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US 2016/0096867 A1Published application
CONFORMATIONALLY-PREORGANIZED, MiniPEG-CONTAINING GAMMA-PEPTIDE NUCLEIC ACIDS
AssigneeCarnegie Mellon University Center for Technology Transfer & Enterprise
InventorsDanith H. LY, Srinivas RAPIREDDY, Bichismita SAHU
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Abstract
The present invention relates to γ-PNA monomers according to Formula I where substituent groups R1, R2, R3, R4, R5, R6, 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.
Claims21
1-18. (canceled)
A compound according to Formula VIII
- wherein,
- 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), O-nitroveratryloxycarbonyl (Nvoc), 1-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
- each of R1 and R2 is independently selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C5)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene, (C3-C8)cycloalkyl(C1-C6)alkylene,
- provided that at least one of R1 and R2 is selected from the group consisting of
- each of R3 and R4 is independently selected from the group consisting of hydrogen (H),
- R5 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)alkylene;
- R7 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, substituted or unsubstituted (C3-C8)aryl and (C3-C8)aryl(C1-C6)alkylene;
- P2 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
- P3 selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)alkylene;
- x is an integer from 1 to 10, inclusive;
- and
- y is an integer from 1 to 9, inclusive.
9 more elements
A method comprising:
- (a) providing a solid support of the formula XXX comprising one or more amine groups
- (b) providing amine-protected PNA monomers or amine-protected gamma-PNA monomers in sufficient amounts to produce a peptide nucleic acid (PNA) oligomer having a pre-determined sequence;
- (c) activating a carboxylic acid group of one of said amine-protected PNA monomers or one of said amine-protected gamma-PNA monomers according to the sequence of the pre-determined PNA oligomer sequence to be prepared to thereby produce an activated PNA monomer or activated gamma PNA monomer, wherein said amine-protected PNA monomer or said amine-protected gamma-PNA monomer comprises an amine protecting group;
- (d) contacting the provided support of formula XXX with said activated PNA monomer or activated gamma PNA monomer prepared according to step (c) to thereby couple said activated PNA monomer or activated gamma PNA monomer to one or more of the amine groups of said support;
- (e) removing the amine protecting group of said coupled amine-protected PNA monomer or said amine-protected gamma-PNA monomer to thereby regenerate a support of formula XXX comprising one or more amine groups, wherein said amine groups are the amine groups of said amine-protected PNA monomer or said amine-protected gamma-PNA monomer that was activated according to step (c) and coupled according to step (d);
- and
- (f) repeating steps (c), (d) and (e) until the peptide nucleic acid (PNA) oligomer of the pre-determined sequence has been prepared, provided that step (c) is performed at least once using an amine-protected gamma PNA monomer of formula XI
- wherein,
- X is selected from the group consisting of adenine, cytosine, guanine, thymine, uracil, modified nucleobases, fluorophores and aromatic ligands;
- 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), O-nitroveratryloxycarbonyl (Nvoc), 1-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
- each of R1 and R2 is independently selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene, (C3-C8)cycloalkyl(C1-C6)alkylene,
- provided that at least one of R1 and R2 is selected from the group consisting of
- each of R3 and R4 is independently selected from the group consisting of hydrogen (H),
- R5 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)alkylene;
- P2 is selected from the group consisting of linear or branched (C1-C8)alkyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
- P3 selected from the group consisting of linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)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.
17 more elements
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 oligomer 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 R1 and R2 is independently selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene, (C3-C8)cycloalkyl(C1-C6)alkylene,
- provided that at least one of R1 and R2 is selected from the group consisting of
- each of R3 and R4 is independently selected from the group consisting of hydrogen (H),
- R5 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)alkylene;
- P2 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
- P3 selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)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.
12 more elements
A compound according to Formula XXXI
- wherein
- Z is selected from the group consisting of hydroxyl (OH), iodine (I), 4-toluenesulfonate and methanesulfonate;
- R5 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)alkylene;
- 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), O-nitroveratryloxycarbonyl (Nvoc), 1-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl (Dde), diathiasuccinoyl (Dts), benzothiazole-2-sulfonyl (Bts), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
- each of R1 and R2 is independently selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)hydroxylalkyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene, (C3-C8)cycloalkyl(C1-C6)alkylene,
- provided that at least one of R1 and R2 is selected from the group consisting of
- P2 is selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), tosylate (Tos), allyloxycarbonyl (alloc), trityl (Trt), monomethoxytrityl (MMT) and dimethoxytrityl (DMT);
- P3 selected from the group consisting of hydrogen (H), linear or branched (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)aryl, (C3-C8)cycloalkyl, (C3-C8)aryl(C1-C6)alkylene and (C3-C8)cycloalkyl(C1-C6)alkylene;
- x is an integer from 1 to 10, inclusive;
- and
- y is an integer from 1 to 9, inclusive.
8 more elements
Dependencies are inferred from the claim text.