA oligomer of claim 6 , wherein x is an integer from 1 to 4 inclusive and R 8 is selected from the group consisting of hydrogen (H), methyl, and t-butyl.
8. The PNA oligomer of claim 1 , wherein X is selected from the group consisting of adenine, cytosine, guanine, thymine and uracil.
9. The PNA oligomer of claim 1 , wherein said PNA oligomer is support bound.
10. The PNA oligomer of claim 1 , wherein said PNA oligomer is dissolved in an aqueous solution.
11. The PNA oligomer of claim 1 , wherein said PNA is not support bound.
12. A PNA oligomer of at least two monomer subunits in length that comprises an amine terminus and a carboxy terminus and that comprises at least one gamma PNA monomer subunit, wherein said gamma PNA monomer subunit has the formula XXIII;
wherein
X is selected from the group consisting of adenine, cytosine, guanine, thymine, uracil, modified nucleobases, fluorophores and aromatic ligands;
Y comprises the amine terminus of the PNA oligomer and optionally one or more additional linked PNA monomer subunits;
Z comprises the carboxy terminus of the PNA oligomer and optionally one or more additional linked PNA monomer subunits,
n is 1,
x is an integer from 1 to 10, inclusive and
R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl, provided that at least one of Y or Z comprises at least one additional PNA monomer subunit.
13. The PNA oligomer of claim 12 , wherein X is selected from the group consisting of adenine, cytosine, guanine, thymine and uracil.
14. The PNA oligomer of claim 12 , wherein said PNA oligomer is support bound.
15. The PNA oligomer of claim 12 , wherein said PNA is not support bound.
16. The PNA oligomer of claim 12 , wherein said PNA oligomer is dissolved in an aqueous solution.
17. A PNA oligomer of at least two monomer subunits in length that comprises an amine terminus and a carboxy terminus and that comprises at least one gamma PNA monomer subunit, wherein said gamma PNA monomer subunit has the formula XXIV;
wherein
X is selected from the group consisting of adenine, cytosine, guanine, thymine, uracil, modified nucleobases, fluorophores and aromatic ligands;
Y comprises the amine terminus of the PNA oligomer and optionally one or more additional linked PNA monomer subunits;
Z comprises the carboxy terminus of the PNA oligomer and optionally one or more additional linked PNA monomer subunits,
n is 1,
x is an integer from 1 to 10, inclusive, and
R 8 is selected from the group consisting of hydrogen (H), methyl, ethyl, and t-butyl, provided that at least one of Y or Z comprises at least one additional PNA monomer subunit.
18. The PNA oligomer of claim 17 , wherein X is selected from the group consisting of adenine, cytosine, guanine, thymine and uracil.
19. The PNA oligomer of claim 17 , wherein said PNA oligomer is support bound.
20. The PNA oligomer of claim 17 , wherein said PNA is not support bound.
21. The PNA oligomer of claim 17 , wherein said PNA oligomer is dissolved in an aqueous solution.