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US 7,038,103 B2Granted
Solution phase biopolymer synthesis
AssigneeHubert Koster
InventorsHubert Köster, Ralf Wörl
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Abstract
Multifunctional liquid phase carriers (LPCs) and methods of using LPCs for the preparation of biopolymers are provided. The LPCs are highly symmetrical compounds that possess more than two points of attachment for biopolymer synthesis. The LPCs have the formula Sp(X1)n, where Sp is a highly symmetrical moiety such that all X1 groups are equivalent. X1 is a functional group that is suitable for biopolymer synthesis, including OH, SH, NH2, COOH and the like. Biopolymers that may be produced using the methods provided include oligonucleotides, peptides, protein nucleic acids (PNAs) and oligosaccharides. Analogs of the biopolymers may also be prepared using the methods.
Claims12
A liquid phase carrier (LPC) that has formula (Id):
- wherein:
- Z is any combination of 1–12 units selected from 1,4-phenylene and methylene units, which units may be combined in any order;
- t is 1;
- X1 is OH, SH, NH2, COR5 or COOR4 where R4 is selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, and R5 is halide, heteroaryl or pseudohalide;
- n is 3 or 4;
- with the proviso that if Z is methylene, then Z contains more than three methylene units;
- Y2 is CH;
- X1, Y2 and Z are unsubstituted or substituted with one or more substituents each independently selected from Q;
- and Q is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl or diarylaminosulfonyl.
6 more elements
A liquid phase carrier (LPC), selected from the group consisting of 1,3,5-tris{2,5-diaza-9-(5′-O-(4,4′-dimethoxytriphenyl-methyl)-2′-deoxythymidine-3′-O-yl)-1,6,9-trioxononyl}-benzene ((DMT-dT)3-Aryl-LPC), and 1,3,5-tris(9-(2′-deoxythymidin-3′-O-yl)-2,5-diaza-1,6,9-trioxononyl)-benzene (dT3-Aryl-LPC).
A method of solution phase biopolymer synthesis, comprising the steps of:
- (a) reacting an LPC with a first monomer N1;
- wherein the LPC has formula (Id):
- wherein:
- Z is any combination of 0–12 units selected from 1,4-phenylene and methylene, which units may be combined in any order;
- t is 0 or 1;
- X1 is OH, SH, NH2, COR5 or COOR4, where R4 is selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
- and R5 is halide, heteroaryl or pseudohalide;
- n is 3 or 4;
- Y2 is CH;
- X1, Y2 and Z are unsubstituted or substituted with one or more substituents each independently selected from Q;
- and Q is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl or diarylaminosulfonyl;
- (b) separating and purifying the product of step (a);
- (c) reacting the product of step (b) with a second monomer N2, a dimer N2–N3 or a trimer N2–N3–N4;
- and
- (d) repeating steps (b) and (c) to produce an LPC-bound biopolymer having m monomers, where m is 3 to 100, wherein:
- N1, N2, N3 . . . Nm are biopolymer monomers;
- and
- the dimers and trimers comprise the monomers.
15 more elements
A method of solution phase biopolymer synthesis, comprising the steps of:
- (a) reacting an LPC with a first monomer N1;
- wherein the LPC has formula (Id):
- wherein:
- Z is any combination of 0–12 units selected from 1,2-, 1,3- or 1,4-phenylene and methylene, which units may be combined in any order;
- t is 0 or 1;
- X1 is OH, SH, NH2, COR5 or COOR4, where R4 is selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;
- and R5 is halide, heteroaryl or pseudohalide;
- n is 3 or 4;
- Y2 is CH;
- X1, Y2 and Z are unsubstituted or substituted with one or more substituents each independently selected from Q;
- and Q is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, aryloxycarbonylamino, azido, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl or diarylaminosulfonyl;
- (b) separating and purifying the product of step (a);
- (c) reacting the product of step (b) with a second monomer N2, a dimer N2–N3 or a trimer N2–N3–N4;
- and
- (d) repeating steps (b) and (c) to produce an LPC-bound biopolymer having m monomers, where m is 3 to 100, wherein:
- N1, N2, N3 . . . Nm are biopolymer monomers;
- the dimers and trimers comprise the monomers;
- and
- the protocol used in steps (c) and (d) to synthesize the biopolymer is the phosphoramidite protocol.
16 more elements
Dependencies are inferred from the claim text.