Solid-phase saccharide sensing compounds

• US 20060223189A1
• Filed: 03/28/2003
• Published: 10/05/2006
• Est. Priority Date: 03/28/2003
• Status: Active Grant

• Current Assignee: Terumo Kabushiki Kaisha (Terumo Corporation)
• Original Assignee: Terumo Kabushiki Kaisha (Terumo Corporation)
• Inventors: Kawanishi, Tetsuro, Romey, Mathew Albert, Shinkai, Seiji, Zhu, Peter C., Holody, Mark Z.
• Granted Patent: US 7,297,548 B2
• Time in Patent Office: Days
• US Class Current: 436/90
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

The present invention provides solid-phase saccharide dyes. The dyes are bisboronic acids covalently bonded to a solid substrate. The dyes selectively conjugate with saccharides, particularly glucose, and register a signal. The signal is proportional to the quantity of saccharide. Thus, the dyes of the present invention are useful for measuring and monitoring saccharide levels, particularly in biological fluids such as blood.

Claims

1. A compound of the formula:

2. The compound of claim 1, wherein Q is selected from the group consisting of:

3. The compound of claim 1, wherein the difference between the excitation peak and the emission peak upon saccharide conjugation is at least about 40 nm.

4. The compound of claim 1, wherein the relative intensity of the fluorescence of the molecule is greater than about 1.5 across the physiological range of glucose concentration.

5. The compound of claim 2, wherein said acyl group is acetyl.

6. The compound of claim 1, wherein Q is:

7. The compound of claim 1, wherein said linker arm is selected from the group consisting of:

—

X—

Y, —

X—

O—

Y, —

X—

NH—

Y, —

X—

N═

Y, —

X—

NR—

Y, X—

CO—

Y, —

X—

COO—

Y, —

X—

OCO—

Y, —

X—

NHCO—

Y, —

X—

CONH—

Y, —

X—

N═

C(O—

Y)₂, —

X—

NHCH(NH₂)—

O—

Y, —

X—

S—

Y, —

X—

S—

S—

Y, —

X—

SO₂NH—

Y and —

X—

NHS₂—

Y;

wherein;

R is alkyl, alkenyl, aryl, arylalkyl, or acyl;

X is a saturated or an unsaturated hydrocarbon chain; and

Y is a solid-phase material.

8. The compound according to claim 7, wherein the solid-phase material is a biocompatible polymer selected from the group consisting of cellulose, polystyrene, polyamide, polyethersulfone, polyethyleneglycol, polypropyleneglycol, polyvinylalcohol, polysiloxane, nylon, and copolymers thereof.

9. The compound of claim 8, wherein the solid-phase material is a regenerated cellulose or nylon.

20. A sensor for detecting the concentration of saccharide in a biological fluid comprising a fluid conduit wherein a compound of claim 1 is covalently attached to an interior wall of the conduit such that the compound is in contact with fluid flowing through the conduit.

21. A method for detecting the concentration of saccharide in a biological fluid comprising contacting a biological fluid with an immobilized compound of claim 1, and measuring the relative intensity of fluorescence of the compound.

22. A method for immobilizing a compound of claim 1 comprising reacting a compound of the formula:

23. The method of claim 22, wherein the activated polymer is cross-linked with ethylenediamine.

24. A method for immobilizing a compound of claim 1 comprising reacting a compound of the formula:

25. A method for immobilizing a compound of claim 1 comprising reacting a compound of the formula:

10. A compound of the formula:

11. The compound of claim 10 wherein R₁ and R₂ are both —

CH₂—

C(O)—

OH or —

C₆H₁₂—

NH₂.

12. The compound of claim 10, wherein R₁ and R₂ both include a polypropyleneglycol spacer between the saccharide dye and the solid-phase material.

13. A compound of the formula:

14. The compound of claim 13, wherein the difference between the excitation peak and the emission peak for the compound upon saccharide conjugation is about 40 nm or greater.

15. The compound of claim 13, wherein the compound has a fluorescence relative intensity of at least about 1.4 upon saccharide conjugation.

17. The compound of claim 14, wherein the excitation-emission differential of the dye upon saccharide conjugation is about 70 nm or greater.

18. The compound of claim 14, wherein the relative intensity of the fluorescence of the dye is about 2.0 across the physiological range of glucose.

19. The compound of claim 14, wherein the polymeric solid-phase support is a regenerated cellulose or activated nylon.

16. A compound of the formula: