Detection of glucose in solutions also containing an alpha-hydroxy acid or a beta-diketone

• US 20030082663A1
• Filed: 07/03/2002
• Published: 05/01/2003
• Est. Priority Date: 01/05/2001
• Status: Active Grant

• Current Assignee: Sensors For Medicine and Science Incorporated
• Original Assignee: Sensors For Medicine and Science Incorporated
• Inventors: Daniloff, George Y., Kalivretenos, Aristotle G., Nikolaitchik, Alexandre V.
• Granted Patent: US 6,800,451 B2
• Time in Patent Office: Days
• US Class Current: 435/14
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: G01N 33/533 with fluorescent label
• CPC Class Codes: G01N 33/542 with steric inhibition or signal modification, e.g. fluorescent quenching
• CPC Class Codes: G01N 33/582 with fluorescent label
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: Y10T 436/144444 Glucose

Abstract

Compositions and methods for determining the presence or concentration of glucose in a sample which may also contain an alpha-hydroxy acid or a beta-diketone. The method uses a compound having at least two recognition elements for glucose, oriented such that the interaction between the compound and glucose is more stable than the interaction between the compound and the alpha-hydroxy acid or beta-diketone, such that the presence of the alpha-hydroxy acid or the beta-diketone does not substantially interfere with said determination.

Claims

1. A method for detecting the presence or concentration of glucose in a sample which may also contain an alpha-hydroxy acid or a beta-diketone, which comprises:

a) exposing the sample to a compound having at least two recognition elements for glucose, oriented such that the interaction between the compound and glucose is more stable than the interaction between the compound and the alpha-hydroxy acid or beta-diketone, said compound also containing a detectable moiety having a detectable quality that changes in a concentration-dependent manner when said compound is exposed to glucose in said sample; and

b) measuring any change in said detectable quality to thereby determine the presence or concentration of glucose in said sample, wherein the presence of the alpha-hydroxy acid or the beta-diketone does not substantially interfere with said determination.

2. The method of claim 1, wherein the compound has the following structure:

3. The method of claim 2, wherein R₈ is selected from the group consisting of boronic acid, boronate ion, arsenious acid, arsenite ion, telluric acid, tellurate ion, germanic acid, germanate ion, and combinations thereof.

4. The method of claim 3, wherein each R₈ is a boronic acid group.

5. The method of claim 2, wherein the compound comprises at least two detectable moieties that are capable of energy transport from one to the other, and wherein said energy transport is modulated by the presence of glucose in the sample.

6. The method of claim 2, wherein at least one of R, R₁, R₂, R₄, R₅, R₉ or R₁₀ comprises a fluorophore moiety and further wherein at least one of those groups comprises a quenching moiety, and wherein said fluorophore is either quenched or dequenched when said compound interacts with glucose in the sample.

7. The method of claim 2, wherein the compound comprises a fluorophore, and the fluorescence of said fluorophore is modulated by the interaction of said compound with glucose.

8. The method of claim 1, wherein the sample is a physiological fluid.

9. The method of claim 8, wherein the physiological fluid is selected from the group consisting of blood, plasma, serum, interstitial fluid, cerebrospinal fluid, urine, saliva, intraocular fluid, lymph, tears, sweat, and physiological buffers.

10. The method of claim 1, wherein the compound is exposed to the sample in solution.

11. The method of claim 1, wherein the compound is immobilized on or within a solid support.

12. The method of claim 11, wherein the solid support is a polymeric matrix.

13. The method of claim 1, wherein the compound is associated with an implantable device, and wherein step a) takes place in vivo.

14. The method of claim 2, wherein R is an anthracene residue;

R₁, R₂, R₃, R₄ and R₅ are hydrogen;

R₆ and R₇ are dimethylamine residues;

each R₈ is a boronic acid group;

one or both of R₉ and R₁₀ are aliphatic carboxylic acid residues; and

each Z is carbon.

15. The method of claim 14, wherein one or both of R₉ and R₁₀ are propionic acid residues.

16. The method of claim 2, wherein R is a hexamethylene residue;

R₁, R₂, R₃, R₄ and R₅ are hydrogen;

R₆ and R₇ are dimethylamine residues;

each R₈ is a boronic acid group;

R₉ is a naphthalimide residue;

R₁₀ is a dimethylaminobenzyl residue; and

each Z is carbon.

17. The method of claim 2, wherein R is an anthracene residue;

R₁, R₂, R₃, R₄ and R₅ are hydrogen;

R₆ and R₇ are dimethylamine residues;

each R₈ is a boronic acid group;

R₉ and R₁₀ are the same or different and are selected from the group consisting of a methacrylamidoalkyl residue, a methacroyloxyethoxyalkyl residue, a hydroxyethoxyalkyl residue, and an aminoalkyl residue; and

each Z is carbon.

18. The method of claim 2, wherein the compound is selected from the group consisting of:

9-[N-(2-boronobenzyl)-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9,10-bis [N-(2-boronobenzyl)-N-[2-(carboxyethyl)amino]-methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methylanthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[5-aminopentylamino]-methyl]anthracene; and

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido) propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[6-(cyclohexanecarboxamido)hexylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(carboxyethyl)amino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[3-(N-6-(9-anthracenecarboxamido)hexylamino carbonyl)ethylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[6-(3-carboxypropionamido)hexylamino]methyl]anthracene;

N-(3-Methacrylamidopropyl)-4-[2-N-[[2-(borono)benzyl]-[6-(N-[2-(borono)benzyl]-6-N-(3-carboxypropanamidoethyl)aminohexyl]]aminoethylamino]napht halene-1,8-dicarboximide;

N-Butyl-4-[2-N-[[2-(borono)benzyl]-[6-(N-[2-(borono)benzyl]-6-N-(2-methacrylamidoethyl)aminohexyl]]aminoethylamino]naphthale ne-1,8-dicarboximide; and

salts thereof.

25. The compound of claim 1, wherein R is an anthracene residue;

R₁, R₂, R₃, R₄ and R₅ are hydrogen;

R₆ and R₇ are dimethylamine residues;

each R₈ is an optionally protected boronic acid group;

R₉ and R₁₀ are the same or different and are selected from the group consisting of a methacrylamidoalkyl residue, a methacroyloxyethoxyalkyl residue, a hydroxyethoxyalkyl residue, and an aminoalkyl residue; and

each Z is carbon.

19. A compound having the following structure

20. The compound of claim 19, wherein R₈ is selected from the group consisting of boronic acid, boronate ion, arsenious acid, arsenite ion, telluric acid, tellurate ion, germanic acid, germanate ion, all optionally protected, and combinations thereof.

21. The compound of claim 20, wherein each R₈ is an optionally protected boronic acid group.

22. The compound of claim 19, wherein the compound comprises a fluorophore, and the fluorescence of said fluorophore is modulated by the interaction of said compound with glucose.

23. The compound of claim 19, wherein R is an anthracene residue;

R₁, R₂, R₃, R₄ and R₅ are hydrogen;

R₆ and R₇ are dimethylamine residues;

each R₈ is an optionally protected boronic acid group;

one or both of R₉ and R₁₀ are aliphatic carboxylic acid residues; and

each Z is carbon.

24. The compound of claim 23, wherein one or both of R₉ and R₁₀ are propionic acid residues.

26. The compound of claim 19, wherein the compound is selected from the group consisting of:

9-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]-10-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-hydroxyethoxy)ethylamino]-methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[2-(carboxyethyl)amino]-methyl]anthracene;

9,10-bis[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[3-(methacrylamido)propylamino]methylanthracene;

9,10-bis [N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methylanthracene;

9-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9,10-bis [N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]anthracene;

9,10-bis [N-(2-boronobenzyl)-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[5-aminopentylamino]-methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido) propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[6-(cyclohexanecarboxamido)hexylamino]methyl]anthracene;

9-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[6-(cyclohexanecarboxamido)hexylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(carboxyethyl)amino]methyl]anthracene;

9-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[3-(N-6-(9-anthracenecarboxamido)hexylamino carbonyl)ethylamino]methyl]anthracene;

9-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(N-6-(9-anthracenecarboxamido)hexylamino carbonylethylaminomethyl]anthracene;

9-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl -1,3,2-dioxaborolano)benzyl]-N-[6-(3-carboxypropionamido)hexylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[6-(3-carboxypropionamido)hexylamino]methyl]anthracene;

N-(3-Methacrylamidopropyl)-4-[2-N-[[2-(borono)benzyl]-[6-(N-[2-(borono)benzyl]-6-N-(3-carboxypropanamidoethyl)aminohexyl]]aminoethylamino]napht halene-1,8-dicarboximide;

N-Butyl-4-[2-N-[[2-(borono)benzyl]-[6-(N-[2-(borono)benzyl]-6-N-(2-methacrylamidoethyl)aminohexyl]]aminoethylamino]naphthale ne-1,8-dicarboximide; and

salts thereof.

27. A detection system for detecting the presence or concentration of glucose in a sample which may also contain an alpha-hydroxy acid or a beta-diketone, which comprises a compound having the following structure

28. The detection system of claim 27, wherein RB is selected from the group consisting of boronic acid, boronate ion, arsenious acid, arsenite ion, telluric acid, tellurate ion, germanic acid, germanate ion, all optionally protected, and combinations thereof.

29. The detection system of claim 28, wherein each R₈ is an optionally protected boronic acid group.

30. The detection system of claim 27, wherein the compound comprises a fluorophore, and the fluorescence of said fluorophore is modulated by the interaction of said compound with glucose.

31. The detection system of claim 27, wherein R is an anthracene residue;

R₁, R₂, R₃, R₄ and R₅ are hydrogen;

R₆ and R₇ are dimethylamine residues;

each R₈ is an optionally protected boronic acid group;

one or both of R₉ and R₁₀ are aliphatic carboxylic acid residues; and

each Z is carbon.

32. The detection system of claim 31, wherein one or both of R₉ and R₁₀ are propionic acid residues.

33. The detection system of claim 27, wherein R is an anthracene residue;

R₁, R₂, R₃, R₄ and R₅ are hydrogen;

R₆ and R₇ are dimethylamine residues;

each R₈ is a boronic acid group;

R₉ and R₁₀ are the same or different and are selected from the group consisting of a methacrylamidoalkyl residue, a methacroyloxyethoxyalkyl residue, a hydroxyethoxyalkyl residue, and an aminoalkyl residue; and

each Z is carbon.

34. The detection system of claim 27, wherein the compound is selected from the group consisting of:

9-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]-10-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-hydroxyethoxy)ethylamino]-methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[2-(carboxyethyl)amino]-methyl]anthracene;

9,10-bis[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[3-(methacrylamido)propylamino]methylanthracene;

9,10-bis[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methylanthracene;

9-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(2-hydroxyethoxy)ethylamino]methyl]anthracene;

9,10-bis [N-[2-(5,5-dimethylborinan-2-yl)benzyl]-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[2-(2-methacroyloxyethoxy)ethylamino]methyl]anthracene;

9,10-bis[N-(2-boronobenzyl)-N-[5-aminopentylamino]-methyl]anthracene; and

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido) propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[6-(cyclohexanecarboxamido)hexylamino]methyl]anthracene;

9-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[6-(cyclohexanecarboxamido)hexylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[2-(carboxyethyl)amino]methyl]anthracene;

9-[N-[2-(4,4,5,5, -tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[3-(N-6-(9-anthracenecarboxamido)hexylamino carbonyl)ethylamino]methyl]anthracene;

9-[N-[2-(4,4,5,5, -tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(N-6-(9-anthracenecarboxamido)hexylamino carbonylethylaminomethyl]anthracene;

9-[N-[2-(4,4,5,5, -tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)benzyl]-N-[6-(3-carboxypropionamido)hexylamino]methyl]anthracene;

9-[N-(2-boronobenzyl)-N-[3-(methacrylamido)propylamino]methyl]-10-[N-(2-boronobenzyl)-N-[6-(3-carboxypropionamido)hexylamino]methyl]anthracene;

N-(3-Methacrylamidopropyl)-4-[2-N-[[2-(borono)benzyl]-[6-(N-[2-(borono)benzyl]-6-N-(3-carboxypropanamidoethyl)aminohexyl]]aminoethylamino]napht halene-1,8-dicarboximide;

N-Butyl-4-[2-N-[[2-(borono)benzyl]-[6-(N-[2-(borono)benzyl]-6-N-(2-methacrylamidoethyl)aminohexyl]]aminoethylamino]naphthale ne-1,8-dicarboximide; and

salts thereof.