Precise tuning of cationic cyclophanes toward highly selective fluorogenic recognition of specific biophosphate anions

Article abstract of DOI:10.1021/ol500613y

Cationic cyclophanes with bridging and spacer groups possess well-organized semirigid cavities and are able to encapsulate and stabilize anionic species through diverse molecular interactions. We highlight the precise tuning of functionalized cyclophanes

Full text of DOI:10.1021/ol500613y

Letter
pubs.acs.org/OrgLett
Precise Tuning of Cationic Cyclophanes toward Highly Selective
Fluorogenic Recognition of Specific Biophosphate Anions
Muhammad Yousuf,†,§ Nisar Ahmed,*,‡ Bahareh Shirinfar,‡ Vijay Madhav Miriyala,† Il Seung Youn,†,§
and Kwang S. Kim*,§
†Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, Korea
‡Organic Chemistry Institute, University of Zurich (UZH), Winterthurerstrasse 190, 8057 Zurich, Switzerland
̈
̈
§Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea
S
* Supporting Information
ABSTRACT: Cationic cyclophanes with bridging and spacer groups
possess well-organized semirigid cavities and are able to encapsulate
and stabilize anionic species through diverse molecular interactions. We
highlight the precise tuning of functionalized cyclophanes toward
selective recognition of AMP, GTP, and pyrophosphate (PPi) using
fluorescence, NMR spectroscopy, and density functional theory (DFT).
olecular recognition, in its broadest sense, refers to the
stabilizing guest molecules in defined cavities through non-
Minteraction between host and guest molecules and is covalent interactions.9 Water-soluble cyclic systems having ionic
generally governed by noncovalent forces.1 Among various types
H-bonding could be a good choice to develop chemosensors for
selective discrimination of biologically important targets as
compared to open systems.10 However, cyclic systems are very
hydrophobic and have low solubility in water.11 Thus, it is
difficult to synthesize cyclic systems that are soluble under
physiological conditions and undergo specific interactions with
anionic moieties.12
of noncovalent interactions, H-bonding is a proven, effective way
of binding, but other forces including π−π, cation−π, and π+−π
interactions also have their own importance in molecular
recognition.2 The importance of molecular recognition in
various biological processes has helped chemists to design
molecular systems with fascinating properties.3 Anions are
ubiquitous in nature and play a significant role in numerous
biological functions; thus considerable efforts have been devoted
to develop detection methods for anions. Fluorescent sensors are
powerful tools to monitor biologically relevant species because of
the simplicity and high sensitivity of fluorescence.4 The design of
a suitable receptor for selective discrimination of a specific
biomolecular anion in the presence of interfering analytes
requires a complete understanding of all the structural features of
the receptor and guest anion as well as the interactions favored by
the anion of interest.5 Though noncovalent interactions are
weaker than covalent ones, the cooperative effect of such
interactions aids to strengthen selective recognition. Thus,
receptors having specific binding motifs, capable of specific
noncovalent interactions, are expected to act as selective
molecular probes.6
Fluorescent cyclophanes with defined cavities have proven to
be a good choice for molecular recognition, drug delivery, and
anion sensing for biologically important anionic moieties.7
Fluorescent cyclophanes consist of fluorophore units linked
together through suitable bridging and spacer groups.8 They
have unique geometries and give a quick response in fluorescence
through bridges. The cavity size as well as the fluorogenic
properties exhibited by these systems could be varied by altering
the fluorophore moiety, the bridging unit, and the spacer groups.
Then, such cyclic systems are capable of encapsulating and
The molecular recognition by cyclic probes is generally based
on neutral or charged H-bonds. Charged H-bond interactions for
anions occur by amide, pyrrole, urea, ammonium, and
guanidinium groups through the N−H···A− interaction. It has
been observed that positively charged imidazolium function-
alized receptors are fairly soluble in water and capable of binding
with anions through ionic (C−H)+···A− interactions.8 Thus,
utilization of the ionic H-bonding by the designed positively
charged imidazolium based receptors with specific cavity sizes
would enhance the binding affinity for selective recognition of
anions.13−15 There have been a number of reports regarding
cyclophane systems that recognize biomolecular anions under
physiological conditions.11,12 However, to the best of our
knowledge there is no report that describes the significance of
different structural functionalities of cyclopane systems for
selective recognition of biomolecular anionic species. In this
study, we demonstrate that a slight variation of the fluorophore
or spacer group created a great effect on the sensitivity and
selectivity of receptors toward recognition of important
biomolecular anions. Herein, we designed three different
water-soluble imidazolium based probes (1−3) by careful tuning
of fluorophores and spacer groups (Figure 1).
Received: February 26, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Figure 1. Probes 1, 2, and 3.
Figure 3. (a) Fluorescent emission changes of 2 (10 μM) upon addition
of TBA salts (10 equiv) of Cl−, I−, Pi, PPi, and sodium salts (10 equiv) of
AMP, ADP, ATP, GMP, GDP, GTP, CTP, UTP, TTP (slit width = 5
nm; λexc = 365 nm). (b) Fluorescence spectra of 3 (10 μM) upon
addition of the sodium salts of AMP, ADP, ATP, GMP, GDP, GTP,
−
CTP, TTP, UTP and TBA salts of F−, Cl−, I−, CH3CO2 , Pi, PPi,
−
NO3 (10 equiv) (slit width = 5 nm; λexc = 290 nm).
and excimer (495 nm) peaks.21 The concentration independent
changes in the monomer-to-excimer (I429/I498) ratio indicate
intramolecular excimer formation (Figure S21). The fluores-
cence spectrum of 1 with anions is in Figure 2a which shows the
maximum fluorescence enhancement at the monomer upon the
addition of AMP. Other anions gave more or less fluorescence
quenching in monomer and excimer peaks (Figure 2a). This
shows unique fluorescence discrimination of AMP from the
structurally similar nucleoside phosphates (Figure S25). Figures
S22−S24 show the fluorescence titrations of 1 with AMP, ADP,
and ATP (0−100 equiv). There was a significant fluorescence
enhancement in monomer and quenching in excimer upon the
addition of AMP to 1, a moderate change in the case of ADP, and
a very small change in ATP. The ratio for AMP (I429/I498) is large
enough to discriminate ADP and ATP (Figure S25), and most
importantly it can serve as the calibration curve for the detection
of AMP (Figure 2b).
Figure 2. (a) Fluorescent emission changes of 1 (10 μM) upon addition
of n-tetrabutylammomonium salts (100 equiv) of H2PO4 , PPi, and
sodium salts (10 equiv) of AMP, cAMP, ADP, ATP, GMP, GTP, CMP,
CTP, UMP, UTP, TMP, and TTP (slit width = 5 nm; λexc = 365 nm).
(b) Ratiometric calibration curve I429/I498 as a function of the
concentration of AMP, ADP, and ATP.
−
It remained a challenging task to design and synthesize a
particular receptor which selectively recognizes a mono-
phosphate nucleotide in comparison to di- or triphosphate
analogues. We have designed anthracene based probe 1 having
imidazolium units with bridging benzyl moieties, for fluorogenic
sensing of AMP. Probe 1 gives a selective fluorescence
enhancement response to AMP with subsequent quenching in
the excimer in comparison to other nucleosides including ADP
and ATP under physiological conditions. The adenine base in
AMP acts as a fluorescence enhancer, resulting in fluorescence
enhancement of probe 1. The bridging benzyl group of probe 1
plays a major role in sensing of AMP by providing an additional
π−π interaction to the adenine moiety of AMP. To the best of
our knowledge probe 1 is the first fluorogenic probe for selective
sensing of AMP in aqueous media at physiological pH. Probe 2
has the acridine moiety as a fluorophore unit, and the
imidazolium moiety as a binding site for GTP recognition. The
electron-withdrawing nitrogen heteroatom in acridine assists in
strengthening H-bonding with the guanine base of GTP and gave
selective fluorescence quenching at physiological pH. Probe 2
shows ∼87% fluorescent quenching with GTP, which makes this
probe better than those in previous reports.13,16 Probe 3 has a
naphthalene−imidazolium based cyclic structure which senses
selectively pyrophosphate (PPi) in the presence of other
inorganic or biomolecular anions via excimer formation due to
π−π interactions17 between fluorophore moieties.18
Visual inspection of color changes in the aqueous solution of 2
shows selective sensing of GTP through fluorescence quenching
(Figure S30). The emission spectra of 2 in aqueous solution
show broad fluorescence (Figure S32) which indicates strong H-
bonding with water molecules.22 Probe 2 displayed minor
changes in fluorescence upon the addition of anions except GTP
(Figure 3a). However, GTP displayed the most significant
fluorescence quenching with probe 2 (Figure S31). Fluorescence
spectra of probe 2 illustrates the quenching effect upon the
addition of GTP, which might be due to strong interactions with
probe 2 in the competitive solvent (Figures 3a and S33).
The fluorescence spectra of probe 3 show the structured
naphthalene monomer emission centered at 356 nm (Figure 3b).
Probe 3 displayed decreased fluorescence with inorganic anions
−
−
−
F−, Cl−, I−, CH3CO2 , H2PO4 , and NO3 . Probe 3 showed
significant fluorescence quenching with nucleobases AMP, ADP,
ATP, GMP, GDP, GTP, CTP, TTP, and UTP because of the
enhanced photoinduced electron transfer (PET) by the
introduction of the electron-rich anionic moieties. On the
other hand, a unique change was observed in the emission
spectrum with PPi. The addition of PPi induced not only the
quenching effect but also a structureless band with an emission
maximum at 407 nm. Figures 3b shows the fluorescence
quenching at 356 nm and the formation of a unique structureless
band with increasing concentration of PPi at 407 nm. The new
peak at 407 nm can be attributed to excimer formation because
no significant changes were observed in UV absorption (Figure
S46) even by adding a large amount of PPi, excluding a charge-
transfer mechanism.
Initially, 1-(1H-imidazol-1-ylmethyl)-1H-imidazol,19 4,5-bis-
(bromomethyl)acridine,20 and 1,1′-(phenylmethylene)-bis(1H-
imidazole) were synthesized. The synthesis of probes 1−3 was
carried out with some modifications of previous proce-
dures,14b,15c,16d and the details are described in the Supporting
Information (SI). Fluorescence studies were performed in
aqueous solution at pH 7.4 (0.01 M HEPES buffer). First,
probe 1 was monitored for anions recognition studies. Visual
features show blue fluorescence enhancement upon the addition
of AMP (Figure S20). Probe 1 displayed monomer (430 nm)
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Letter
and peak broadening and upfield shifts of bridged methylene
protons Hc,h (0.2−0.3 ppm), due to strong ionic binding of the
phosphate group of AMP. A slight broadening and upfield shift of
anthracene ring protons Hb,e (0.1−0.2 ppm) were also observed.
There was an upfield shift of protons Hi,j (0.2−0.3 ppm) of the
adenine moiety. The relatively weak NOE correlation between
the Hj proton of adenine and the Hb proton of the anthracene
moiety indicate the presence of the adenine moiety close enough
to the anthracene moiety to have the H−π interaction (Figure
S6). The peak splitting and broadening accompanied by upfield
shifts of benzene protons Hf (<0.2 ppm) was observed with a
subsequent weak NOE signal between benzene protons Hf and
the acridine protons Hi,j, indicating the presence of the acridine
moiety of AMP in the vicinity of the benzene ring (Figure S6).
A 1H NMR titration experiment of probe 2 upon interaction
with GTP (Figure S14) caused quenching with an upfield shift
(<0.2 ppm) of imidazolium protons (C−Ha)+, upfield shifts
(<0.1 ppm) of He,f, and broadening with slight upfield shifts of
methylene protons Hh,i (<0.2 ppm), indicating strong binding of
the phosphate groups of GTP with probe 2 (Figure S14).
Significant quenching with the upfield shift of acridine proton Hb
(<0.2 ppm) was noted which is at the para position to nitrogen,
indicating H-bonding with the nucleobase of GTP. Also the
upfield shifts (<0.2 ppm) of Hj and Hk protons of GTP were
observed. Owing to different chemical shifts accompanied by
broadening of the Hb proton compared to other acridine protons,
the splitting of acridine protons and the absence of an NOE
correlation between Hj and acridine (Figure S13) suggest some
additional interactions of the nucleic base of GTP with the
acridine moiety of 2 in the T-shape. Here, the amino group of the
guanine moiety interacts with the heteroatom of fluorophore
through H-bonding and, hence, causes effective fluorescence
quenching.13
Figure 4. Optimized structures of 1-AMP and 3-PPi using DFT(B97-
D3/TZVPP) and 2-GTP using DFTB.
The competitive binding experiments were conducted for
probe 1 in 100 equiv of Pi, PPi, cAMP, ADP, ATP, GMP, GTP,
CMP, CTP, UMP, UTP, TMP, or TTP, and the fluorescence
intensity for AMP was found to be unaffected (Figure S26). The
presence of 10 equiv of GTP was unaffected by the addition of 10
equiv of competing anions for probe 2 (Figure S35). In the case
of probe 3 it was found that the fluorescence intensity of 3 in the
presence of 10 equiv of PPi was unaffected by the addition of 10
equiv of competing anions (Figure S37). The calculated binding
stoichiometries, binding constants,23 and detection limits24 for
probes 1−3 with selected anions are summarized in Table S1.
The absorption spectra of 1 (Figure S44) show the characteristic
absorption maximum at 376 nm due to the anthracene moiety.
The maximum absorption increase was observed with AMP (100
equiv), and the maximum absorption decrease was found with
GTP (100 equiv). The absorption spectra of 2 (Figure S45)
show the characteristic absorption maximum at 356 nm due to
the acridine moiety. The absorption spectra of 2 with GTP (10
equiv) show a slight increase in absorption with a distinguished
red shift by 3 nm. Moreover quantum yields of probes 1, 2, and 3
are calculated to be 0.27, 0.13, and 0.24, respectively (see SI).
Probe 1 shows fluorescence quenching in the excimer and
enhancement in the monomer during complexation with AMP
(1:1 (1-AMP)) through strong ionic interactions. In the complex
the π−π interaction between anthracene moieties of probe 1
might become weak and develop strong interactions with the
adenine moiety of AMP through the H−π interaction which
might result in fluorescence enhancement in the monomer and
quenching in the excimer (Figure 4). A remarkable fluorescence
quenching in probe 2 was observed during complexation with
GTP (1:1 (2-GTP)) through ionic interactions. We propose that
such strong fluorescence quenching might be due to strong H-
bonding between the −NH2 group of the guanine moiety and
heteroatom (N) in the acridine moiety of probe 2 in a
perpendicular edge-to-face orientation (Figure 4). While the
binding mode of probe 3 is 2:1 for PPi, the characteristic
fluorescence response indicates different types of interaction. As
in Figure 4, we postulate that probe 3 bound PPi through the
ionic interaction of the imidazolium protons (C−H)+ with the O
atoms of phosphate groups. The excimer emission exhibited by
3-PPi originates from the intermolecular π−π interaction
between fluorophore moieties of two molecules of receptor 3.
To monitor physical interactions of probes (1−3) with AMP,
A 1H NMR titration experiment of probe 3 upon the addition
of PPi (Figure S19) caused quenching, an upfield shift (<0.4
ppm) of the imidazolium protons (C−Ha)+, upfield shifts (<0.2
ppm) of Hc,d, and peak broadening and splitting of Hg,h protons
of the methylene groups accompanied by an upfield shift (<0.2
ppm), due to strong binding of the phosphate group of PPi
(Figure S19). Splitting and upfield shifts (<0.2 ppm) of the
aromatic protons of naphthalene could be attributed to the π−π
interaction between two receptor naphthalene moieties which
would be responsible for excimer formation.
Conformational analysis of probes 1−3 was carried out to
theoretically determine the lowest energy conformers and their
binding modes with specific anions. The computational details
are in the SI. The strong H−π interactions in 1-AMP and 2-GTP
would cause fluorescence enhancement and quenching at the
monomer, respectively. In the binding mode of 1-AMP, the H2
and −NH2 of the adenine moieties of AMP interact with the
́
anthracene moieties of probe 1 at distances of ∼2.7 and ∼2.8 Å
via H−π interaction, respectively13,16 (Figure 4). On the other
hand, 2-GTP shows H−π interaction at a distance of ∼2.7 Å
between the fluorophore (acridine moiety) and quencher
(−NH2), which indicates more conspicuous fluorescence
quenching compared with 2-GDP showing H−π at a distance
of ∼3.3 Å in 2-GDP (Figure S48h).13,16 Moreover, the longer
phosphate in GTP makes it bind tighter to 2 (Figure 4). In the
binding mode of 3-PPi, the imidazolium protons in the proximity
of PPi interact with the O atoms of the phosphate group at a
distance of ∼2.0−2.5 Å. The interactions between PPi and two
molecules of 3 via imidazolium protons bring the fluorophore
moieties close to each other at a distance of ∼3.0−3.6 Å (Figure
1
GTP, and PPi, H NMR titration experiments were conducted
(Figures S7, S14, S19). 2D NOESY of 1 and 2 with AMP and
GTP were also recorded (Figures S6 and S13, respectively) in
order to investigate the proposed binding pattern. The addition
of AMP to 1 (Figure S7) caused the upfield shift (<0.2 ppm) of
imidazolium protons (C−Ha)+ with the quenching effect, upfield
shifts of the remaining imidazolium protons Hd,g (0.2−0.3 ppm),
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1
the experimental H NMR data (Figure S19) which show
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The experiments and calculations reported here provide new
insights into the selectivities of novel fluorescent chemosensors
which sense AMP, GTP, and PPi through fluorescence
enhancement/quenching over other biologically relevant anions
in an aqueous solution of physiological pH 7.4. The bridging
benzyl moiety of 1 plays a major role in attaining selective
fluorescence enhancement/quenching (monomer/excimer) to-
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ionic interactions. Significant and selective fluorescence
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ASSOCIATED CONTENT
* Supporting Information
Experimental details. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
(12) (a) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kimks@unist.ac.kr (K.S.K.).
*E-mail: nisar.ahmed@chem.uzh.ch (N.A.).
Notes
́ ́
(b) Molina, P.; Tarraga, A.; Oton, F. Org. Biomol. Chem. 2012, 10,
1711−1724. (c) Suresh, V.; Ahmed, N.; Youn, I. S.; Kim, K. S. Chem.
Asian J. 2012, 7, 658. (d) Xu, Z.; Singh, N. J.; Kim, S. K.; Spring, D. R.;
Kim, K. S.; Yoon, J. Chem.Eur. J. 2011, 17, 1163.
The authors declare no competing financial interest.
(16) (a) Kang, N.-Y.; Ha, H.-H.; Yun, S.-W.; Yu, Y. H.; Chang, Y.-T.
Chem. Soc. Rev. 2011, 40, 3613. (b) McCleskey, S. C.; Griffin, M. J.;
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Shirinfar, B.; Youn, I.-S.; Bist, A.; Suresh, V.; Kim, K. S. Chem. Commun.
2012, 48, 2662.
ACKNOWLEDGMENTS
■
This work was supported by NRF (National honor scientist
program: 2010-0020414) and KISTI (KSC-2011-G3-02).
Funding by Novartis (postgraduate fellowship to N.A.) is
gratefully acknowledged.
(17) Kim, K. S.; Tarakeshwar, P.; Lee, J. Y. Chem. Rev. 2000, 100, 4145.
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