Medication detection by a combinatorial fluorescent molecular sensor

Article abstract of DOI:10.1002/anie.201206374

Working together to uncover the truth: A molecule-sized diagnostic system combining several recognition elements and four fluorescence-emission channels enabled the identification of a wide range of pharmaceuticals on the basis of distinct photophysical p

Full text of DOI:10.1002/anie.201206374

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DOI: 10.1002/anie.201206374
Molecular-Scale Diagnostics
Medication Detection by a Combinatorial Fluorescent Molecular
Sensor**
Bhimsen Rout, Linor Unger, Gad Armony, Mark A. Iron, and David Margulies*
There is wide interest in the development of fluorescent
molecular sensors triggered by several input signals and their
application as computation and analytical devices.[1] Such
sensors can imitate the function of electronic logic gates and
circuits[2] and can also be applied to cellular imaging,[3] to
clever chemosensing,[4] and as digital molecular tags.[5] The
development of a “lab on a molecule”[6] for the simultaneous
identification of Na+, H+, and Zn2+ highlights an exciting
prospect for this field. Specifically, it shows the potential for
the creation of molecular-scale analytical systems with high
sensitivity[7] and high-throughput detection capabilities, akin
to microarray sensing devices.
An inherent limitation of the use of these unimolecular
fluorescent sensors[2–6] is the need to design a receptor for
each target, which significantly limits their multiplicity.
Therefore, an alternative class of “lab on a molecule” was
developed in which the sensor–analyte interactions are
monitored by an array of detection methods.[8,9] The efficiency
of this approach was demonstrated with the selective
detection of several metal ions by a sensor molecule bearing
only one type of receptor.[8] This important advance,[10]
however, involves the use of different instrumentations,
which may complicate high-throughput analysis.
Herein, we describe the design and function of a combi-
natorial fluorescent sensor that takes molecular-scale diag-
nostics[3–12] a step further. The molecular analytical system
presented herein combines several recognition elements as
well as four emission channels and utilizes distinct photo-
physical processes that enable us to identify a wide range of
pharmaceuticals and analyze drug concentrations and combi-
nations in urine samples in a high-throughput manner.
The development of methods for the verification of drug
content at point-of-care has been receiving growing interna-
tional attention.[15] We therefore selected four drug families
commonly associated with counterfeiting or medication
errors as test cases for our molecular sensor (Scheme 1; see
Figure S1 in the Supporting Information). Macrolides, amino-
glycosides, and rifamycins are large families of antibiotics
whose counterfeits are highly prevalent in the developing
world.[16] Cardiac glycosides, used for treating heart condi-
tions, have been associated with substandard medication in
developed countries[15] and are often involved in medication
errors owing to their narrow therapeutic window and adverse
drug interactions.[17]
A third strategy that enables high-throughput, multi-
analyte sensing by individual molecules is combinatorial
sensing.[11,12] By use of the “nose/tongue” approach,[13]
a chromophoric ligand[11] and, more recently, a 13C-labeled
molecule[12] were cleverly designed to differentiate between
metal ions and fullerenes, respectively. Although these
systems do not operate in the fluorescence mode and so far
cannot compete with the remarkable abilities of cross-
reactive sensor arrays to discriminate between organic com-
pounds and biomolecules,[14] they indicate the potential for
the development of multianalyte fluorescent molecular
sensors with superior analytical capabilities.
[*] Dr. B. Rout, L. Unger, G. Armony, Dr. D. Margulies
Department of Organic Chemistry
Weizmann Institute of Science, 76100, Rehovot (Israel)
E-mail: david.margulies@weizmann.ac.il
Homepage: www.weizmann.ac.il/Organic_Chemistry/Margulies
Dr. M. A. Iron
Department of Chemical Research Support
Weizmann Institute of Science, 76100, Rehovot (Israel)
[**] This research was supported by the Peter and Patricia Gruber
Foundation and by the Helen and Martin Kimmel Center for
Molecular Design. D.M. is the incumbent of the Judith and Martin
Freedman Career Development Chair. We thank Dr. Leila Motiei for
fruitful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206374.
Scheme 1. Representative structures of the a) macrolide, b) cardiac
glycoside, c) rifamycin, and d) aminoglycoside drug families.
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To be able to identify different macrolides, aminoglyco-
sides, cardiac glycosides, and rifamycins with a single fluo-
rescent molecule, we designed and synthesized sensor 1,
which combines hydrophobic recognition elements with
boronic acid functionalities (Scheme 2; see the Supporting
Scheme 2. a) Structure of the monomolecular combinatorial sensor 1.
The emission wavelength of each dye, stereogenic centers, and the
components involved in PET and ICT processes are indicated.
Information for synthetic details). The latter have been used
extensively for the recognition of carbohydrates and their
derivatives with individual fluorescent molecular sensors[18] or
through colorimetric arrays.[14h–o] In 1, three phenyl boronic
acids form diol-binding receptors, while four spectrally over-
lapping fluorophores, namely, naphthalene (Naph), fluorenyl
(Flu), anthracene (An), and dansyl (Dan), serve as hydro-
phobic units and as reporters that can transduce the binding
event into a measurable optical signature. The attachment of
these components to a cis-amino-l-proline scaffold provides
a flexible and chiral molecular cavity that can accommodate
and discriminate between the different medications. The
binding of different analytes distinctly affects the emission of
each dye by interfering with the photoinduced electron
transfer (PET), internal charge transfer (ICT), and fluores-
cence resonance energy transfer (FRET) processes. The
combination of these effects provides a vast number of
unique optical signatures.
Figure 1a shows the excitation and emission spectra of the
individual fluorescent receptors, specifically, each boronic
acid–dye pair (i.e., Naph*, An*, and Dan*) and a fluorenyl–
aspartic acid derivative (Flu*). The emission spectra of Naph*
and Flu* overlap with the excitation spectra of An* and
Dan*. Therefore, illumination at 270 nm should result in an
emission pattern ranging across the UV/Vis spectrum (Fig-
ure 1b) owing to FRET between the donors (i.e., naphtha-
lene and fluorenyl) and acceptors (i.e., dansyl and anthra-
cene) as well as direct excitations, mainly of naphthalene,
fluorenyl, and dansyl. An additional energy-transfer process
that occurs to a lesser extent involves FRET between
anthracene and dansyl. Because FRET largely depends on
the distances between the donors and acceptors, conforma-
tional changes that occur upon drug binding is one factor that
contributes to the generation of distinct fluorescence signa-
tures.
Figure 1. a) Normalized excitation and emission spectra of fluorenyl–
aspartic acid (Flu*), naphthalene–boronic acid (Naph*), anthracene–
boronic acid (An*), and dansyl–boronic acid (Dan*) derivatives
dissolved in methanol. b) Schematic representation of the possible
intramolecular FRET processes upon excitation at 270 nm. Boc=tert-
butoxycarbonyl.
To be able to differentiate between drug molecules that
may not inflict substantial structural changes, we incorporated
two PET-based sensors,[18b] namely, naphthalene–boronic acid
and the well-known anthracene–boronic acid,[19] into the
structure of 1 (Scheme 2). In this way, the binding of a drug
molecule to a boronic acid adjacent to a nitrogen atom and
a fluorophore should directly trigger an increase in their
emission intensity. Another outcome of PET is quenching of
the emission of the naphthalene donor, which may disrupt the
overall FRET processes required for operating the sensor.
Therefore, we incorporated an additional fluorescence donor
(i.e., a fluorenyl group) into the sensor to ensure efficient
energy transfer to anthracene and dansyl, as well as to
increase the variability of the optical patterns generated by
the molecular device.
A third signaling mechanism that further contributes to
the discrimination ability of the sensor is ICT.[7] Dansyl is an
environmentally sensitive ICT probe commonly used to
monitor supramolecular host–guest interactions. We reasoned
that the binding of a guest molecule within the cavity[20] would
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induce a change in its immediate environment, for example,
by disrupting intramolecular hydrogen bonds or p-stacking.
The structure of 1 optimized by using density functional
theory (DFT) supports the possibility of such intramolecular
interactions (Figure 2). The modeling shows that the molecule
Figure 3. Representative emission signatures generated by 1 (black)
upon the addition of 5 mm ouabain (red), 5 mm digitoxin (green),
5 mm digoxin (orange), 5 mm erythromycin (blue), 100 mm rifampicin
(light blue), and 100 mm rifabutin (brown). Excitation wavelength:
270 nm.
Figure 2. DFT-optimized structure of 1 (C gray, N blue, O red, B pink,
S yellow; hydrogen atoms are omitted for clarity).
forms a flexible and structurally preorganized cavity in which
the four dyes and three phenyl boronic acid groups project in
the same direction (see the Supporting Information for
computational details). Importantly, the structure is main-
tained through intramolecular hydrogen bonds and p-stack-
ing. For example, the phenyl boronic acid next to the dansyl
group forms p-interactions with the adjacent aromatic ring
(Figure 2), whereas its hydroxy groups are hydrogen-bonded
to an amide and an amine on the neighboring arm as well as to
a nearby carbonyl group (see Figure S3 in the Supporting
Information).
We tested the efficiency of the design by determining the
ability of 1 to generate unique optical signatures for different
drugs (Figure 3). Excitation of the sensor at 270 nm resulted
in fluorescence emission across the UV/Vis spectrum, as
expected from intramolecular FRET processes (Figure 1).
The addition of cardiac drugs or antibiotics to a solution of
1 in methanol resulted in readily distinguishable changes in
the different emission channels. Interestingly, whereas macro-
lides, aminoglycosides, and cardiac glycosides were detected
at a 5 mm concentration, a much higher sensitivity for
rifamycins (i.e., rifampicin, rifabutin) was observed, presum-
ably as a result of additional p-interactions and quenching of
fluorescence by their aromatic core. Thus, rifamycins can be
identified at low micromolar concentrations (Figure 3,
Figure 4).
Figure 4. PCA mapping of emission patterns generated by the cardiac
glycosides (3–5, red), macrolides (6–9, blue), and aminoglycosides (10
and 11, green) at a concentration of 5 mm, by the rifamycins (12 and
13, brown) at a concentration of 100 mm, and by a double amount of
digoxin (2, red).
ingredients (e.g., erythromycin instead of roxithromycin[21]),
no active ingredients, or incorrect doses.[16] Similarly, the
recent discovery of incorrect doses of digoxin (2, 3) in tablets
of the drug in the USA led to an urgent recall of the drug
nationwide.[15] Drugs randomly selected from the training set
could be identified by our sensor with 93% accuracy.
Principal component analysis (PCA) was applied (see the
Supporting Information) to distinguish between the emission
patterns generated by the medications considered in this
study (Figure 4, drugs 2–13). These drugs are commonly
involved in cases of forgery or poor-quality manufacturing.
For example, in many developing countries, about 30% of the
most essential antibiotics, such as erythromycin (6), roxithro-
mycin (7), and rifampicin (12), may contain the wrong
Beyond the authentication of commercially available
drugs, analytical systems that can detect various drug
concentrations and combinations play an important role in
pharmacokinetic studies. For example, the parallel analysis of
rifampicin and d-xylose levels in urine is used to diagnose
rifampicin malabsorption in HIV patients with tuberculo-
sis.[22] In such studies, patients are given a normal dose of
rifampicin and a much larger amount of the saccharide.[23]
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To demonstrate the potential of combinatorial molecular
sensors to distinguish between various drug concentrations
and combinations within medicinally relevant samples, we
subjected 1 to human urine loaded with different ratios of d-
xylose and rifampicin. Samples with just rifampicin (sam-
ple A) or d-xylose (sample F) induced distinct changes in the
emission patterns (Figure 5a). Notably, the addition of
sample A resulted in a substantial decrease in anthracene
and dansyl fluorescence, whereas the addition of sample F
mainly led to an enhancement in their emissions (Figure S2).
Similar measurements were performed with urine samples
containing different antibiotic/saccharide ratios, and PCAwas
used to differentiate between the patterns generated at the
four emission channels in which the maximal intensity
changes were observed (Figure 5b). The molecular diagnostic
system was able to identify unknown urine–drug samples with
a 97% success rate.
such sensors in pharmacokinetics, therapeutic drug monitor-
ing, and medicinal diagnostics. Moreover, it shows the
feasibility of developing fluorescent molecular sensors with
remarkable analytical abilities. The combinatorial sensor
described herein, for example, is extremely simple to operate,
since it avoids the need for device integration and it utilizes
a single instrumentation, a single excitation wavelength, and
a single incubation step, all of which enable straightforward
analysis. We expect this study to contribute to the develop-
ment of information processing at the molecular level[1,2] and,
in particular, to multianalyte, molecular-scale diagnostics.[3–12]
Received: August 8, 2012
Published online: October 12, 2012
Keywords: analytical methods · combinatorial sensors ·
.
fluorescent probes · molecular devices · photophysics
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