A color sensor for catecholamines

Article abstract of DOI:10.1002/anie.200462702

(Graph Presented) Right in front of your eyes: Upon addition of a catecholamine to a catechol-containing receptor precomplexed with a dye, a change in color from orange to deep red signals the release of the dye and capture of the guest (see picture). This simple competition experiment allows exact quantitative determination of the concentration of catecholamines in complex mixtures, such as that of adrenaline in urine samples.

Full text of DOI:10.1002/anie.200462702

Angewandte
Chemie
Colorimetric Sensors
A Color Sensor for Catecholamines**
Michael Maue and Thomas Schrader*
Dedicated to Professor Christian Reichardt
on the occasion of his 70th birthday
Catecholamines are characterized by their phenylethylamine
skeleton, which carry two phenolic ortho-hydroxy groups. The
level of these and related compounds in blood and urine
reflects the biodegradation efficiency of aromatic amino
acids, especially tyrosine, and plays an important role in
diagnostic purposes. Patients suffering from phaeochromocy-
toma display a critically elevated concentration of the
catecholamine adrenaline in their blood which inevitably
leads to heart failure and death.[1] Malfunction of the
catecholamine dopamine-responsive neurons is a key feature
for Parkinsonꢀs disease.[2] Usually, noradrenaline and adrena-
line are determined in blood and urine samples through
HPLC analyses with electrochemical or neurochemical
detection.[3] In recent years, a large number of catechol-
amine-receptor structures have been designed for organic
solvents, some as ditopic host molecules with recognition sites
[*] M. Maue, Prof. T. Schrader
Fachbereich Chemie
Universitꢀt Marburg
Hans-Meerwein-Strasse
35032 Marburg (Germany)
Fax: (+49)6421-28-25544
E-mail: schradet@staff.uni-marburg.de
[**] The authors are indebted to Dr. Uwe Linne for ESI-HRMS
measurements. We gratefully acknowledge Martin Mꢁnzel for his
preparative work. M.M. thanks the Fonds der Chemischen Industrie
for a Ph.D. grant. The coupling reagent T3Pa (1-propylphosphonic
acid cyclic anhydride) was generously provided by Clariant GmbH,
Frankfurt-Hoechst.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200462702
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for both parts of the guest.[4] However, only very few of these
molecules with a high selectivity for the corresponding
guests.[19] For example, Cooper and James covalently attached
a phenylboronic acid to a crown ether through an anthracene
spacer and obtained a fluorescent sensor for d-glucosamine
hydrochloride.[19a,c]
receptors operate in pure aqueous solution.[5] To this end,
receptors have been embedded in membranes[6] or sol-gel
films.[7] RNA aptamers[8] represent a bioorganic solution to
the problem of dopamine recognition. A less selective
alternative is the fabrication of immobilized monotopic
receptor structures with simple functional groups on electro-
des, for example, in a polymer matrix,[9] on silica particles or
other solids,[10] or on biofilms containing polyphenolases.[11]
Recently a certain shape-selectivity has been achieved for the
slim dopamine skeleton with designed cyclophanes.[12] How-
ever, almost none of the preceding examples are selective for
catecholamines in complex mixtures that contain other
amines, amino acids, and neurotransmitters. Herein we
present a receptor that combines our bisphosphonate recog-
nition motif, which is selective for amino alcohols,[13] with a
boronic acid, which is highly selective for catechols. In a
simple competition experiment with a catechol-containing
dye, a color signal is induced that indicates the presence of
catecholamines and allows an exact quantitative determina-
tion of the concentration of catecholamines in complex
mixtures, for example, in urine samples.
In our rational design, we bridged a xylylene bisphos-
phonate unit for aminoalcohol recognition and a toluenebor-
onic acid moiety for binding to catecholamine with a non-
proteinogenic amino acid of appropriate length in the aim of
using the amine group as an internal base. To this end, the N-
acyl-protected amino acid was coupled to the readily avail-
able m-aminoxylylene bisphosphonate,[20] and the coupled
product was then deprotected and monodealkylated at its
phosphonate ester groups. In the final step, the dilithium salt
was subjected to a reductive amination sequence with o-
formylphenylboronic acid.[21] The resulting benzylamine, the
desired receptor molecule, was obtained as a water-soluble,
colorless solid (Scheme 1). Three different spacer groups
were chosen: m-aminomethylbenzoic acid acts as a semirigid
building block in 1, whereas GABA (g-aminobutyric acid) as
the secondary and tertiary amine in 2 and 3, respectively,
provides a flexible alkyl chain.
The groups of Shinkai and Czarnik have used multiple
boronic acid moieties extensively for the covalent recognition
of cis-glycol units in sugars.[14,15] Numerous examples of
derivatives with a secondary or tertiary benzylic amine
functionality ortho to a phenylboronic acid have been
reported,[16] and even in aqueous solution, the thermodynami-
cally stable tetrahedral zwitterionic intermediate is formed
almost quantitatively.[17] However, much less is known about
the related formation of boronic acid esters with catechols,
although the flat 1,2-arrangement of both acidic hydroxy
groups should facilitate this condensation even more. Early
investigations by Smith and co-workers described transport
agents based on arylboronic acids for catecholamines.[18]
Other groups combined the boronic acid moiety with binding
motifs for other functionalities to synthesize ditopic receptor
Upon equilibration of the ditopic receptors with nor-
adrenaline, a second set of signals were observed in the
1H NMR spectrum which correspond to the catechol-boro-
nate zwitterion (Figure 1). In our case, formation of the
catechol-borane is slow on the NMR timescale. Distinct
signals appeared for both the host (amino alcohol) and guest
(catechol) parts. This effect was examined in buffered
aqueous solution (NaH2PO4 (100 mm), pH 7.0). Recently a
weak phosphate–boronic acid interaction was described
which could also interfere in our system.[22] To verify this, a
“model” NMR titration between a boronic acid derivative
and catechol was carried out in the presence and absence of
phosphate buffer. The corresponding binding constant was
not affected by the presence of phosphate anions, so we
conclude that the influence of coordination of the boronic
Scheme 1. Synthetic route with reductive amination as the key step to the ditopic adrenaline receptors 1–3, which carry a boronate and a
bisphosphonate group bridged by non-proteinogenic amino acids. PG=protecting group, Boc=tert-butyloxycarbonyl, Z=benzyloxycarbonyl,
T3P=1-propylphosphonic acid cyclic anhydride, NMM=N-methylmorpholine, TFA=trifluoroacetic acid.
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Table 1: Association constants between amines and/or diols and ditopic
receptors 1–3.[a]
Guest
1
2
3
Ka [mÀ1 [b]
]
Ka [mÀ1 [b]
]
Ka [mÀ1 [b]
]
catechol
50
190
–
150
200
–
350
550
590
adrenaline
DOPA[c]
dopamine
180
190
<10
<10
230
340
<10
<10
630
690
<10
<10
noradrenaline
tyrosine ester
phenylalanine ester
[a] Determined from 1H NMR titrations in buffered aqueous solution
(Na2HPO4/NaH2PO4 (100 mm)) at 208C. [b] Error values were calculated
as standard deviations from three independent measurements; all
values were between 4% and 12%. [c] DOPA=3,4-dihydroxyphenyl-
alanine.
Figure 1. Model binding 1H NMR experiment for the quantitative deter-
mination of the Ka value between phenylboronic acid (host), precom-
plexed with piperidine, and catechol. a) Free host, b)–d) host in the
presence of 0.6 (b), 1.0 (c), and 1.6 equivalents (d) of catechol. A new
set of signals appear for the protons of the host (d>7 ppm) and the
guest (d<7 ppm). Binding constants (Ka) can be calculated from the
ratio of free:complexed host (b) or free:complexed guest (d).
mitters are also neglected, such as glycine, glutamate, GABA,
and acetylcholine.
The high selectivity of our new receptor molecules for
catecholamines prompted us to develop a color assay for their
detection in complex mixtures. Recently a simple dopamine
sensor which comprised a boronic acid tethered to a
fluorescent reporter group was reported.[5] Secor and Glass
very recently reported a related system that featured a
coumarin aldehyde for chromophoric response.[25] Our
approach relies on precomplexation of alizarin complexone
((3,4-dihydroxy-2-anthraquinonylmethyl)iminodiacetic acid)
by the receptor and its subsequent displacement by the guest
of choice. This concept has been introduced in several elegant
contributions by Anslyn and co-workers who used competi-
tion experiments for citrate and tartrate ion sensing.[26] The
dye compound carries a relatively acidic catechol moiety
incorporated into its anthraquinone chromophore, and—in its
zwitterionic form—also an ammonium ion.[27] In a similar
approach, the groups of Wang and James established a
fluorometric and colorimetric system using the alizarine
red S–boronic acid interaction.[28] 1H NMR titrations of a
mixture of alizarin complexone and increasing amounts of 2
acid to phosphate ions is negligible. Analysis of the ratio
between free host, guest, and complex revealed binding
constants (Ka) in the order of 200–700mÀ1 for adrenaline
derivatives, but significantly smaller values for catechol itself
(Ka ꢀ 50–300mÀ1).[23] Together with distinct changes in the
chemical shifts in the bisphosphonate and amino alcohol
region, these findings indicate a simultaneous cooperative
participation of the ammonium-boronate and the bisphos-
phonate in the binding of catecholamine. Relative to conven-
tional NMR titrations, this is a very economic and convenient
procedure for the accurate determination of Ka values: by
variation of the host:guest stoichiometry, each mixture gives
an association constant with very small deviations (see
Table 1).
Probably owing to its C-4 linker, the rigid benzoic acid
spacer in 1 produced only a relatively weak adrenaline
receptor and gave a Ka value of 190mÀ1 upon association with
noradrenaline. A little more effective was the flexible C-3
alkyl chain of the GABA spacer in 2 with a Ka value of
340mÀ1, which was further improved by introduction of a
second N-alkyl group to produce a superior electron-pair
donor in the form of the tertiary amine bridge in 3. The
resulting association constant of 3 with noradrenaline almost
reached 700mÀ1, while with its N-isopropyl derivative iso-
reveal a rather high binding constant of Ka ꢀ 1700mÀ1
.
Formation of the complex was also accompanied by a
strong bathochromic shift in the absorption maximum of the
dye. Figure 2 illustrates the resulting UV/Vis absorption
curves obtained, as well as a clear isosbestic point and the
concomitant color change from deep red (bordeaux) to
orange.[29] As soon as a competing catecholamine is added, the
dye is successively replaced and released into the free
solution, and the color change is reverted. A large excess of
the guest finally restores the original spectrum of the dye.
From the quantitative evaluation of the decrease in
intensity at the new absorption maximum at 460 nm, binding
constants were calculated for the guest molecules discussed
above and lie in exactly the same relative order as those
determined by NMR titrations, but remain somewhat lower
(Figure 3a, Table 2).[30] Upon changing the solvent from pure
proterenol, Ka reached almost 800mÀ1 [24]
Although the
.
affinities towards adrenaline derivatives in buffered aqueous
solution are still moderate, the new receptor family is
extremely selective for catecholamines. Simple biogenic
amines such as phenylethylamine are not bound at all, and
aliphatic diols such as glucose are likewise rejected. Even
more impressive is the phenylalanine, tyrosine, and DOPA
series, which shows exclusive interaction between the ditopic
receptors and the dihydroxy amino acid. Other neurotrans-
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Figure 2. Competitive color assay that relies on the displacement of precomplexed alizarin complexone with concomitant color change. a) Lewis
acidic/basic structures of the host 3. b) Corresponding UV/Vis absorption curves of alizarin complexone with 2, with deep red (bordeaux) and
orange colors indicating the free and complexed states, respectively, of the alizarin dye. The isosbestic points indicate the direct interconversion
of both states.
Table 2: Association constants between amines and/or diols and ditopic
receptors 1–3.[a]
Guest
1
2
3
Ka [mÀ1 [b]
]
Ka [mÀ1 [b]
]
Ka [mÀ1 [b]
]
catechol
adrenaline
DOPA
60
160
–
150
210
–
100
310
270
dopamine
noradrenaline
alizarin complexone
170
180
2050
220
250
1620
280
350
3440
[a] Determined by UV/Vis spectroscopy from competition experiments in
buffered aqueous solution (NaH2PO4 (100 mm)) at 208C. [b] Error
values were calculated as standard deviations from three independent
measurements; all values were between 4% and 10%.
water to a 3:1 mixture of methanol/water (HEPES (N-(2-
hydroxyethyl)-piperazine-N’-2-ethanesulfonic acid) buffer
(150 mm), pH 7.0), the Ka value for alizarin complexone
increases from 3300mÀ1 to 7000mÀ1. However, the expected
rise in noradrenaline binding could not be confirmed: the
determined association constant remained at 330mÀ1 in this
system. In general, catecholamines are again bound in the
range of 300–400mÀ1, catechol somewhat less tightly with
200mÀ1 and simple amines such as phenylethylamine are not
bound at all. With the latter, no color change whatsoever
could be detected which underlies the extreme selectivity of
the receptor for catecholamines. Again a large number of
other potential guests were examined, with the satisfying
result that only catecholamines and no other amino acids,
sugars,[31] neurotransmitters, or biogenic amines produced any
positive responses (Figure 3b).
Consequently, we measured the decrease in absorption,
brought about by noradrenaline during the competition
experiment, at varying concentrations of analyte in the
linear range of the Beer–Lambert law, between 10À4 m and
10À2 m, and obtained a straight calibration line. Extrapolation
of the DA values measured from unknown samples of this
neurotransmitter led to concentrations which were in excel-
lent agreement with the amounts weighed (Figure 4). These
values were exactly reproduced (less than 15% difference) in
complex mixtures with up to 10 different competing amines or
Figure 3. a) Binding curves obtained from the UV/Vis titrations of
receptor 3 (1 mm) with various analytes by indirect visualization of
their affinities through the respective decrease in the absorbance at
l=460 nm (A460) of the receptor-precomplexed alizarin dye (1 mm).
Methoxytyrosine hydrochloride (black rhombus); fructose (gray tri-
angle); catechol (gray square); noradrenaline (light-gray rhombus).
b) Selectivity of the new ditopic receptor 3 for catecholamines as illus-
trated by changes in absorption DA460 at the absorption maximum of
the dye–3 complex (1 mm each) after the addition of 5 equivalents of
guest in the color assay. NA=noradrenaline, Ser=serine,
Phe=phenylalanine, Ala=alanine, His=histidine, Lys=lysine,
Trp =tryptophan, Glu=glutamate, GABA=g-aminobutyric acid, Gly=
glycine, 5HT=serotonin, ACh=acetylcholine, GlcN=glucosamine,
Glc=glucose, Fru=fructose, Sac=saccharose, VitC=vitamin C,
Crea=creatinine.
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solution of alizarin complexone (1 mm) was prepared in phosphate
buffer (150 mm, pH 6.9). Solutions of hosts 1–3 ( ꢀ 20 mm) were
prepared from this buffered solution of alizarin complexone to avoid
dilution of the dye during the titration. An aliquot of the solution of
alizarin complexone (400 mL) was taken in a cuvette (2-mm inner
diameter) and treated stepwise with the hosts 1–3 (0–6 equiv). The
reference cuvette was filled with phosphate buffer (150 mm; 400 mL).
After every addition of host, the mixture was equilibrated for 30 s
before the corresponding spectrum was measured. The binding
constant was determined by nonlinear regression of the curve of DA
versus [host] at a specific wavelength. In all cases, the absorption at
460 nm (lmax of the alizarin complexone–host complex) was used as
the maximum changes in the absorption were observed at this specific
wavelength.
Determination of the complexation constants for the guests
catechol, adrenaline, dopamine, and noradrenaline with hosts 1–3 by
competitive UV/Vis titration: The solution of alizarin complexone
(1 mm in phosphate buffer (150 mm)) prepared above was treated
with host 1–3, such that a 1:1 mixture was obtained. The stock
solutions of guests were prepared using
Figure 4. Benesi–Hildebrandt plot of the linear relationship between
reciprocal absorption and reciprocal concentration of noradrenaline
(NA).[32] a–d) Analytical samples of unknown concentration of nor-
adrenaline which were determined by extrapolation from the observed
1/DA460 value to the 1/[NA] axis. Such calibration curves were used for
all subsequent adrenaline determinations.
the solution of alizarin complexone–host
Table 3: Quantitative detection of noradrenaline (NA) in a complex mixture of 11 different analytes in
approximately equimolar concentrations, as well as detection in the millimolar regime of noradrenaline
and total catecholamine (Cat) in a sample of human urine.
complex, again to avoid dilution of the
dye during the titration. An aliquot of
the solution of alizarin complexone–host
(1 mm each in phosphate buffer
(150 mm)) complex (400 mL) was filled
11-compound mixture
[NA]calcd [mm] [NA]found [mm]
Urine
[NA]calcd [mm]
[NA]found [mm]
[Cat]calcd [mm]
[Cat]found [mm]
in
a cuvette (2-mm inner diameter;
1.3
2.2
7.9
1.5
2.5
6.7
2.7
7.5
8.8
3.3
7.9
9.8
6.4
9.5
13.0
–
7.6
11.3
14.6
–
reference: phosphate buffer) and
treated stepwise with the guests (0–
33 equiv). The DA460 values were used
in the calculation of the corresponding
binding constants (see Supporting Infor-
mation for the detailed procedure).
23.2
22.5
14.9
17.6
Received: November 23, 2004
Published online: March 4, 2005
diols in fivefold molar excess (Table 3). Human urine contains
large amounts of urea, uric acid, creatinine, amino acids,
organic acids, and various salts, as well as the yellow dye
urobilin. Remarkably, even in this highly competitive envi-
ronment, our color assay works and gives reliable results (less
than 20% difference) with the simple calibration curve taken
from the initial competition experiment with pure noradrena-
line (Table 3). As all catecholamines give comparable quan-
titative effects, the total catecholamine concentration can be
calculated from microliter quantities of such a sample, which
contains dopamine, noradrenaline, adrenaline, and DOPA
(Table 3), for example. Together with the simple competition
measurement by UV/Vis spectroscopy, these features char-
acterize the new method as a highly economic and fast assay
for the determination of catecholamines in urine samples.[33]
The selectivity of our new ditopic receptor molecules for
catecholamines in highly competitive environments renders
them useful in situations normally reserved for antibodies.
There is only one drawback: the average level of catechol-
amine in human urine is much lower, in the micromolar
concentration range. We are currently increasing the sensi-
tivity of our assay, on one hand, by optimizing the receptor
affinity for catecholamines and, on the other hand, by
transferring the experiment to fluorescence techniques.
Keywords: host–guest systems · NMR spectroscopy · sensors ·
.
UV/Vis spectroscopy
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