Pyridinium boronic acid quenchers for use in analyte sensors
View Patent ↗Novel pyridinium salts functionalized with boronic acid and methods of making them are disclosed. When combined with a fluorescent dye, the compounds are useful in the detection of polyhydroxyl-substituted organic molecules.
1. The reactive compound:
wherein:
X— is a counterion;
X 1 is —O— or —NH—;
X 2 is —O— or —NH—;
L is a divalent linking group comprising a direct bond or a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from the group consisting of sulfonamide (—SO 2 NH—), amide —(C═O)N—, ester —(C═O)—O—, ether —O—, sulfide —S—, sulfone (—SO 2 —), phenylene —C 6 H 4 —, urethane —NH(C═O)—O—, urea —NH(C═O)NH—, thiourea —NH(C═S)—NH—, amide —(C═O)NH—, and amine —NR—, where R is defined as alkyl having 1 to 6 carbon atoms; and
Z is either a reactive, ethylenically unsaturated group or a reactive functional group, capable of forming a covalent bond with a polymer or matrix.
2. The compound of claim 1 , wherein Z is a reactive, ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl- and styryl-.
3. The compound of claim 1 , wherein Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix selected from the group consisting of —Br, —OH, —SH, —CO 2 H, and —NH 2 .
4. The compound of claim 1 , wherein Z is
wherein R is H or CH 3 .
5. The reactive compound of claim 1 , wherein said compound is:
6. A method of making the compound of claim 5 , comprising the steps of:
7. The compound:
wherein:
Z is a reactive, ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl- and styryl-, or wherein Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix;
Y is a trivalent connecting group selected from
where R is H or a lower alkyl, and
X 1 and X 2 are —O— or —NH—; and
L 1 , L 2 , and L 3 are selected from a direct bond or, a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from sulfonamide (—SO 2 NH—), amide —(C═O)N—, ester —(C═O)—O—, ether —O—, sulfide —S—, sulfone (—SO 2 —), phenylene —C 6 H 4 —, urethane —NH(C═O)—O—, urea —NH(C═O)NH—, thiourea —NH(C═S)—NH—, amide —(C═O)NH—, amine —NR—(where R is defined as alkyl having 1 to 6 carbon atoms) or combinations thereof.
8. The compound of claim 7 , wherein Z is a polymerizable, ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl- and styryl-.
9. The compound of claim 7 , wherein Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix selected from the group consisting of —Br, —OH, —SH, —CO 2 H, and —NH 2 .
10. The compound:
wherein n is an integer from 1-10.
11. A method of making the compound of claim 10 , comprising the steps of:
12. The compound:
wherein:
X − is a counterion;
X 1 is —O— or —NH—;
X 2 is —O— or —NH—;
L is a divalent linking selected from a direct bond or, a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from sulfonamide (—SO 2 NH—), amide —(C═O)N—, ester —(C═O)—O—, ether —O—, sulfide —S—, sulfone (—SO 2 —), phenylene —C 6 H 4 —, urethane —NH(C═O)—O—, urea —NH(C═O)NH—, thiourea —NH(C═S)—NH—, amide —(C═O)NH—, amine —NR—(where R is defined as alkyl having 1 to 6 carbon atoms) or combinations thereof;
Z is a reactive group selected from a coupling group or an olefinically unsaturated group, or Z is
wherein R is H or CH 3 ;
the bond from the central benzene ring is to the ortho, meta or para position on the adjacent pyridinium rings; and
—B(OH) 2 may be in the ortho, meta or para position.
13. The compound:
14. A method of making the compound of claim 13 , comprising the steps of:
15. The compound:
wherein
X − is a counterion;
X 1 is —O— or —NH—;
X 2 is —O— or —NH—;
L is a divalent linker selected from the group consisting of a direct bond and a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from the group consisting of sulfonamide (—SO 2 NH—), amide —(C═O)N—, ester —(C═O)—O—, ether —O—, sulfide —S—, sulfone (—SO 2 —), phenylene —C 6 H 4 —, urethane —NH(C═O)—O—, urea —NH(C═O)NH—, thiourea —NH(C═S)—NH—, amide —(C═O)NH—, amine —NR—(where R is defined as alkyl having 1 to 6 carbon atoms) or combinations thereof;
Z is either a polymerizable ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl-, or styryl- or optionally Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix;
the ambiguously depicted bonds are in the ortho, meta or para position; and
—B(OH) 2 may be in the ortho, meta or para position.
16. The compound of claim 15 , wherein Z is
wherein R is H or CH 3 .
17. The compound of claim 15 , wherein Z is selected from the group consisting of —Br, —OH, —SH, —CO 2 H, and —NH 2 .
18. The compound:
19. A method of making the compound of claim 18 , comprising the steps of:
20. A glucose sensor comprising one or more of the compounds of any one of the claims 1 , 4 , 5 , 7 , 10 , 12 , 13 , and 15 - 18 , and a fluorescent dye.
21. The glucose sensor of claim 20 , wherein said one or more of the compounds are in the form of a polymer.
22. The glucose sensor of claim 20 , further comprising a glucose permeable immobilizing means, e.g., a polymer matrix or a semipermeable membrane.