Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving glucose or galactose
Reexamination Certificate
2002-07-03
2004-10-05
Gitomer, Ralph (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving glucose or galactose
C546S269700
Reexamination Certificate
active
06800451
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the detection of glucose in samples which may also contain potential interfering compounds, such as &agr;-hydroxy acids or &bgr;-diketones.
2. Description of the Related Art
The complexation of carbohydrates, including glucose, with phenylboronic acid has been known for a long time and the reversibility of that interaction has served as a basis for the chromatographic separation of sugars. Specifically, in 1959, Lorand and Edwards reported association constants for aqueous associations of phenylboronic acid with many saturated polyols; binding interactions ranged from very weak (e.g., ethylene glycol, K
d
=360 mM) to moderately strong (e.g., glucose, K
d
=9.1 mM). See J. Yoon, et al.,
Bioorganic and Medicinal Chemistry
1(4):267-71 (1993). The binding mechanism is believed to occur through bonding of adjacent hydroxyl groups on glucose to hydroxyl groups on a boronate moiety.
U.S. Pat. No. 5,503,770 (James, et al.) describes a fluorescent boronic acid-containing compound that emits fluorescence of a high intensity upon binding to saccharides, including glucose. The fluorescent compound has a molecular structure comprising a fluorophore, at least one phenylboronic acid moiety and at least one amine-providing nitrogen atom where the nitrogen atom is disposed in the vicinity of the phenylboronic acid moiety so as to interact intramolecularly with the boronic acid. Such interaction thereby causes the compound to emit fluorescence upon saccharide binding. See also T. James, et al.,
J. Am. Chem. Soc.
117(35):8982-87 (1995).
Additionally, fluorescent sensors using an anthrylboronic acid-containing compound for detecting blood glucose are known in the art. For example, J. Yoon, et al.,
J. Am. Chem. Soc.
114:5874-5875 (1992) describe that anthrylboronic acid can be used as a fluorescent chemosensor for signaling carbohydrate binding, including binding of glucose and fructose.
Unfortunately, compounds which interact with glucose in the manner described above also have a tendency to interact with other compounds having hydroxyl groups, thus reducing the specificity of a glucose assay, especially when assaying physiological samples which may contain interfering amounts of lactate, acetoacetate, etc. For example, some diabetic patients also develop lactic acidosis, in which blood lactate levels are greater than 5 mmol/liter. Thus, there remains a great need for glucose assays which are relatively insensitive to potentially interfering hydroxyl compounds, such as lactate.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to a method for detecting the presence or concentration of glucose in a sample which may also contain an &agr;-hydroxy acid or a &bgr;-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 &agr;-hydroxy acid or &bgr;-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 &agr;-hydroxy acid or the &bgr;-diketone does not substantially interfere with said determination.
In another aspect, the present invention is directed to a compound having the following structure
wherein:
R
1
and R
2
are the same or different and are selected from the following: i) hydrogen; ii) a substituent to modify the pKa and hydrolytic stability of the R
8
moiety, iii) a detectable moiety, or iv) a linking group capable of attachment to a solid support or a polymeric matrix, said support or matrix optionally containing a detectable moiety;
R
3
is hydrogen or a linking group capable of attachment to a solid support or a polymeric matrix, said support or matrix optionally containing a detectable moiety;
R
4
and R
5
are the same or different and are selected from the following: i) hydrogen, ii) a substituent to modify the pKa and hydrolytic stability of the R
8
moiety, iii) a detectable moiety, or iv) a linking group capable of attachment to a solid support or a polymeric matrix, said support or matrix optionally containing a detectable moiety;
each Z is independently carbon or nitrogen;
R
6
and R
7
are the same or different and are i) linking groups having from zero to ten contiguous or branched carbon and/or heteroatoms, or ii) a linking group capable of attachment to a solid support or a polymeric matrix, said support or matrix optionally containing a detectable moiety;
R is selected from the following: i) an aliphatic and/or aromatic spacer containing from 1 to 10 contiguous atoms selected from the group consisting of carbon, oxygen, nitrogen, sulfur and phosphorus, ii) a detectable moiety, or iii) a linking group capable of attachment to a solid support or a polymeric matrix, said support or matrix optionally containing a detectable moiety;
each R
8
is the same or different and is an optionally protected moiety which when unprotected is capable of interaction with the vicinal diol groups present in glucose; and
R
9
and R
10
are the same or different, and are i) hydrogen, ii) a detectable moiety, iii) a group which is a) a linking group capable of attachment to a solid support or a polymeric matrix, said support or matrix optionally containing a detectable moiety, and/or b) includes a functional group capable of altering the physical properties of the compound;
with the proviso that the indicator compound contains at least one detectable moiety associated therewith, either directly or as part of the solid support or polymeric matrix.
In another aspect, the present invention is directed to a detection system which comprises a compound described above.
REFERENCES:
patent: 5503770 (1996-04-01), James et al.
patent: 5516645 (1996-05-01), Daniel et al.
patent: 5998594 (1999-12-01), Goodman et al.
patent: 6063637 (2000-05-01), Arnold et al.
patent: 6344360 (2002-02-01), Colvin et al.
patent: 6366793 (2002-04-01), Bell et al.
patent: 6511814 (2003-01-01), Carpenter
patent: 0 729 962 (1996-09-01), None
Arimori S. Sugar Sensing by Chiral Orientation of Dimeric Boronic Acid Appended Porphyrins Which Show Selectivity for Glucose and Xylose. Chemistry Letters 1996 vol. 1, 77-78.*
DiCesare N. Evaluation of Two Synthetic Glucose Probes for Fluorescence Lifetime Based Sensing. Analytical Biochemistry 2001 294(2)154-160.*
Daniloff G. Continuous Glucose Monitoring: Long Term Implantable Sensor Approach. Diabetes Technology & Therapeutics 1999, 1(3)261-266.*
Shinkai S. Molecular Design of Artificial Sugar Sensing Systems Trends in Analytical Chemistry 1996 15(5)188-194.*
James, Tony D. et al.A glucose-specific molecular fluorescence sensor. Angewandte Chemie (1994), 106(21), 2287-9, XP002222904. German.
Bielecki, Mia et al.A fluorescent glucose sensor binding covalently to all five hydroxy groups of .alpha.—D-glucofuranose. A reinvestigation. Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1999), (3), 449-455, XP002222905.
Sandanayake, K.R.A. Samankumara et al.Molecular design of sugar recognition systems by sugar-diboronic acid macrocyclization. Pure and Applied Chemistry (1996), 68(6), 1207-1212, XP002222906.
Daniloff George Y.
Kalivretenos Aristotle G.
Nikolaitchik Alexandre V.
Gitomer Ralph
Rothwell Figg Ernst & Manbeck P.C.
Sensors for Medicine and Science, Inc.
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