Conformationally-preorganized, miniPEG-containing γ-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 peptide nucleic acid (PNA) monomer having the following formula:
wherein
B is adenine, guanine, cytosine, thymine, or uracil;
P is selected from the group consisting of hydrogen (H), 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), benzhydryloxycarbonyl (Bhoc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
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, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene, and
provided that at least one of R 1 and R 2 is
each of R 3 and R 4 is independently selected from the group consisting of hydrogen (H) and
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;
R 6 is selected from the group consisting of hydrogen (H), linear or branched (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )aryl and (C 3 -C 8 )aryl(C 1 -C 6 )alkylene;
P 1 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);
n is an integer from 0 to 10, inclusive; and
q is an integer from 1 to 10, inclusive.
2. The PNA monomer of claim 1 , wherein one of R 1 and R 2 is independently
and the other of R 1 and R 2 is independently hydrogen (H).
3. The PNA monomer of claim 2 , wherein R 1 is
and R 2 is hydrogen (H).
4. The PNA monomer of claim 2 , wherein R 2 is
and R 1 is hydrogen (H).
5. The PNA monomer of claim 1 , wherein
R 1 is —CH 2 (OCH 2 CH 2 ) q OH; —CH 2 (OCH 2 CH 2 ) q OCH 3 ; —CH 2 (OCH 2 CH 2 ) q OCH 2 CH 3 ; or —CH 2 (OCH 2 CH 2 ) q OC(CH 3 ) 3 ;
R 2 is H;
R 3 , R 4 , R 5 , and R 6 each independently are H;
P is selected from the group consisting of H, 9-fluorenylmethyloxy carbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tosylate (Ts), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), dimethoxytrityl (DMT), and monomethoxytrityl (MMT);
n is 0, 1, or 2; and
q is 1, 2, 3, 4, or 5.
6. The PNA monomer of claim 5 , wherein P is H; n is 1; and q is 1, 2, or 3.
7. The PNA monomer of claim 1 , wherein R 3 and R 4 are H; R 5 is H or —CH 3 ; R 6 is H or —CH 3 ; n is 1; and q is 1, 2 or 3.
8. The PNA monomer of claim 7 , wherein P is 9-fluorenylmethyloxy carbonyl (Fmoc) or tert-butyloxycarbonyl (Boc).
9. The PNA monomer of claim 1 , selected from the following compounds:
wherein P 1 is hydrogen (H), tert-butyloxycarbonyl (Boc) or 9-fluorenylmethyloxy carbonyl (Fmoc); and R is —(OCH 2 CH 2 ) q OH; —(OCH 2 CH 2 ) q OCH 3 ; —(OCH 2 CH 2 ) q OCH 2 CH 3 ; or —(OCH 2 CH 2 ) q OC(CH 3 ) 3 .
10. The PNA monomer of claim 1 having the following formula:
wherein y is 1, 2, 3, or 4 (inclusive).
11. A PNA oligomer comprising the PNA monomer of claim 1 .
12. The PNA oligomer of claim 11 , wherein one of R 1 and R 2 is independently
and the other of R 1 and R 2 is independently hydrogen (H).
13. The PNA oligomer of claim 12 , wherein R 1 is
and R 2 is hydrogen (H).
14. The PNA oligomer of claim 12 , wherein R 2 is
and R 1 is hydrogen (H).
15. The PNA oligomer of claim 11 , wherein
R 1 is —CH 2 (OCH 2 CH 2 ) q OH; —CH 2 (OCH 2 CH 2 ) q OCH 3 ; —CH 2 (OCH 2 CH 2 ) q OCH 2 CH 3 ; or —CH 2 (OCH 2 CH 2 ) q OC(CH 3 ) 3 ;
R 2 is H;
R 3 , R 4 , R 5 , and R 6 each independently are H;
P is selected from the group consisting of H, 9-fluorenylmethyloxy carbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), tosylate (Ts), benzyl (Bn), allyloxycarbonyl (alloc), trityl (Trt), dimethoxytrityl (DMT), and monomethoxytrityl (MMT);
n is 0, 1, or 2; and
q is 1, 2, 3, 4, or 5.
16. The PNA oligomer of claim 11 , wherein P is H; n is 1; and q is 1, 2, or 3.
17. The PNA oligomer of claim 11 , wherein R 3 and R 4 are H; R 5 is H or —CH 3 ; R 6 is H or —CH 3 ; n is 1; and q is 1, 2 or 3.
18. The PNA oligomer of claim 17 , wherein P is 9-fluorenylmethyloxy carbonyl (Fmoc) or tert-butyloxycarbonyl (Boc).
19. The PNA oligomer of claim 11 , comprising a PNA monomer selected from the following compounds:
wherein P 1 is hydrogen (H), tert-butyloxycarbonyl (Boc) or 9-fluorenylmethyloxy carbonyl (Fmoc); and R is —(OCH 2 CH 2 ) q OH; —(OCH 2 CH 2 ) q OCH 3 ; —(OCH 2 CH 2 ) q OCH 2 CH 3 ; or —(OCH 2 CH 2 ) q OC(CH 3 ) 3 .