ZnII-2,2′:6′,2″-terpyridine-based complex as fluorescent chemosensor for PPi, AMP and ADP

Article abstract of DOI:10.1002/ejic.201100125

A new Zn^II-2,2′:6′,2″-terpyridine complex, derivatized with a coumarin moiety (L₁Zn), acts as a fluorescent chemosensor for different biologically important phosphates like PPi, AMP and ADP in mixed aqueous media. Depending on the pr

Full text of DOI:10.1002/ejic.201100125

FULL PAPER
DOI: 10.1002/ejic.201100125
ZnII–2,2Ј:6Ј,2ЈЈ-Terpyridine-Based Complex as Fluorescent Chemosensor for
PPi, AMP and ADP
Priyadip Das,[a] Amrita Ghosh,[a] Manoj K. Kesharwani,[a] Vadde Ramu,[a]
Bishwajit Ganguly,*[a] and Amitava Das*[a]
Keywords: Chemosensors / Zinc / Density functional calculations / Fluorescent probes / Bioinorganic chemistry
A new ZnII–2,2Ј:6Ј,2ЈЈ-terpyridine complex, derivatized with
a coumarin moiety (L1Zn), acts as a fluorescent chemosensor
for different biologically important phosphates like PPi, AMP
and ADP in mixed aqueous media. Depending on the pro-
portion of the aqueous fraction present in the solvent mix-
medium this reagent shows a preference for AMP as com-
pared to ADP, ATP and PPi. The binding affinities of L1Zn
with different phosphate ions and associated shifts in the
electronic spectra were rationalized by DFT calculations.
Such an example of a receptor that is selective for AMP un-
ture, L1Zn shows a preference for different phosphate moie- der physiological conditions is rare in the literature.
ties at physiological pH. In an aqueous acetonitrile (2:3, v/v)
pronounced influence on the molecular orbital energy levels
Introduction
and thereby on the output spectral response. Besides this,
The selective recognition and sensing of biologically im-
Zn2+ does not exhibit any emission quenching effects to flu-
portant phosphate ions have been the focal point of current
orophore because of its electronic (3d104s0) configuration.
research because these ions play crucial role(s) in various
Thus, examples of the Zn2+-based chemosensors for re-
metabolic processes.[1–4] More importantly adenosine tri-
cognition of biological phosphates, which work either in
phosphate (ATP) and pyrophosphate (PPi) are involved in
aqueous environments or under physiological conditions,
energy transduction in organism-controlling metabolic pro-
are relatively more common in the literature than those that
cesses by participation in enzymatic reactions, e.g. DNA
work on the hydrogen-bonded adduct formation pro-
replication, etc.[5–7] Furthermore, the detection of PPi is im-
cedure.[10,11] However, examples of an appropriate receptor
portant in real-time DNA sequencing methods,[8] as well as
that shows preferential binding affinity towards AMP or
in cancer research and is formed by the hydrolysis of ATP
PPi, compared to other common anions like F–, Cl–, Br–,
into adenosine monophosphate (AMP) in cells. AMP and
–
–
–
I–, NO3 , CH3COO–, C6H5COO–, SO42–, HSO4 , H2PO4
adenosine diphosphate (ADP) are well known to play a cru-
cial role in the energy cycle, as well as in various other bio-
logical processes.[9] Accordingly, detection and discrimi-
nation of these phosphates are important for evaluating the
generation of each of these ions during various biological
processes and clarifying their roles in these processes.
Among various methodologies adopted for developing sen-
sor molecules for anionic analytes in aqueous environments,
metal ion–anion coordination is recognized as one of the
most popular for ions with a high hydration energy, e.g.
fluoride, various phosphates, acetate ions. In this regard,
the Zn2+ complex with vacant coordination sites is signifi-
cant as the Zn2+ ion generally has higher affinity towards
phosphate functionality. Higher affinity and stronger ZnII–
phosphate binding is expected to be reflected in the more
and other biologically important phosphate ions like ATP,
CTP, ADP under different mixed aqueous buffer-solvent
environments, are scarce in the literature. This promoted us
to design and synthesize ZnII complexes as a fluorescent
probe for different phosphates like AMP and PPi. Most of
the ZnII complexes, which are used as the receptor for phos-
phate ions, are generally either various derivatives of ZnII–
dipicolylamine[10,11a–11h] or CuII–dipicolylamine,[11i,11j] bar-
ring one recent reference where ZnII–cyclen (1,4,7,10-tetra-
azacyclododecane) is reported to show comparable affinity
towards ATP and PPi.[12a] There are only few examples
available in the literature where CuII/CdII–cyclen derivatives
are used as receptors for AMP/PPi.[12,13a] Though the CuII
complex shows specificity toward PPi, observed binding af-
finity was not appreciable; while the anion binding response
for the CdII–cyclen derivative works on displacement phen-
omena and lacks any specificity towards PPi. In a recent
report, Gao et al. have shown that a dizinc(II)–cyclen deriv-
ative could also be used for specific binding to deoxythymi-
dine and thymidylylthymidine.[13b] In this article we report
synthetic methodology, characterization and binding stud-
[a] Central Salt & Marine Chemicals Research Institute (CSIR),
Bhavnagar, 364002 Gujarat, India
Fax: +91-278-2567562
E-mail: amitava@csmcri.org
ganguly@csmcri.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201100125.
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ZnII–2,2Ј:6Ј,2ЈЈ-Terpyridine-Based Complex
ies of a newly synthesized ZnII–tpy derivative (tpy is ogy (Scheme 1) following a one-step procedure by reacting
2,2Ј:6Ј,2ЈЈ-terpyridine) (L1Zn) as an anion receptor 2 mol-equiv. of 2-acetylpyridine and 1 mol-equiv. of 4-
(Scheme 1). This shows an appreciable preference towards methylbenzaldehyde.[15] This was subjected to the free radi-
–
PPi, compared to other anions like F–, Cl–, Br–, I–, NO3 , cal bromination reaction using NBS as the brominating
–
–
CH3COO–, C6H5COO–, SO42–, HSO4 , HP2O73–, H2PO4
agent.[16] 4Ј-[p-(Bromomethyl)phenyl]-2,2Ј:6Ј,6ЈЈ-terpyridine
in an aq.·HEPES buffer/CH3CN (1:4, v/v) medium; while was isolated in reasonably good yield and was allowed to
in solvent media with a higher proportion of protic solvent react with presynthesized 7-hydroxy-4-methylcoumarin in
[aq. HEPES/CH3CN buffer, 2:3 (v/v)] L1Zn was found to the presence of K2CO3 and a catalytic amount of 18-crown-
bind specifically to AMP and ADP compared with ATP,
6 in dry acetone to yield L1 in reasonable yield
CTP, PPi and all the above mentioned ions. The experimen- (Scheme 1).[17] This was allowed to react with Zn(ClO4)2
tal observations have been corroborated by density func- at room temperature to yield the desired compound. For
tional theory (DFT) calculations.
simplicity L1Zn(H2O)2 is represented as L1Zn.
Spectral Behaviour of L1 and L1Zn
The electronic spectrum recorded for L1 in H2O/CH3CN
(1:4, v/v) (Figure S1) shows three absorption maxima at 251
(ε = 2.3ϫ104 m–1 cm–1), 278 (ε = 2.92ϫ104 m–1 cm–1) and
313 nm (broad absorption band, ε = 1.7ϫ104 m–1 cm–1).
These absorption bands could be assigned to various
πǞπ* transitions, while a weaker nǞπ* transition was
submerged under a stronger πǞπ* transition. Among
these, the band at 251 nm could be assigned to the tpy-
based nǞπ* transition; while bands at longer wavelengths
are presumably from the tpy or coumarin-based πǞπ*
transition (for 278 nm transition) or inter-component
πcoumarin/tpy Ǟπtpy/coumarin*-based transitions (for 313 nm
transition). Luminescence spectra recorded for L1 on exci-
tation at either 278 or 313 nm show similar spectral patterns
with an emission maximum at 380 nm (Figure 1). Two anal-
ogous individual chromophores, 4Ј-(p-methoxyphenyl)-
2,2Ј:6Ј,6ЈЈ-terpyridine (L) (Figure S4) and 7-ethoxy-4-meth-
ylcoumarin (Figure S14), show strong and small broad
max
emission bands at ca. 390 (λabs
(λabs
= 284 nm) and 360 nm
max
= 315 nm), respectively. Data reported earlier for
7-methoxy-4-methylcoumarin is similar to that evaluated
for the ethoxy derivative.[18] Thus, for L1, the emission band
around 380 nm (with λext = 278 or 313 nm) primarily could
be the combination of 2,2Ј:6Ј,6ЈЈ-terpyridine and coumarin-
centre based emission. On binding to the Zn2+ ion through
the coordinating terpyridine unit in L1Zn, two absorption
bands appeared at 286 and 325 nm, along with a distinct
hump at around 347 nm in the H2O/CH3CN (1:4, v/v) sol-
vent medium (Figure 1). The small red shift of the absorp-
tion bands could be explained based on the decrease in the
LUMO energy on binding to the cationic ZnII centre and
presumably this could be attributed to a charge transfer
(CT) spectrum with coumarin as the donor and the ZnII-
bound terpyridyl unit as the acceptor fragment. This pre-
sumption was further supported by the results of the den-
sity functional studies (vide infra). Fluorescence spectra for
Scheme 1.
Results and Discussion
Pyridasyl pyridinium iodide salt and (E)-3-(4-meth- L1Zn show two emission bands at 370 and 456 nm in
ylphenyl)-1-(pyrid-2-yl)prop-2-enone were synthesized and CH3CN (Figure 1) on excitation at λext = 315 nm, while red-
these two reagents were eventually allowed to react for the shifted emission bands appear at 381 and 467 (broad) in
synthesis of 4Ј-(p-methylphenyl)-2,2Ј:6Ј,6ЈЈ-terpyridine fol- the more polar H2O/CH3CN (1:4, v/v) medium (Figure 1).
lowing previously reported methodology.[14] This terpyridyl A further red shift for each of these bands (386 nm and
derivative was also synthesized from an alternate methodol- 480 nm) was observed on increasing the medium polarity
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FULL PAPER
with an increase in the proportion of water [H2O/CH3CN Table 1. Time resolved emission decay constants for L1Zn and
analogous components in an air-equilibrated acetonitrile solution
at 295 K.
(2:3, v/v)] in the mixed solvent medium (Figure 1). The red-
shift of the emission bands on increasing solvent polarity
suggests that the excited state for L1Zn is more polar as
compared to the ground state. Further, excitation spectra
recorded for L1Zn using λems of 379 and 460 nm revealed
that the excitation spectral patterns are different (Fig-
ure S5). These indicate that excited states, which are respon-
sible for the emission bands with maxima at 379 and
460 nm, are different. New emission maxima at ca. 460 nm
could be assigned to the CT process involving the donor
coumarin fragment and acceptor terpyridine moiety bound
to the ZnII centre.
[a] The emission decay constant reported for the analogous com-
pound 4-methyl-7-methoxycoumarin in dioxane is 0.13 ns.[18]
–
–
tion. Apart from I–, NO3 , HSO4 a detectable change in
electronic spectral patterns (Figure S6) could be observed
for all the other anions mentioned. For most of the anions
used, including PPi, a small blue shift in the absorption
band was observed. However, for emission spectra recorded
Figure 1. (A) Absorption spectra of L1 and L1Zn (2.15ϫ10–5 m) in
an aq. HEPES buffer/CH3CN (1:4, v/v) medium. (B) (a) Fluores-
cence spectra of L1 (2.15ϫ10–5 m) in an aq. HEPES buffer/CH3CN
(1:4, v/v) medium, (b) L1Zn (2.15ϫ10–5 m) in a CH3CN (c) in an
aq. HEPES buffer/CH3CN (pH = 7.4) (1:4, v/v) (d) in an aq.
in an acetonitrile medium, a significant change (λext
=
–
314 nm) was observed when PPi, H2PO4 , CH3COO–, F–
and Cl– ion was added; while no such change was observed
for all the other anions studied. The emission band at ca.
HEPES buffer/CH3CN (pH = 7.4) (2:3, v/v) medium using λext
=
315 nm.
Fluorescence decay traces recorded for LZn, 7-ethoxy-4- 460 nm tends to disappear, and enhancements in emission
methylcoumarin and L1Zn in an air-equilibrated acetoni- bands at around 379 nm were observed (Figure S7). This
trile solution, following excitation with either a 340 nm or indicates that binding of these anions to the ZnII centre
280 nm LED source and the respective decay constants are is responsible for the complete quenching of the particular
provided in Table 1. It is evident from Table 1 that on exci- excited state that is related to the 460 nm emission band
tation of L1Zn with the 280-nm LED (for λmon = 465 nm), and is not in equilibrium with the other excited state that
the decay component for the coumarin fragment is higher accounts for the emission maximum at 379 nm. This emis-
compared to the situation where the 340 nm LED is used. sion band is believed to be an intra-ligand (tpy/coumarin)-
The longer and larger component of 2.002 ns (for λext
=
based charge transfer transition in nature. For spectral stud-
280 nm) or 1.74 ns (for λext = 340 nm) could be attributed ies in an aq. HEPES buffer/CH3CN (pH = 7.4) (1:4, v/v)
to the emission decay of the CT state. This is in agreement medium, appreciable changes were observed only for
3–
with the coumarin fragment showing less excitation at 340 HP2O7 (Figure 2). In the electronic spectra a small blue
than at 280 nm.
shift was observed (Figure 2, A); while significant changes
The emission decay constant for the analogous coumarin were observed in the emission spectra (Figure 2, B) in pres-
component (4-hydroxy-7-methoxycoumarin) is reported as ence of HP2O73–. Presumably, the higher energy of hy-
τ = 0.13 ns (λext = 310 nm and λmon = 370 nm) in dioxone dration for F– and RCOO– does not allow these anions to
1
for the (π–π)*-based emission.[18] For LZn a single time coordinate to the ZnII centre; while lower charge density of
–
2–
constant of about 4.465 ns was obtained experimentally. the respective anion like Cl–, Br–, I–, NO3 , SO4 and
–
These values clearly indicate that for L1Zn the emissive state HSO4 presumably accounts for the weaker or negligible
associated with the emission band maxima at 460 nm is dif- binding to the ZnII-based receptor.[19] Insignificant change
ferent from the one that is associated with the emission in the emission spectra was also observed in the presence of
–
band maxima at 379 nm. The CT nature of the emission excess H2PO4 . Attempts to monitor the emission spectral
band at 460 nm is well supported by the results of the den- response in presence of added AMP, ADP, CTP, and ATP
sity functional calculations and is discussed later.
was also not successful as these phosphates were found to
Optical absorption spectra for L1Zn were recorded in the be sparingly soluble in this solvent composition [aq.
absence and presence of various anionic analytes such as HEPES buffer/CH3CN, 1:4 (v/v)].
–
2–
F–, Cl–, Br–, I–, NO3 , CH3COO–, C6H5COO–, SO4
,
An associated binding constant for the formation of
–
–
3–
HSO4 , H2PO4 and HP2O7 (PPi) in an acetonitrile solu- L1Zn–PPi was evalulated using emission intensity data (at
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ZnII–2,2Ј:6Ј,2ЈЈ-Terpyridine-Based Complex
Figure 2. (A) Absorption and (B) emission spectra of the chemosensor (L1Zn) at 2.15ϫ10–5 m in the presence of different anions at
8ϫ10–4 m in an aq. HEPES buffer/CH3CN (pH = 7.4) (1:4, v/v) medium; (C) fluorescence spectra of L1Zn (2.15ϫ10–5 m) in an aq.
HEPES buffer/CH3CN (pH = 7.4) (1:4, v/v) medium in the presence of an increasing concentration of PPi (0–8ϫ10–4 m), λext = 315 nm;
inset: double-logarithmic plot for the above spectral change at 379 nm for λext = 315 nm. Inset: photographs of the quartz cuvette showing
fluorescence of (A) L1Zn and (B) L1Zn–PPi in an aq. HEPES buffer/CH3CN (1:4, v/v) medium after exposing solutions to UV radiation.
λems = 379 nm) obtained from the systematic fluorescence model, PPi is proposed to bind to the ZnII centre only
titration profile (Figure 2, C). The slope of the double-loga- through PαO and this strong binding induces an upfield
rithmic plot [see Equation (2) in the Exp. Section] obtained shift for the Pβ atom in bound PPi. However, strong binding
–
from the experimental data, represents the number of bind- of PPi to the ZnII centre of L1Zn as compared to H2PO4
ing sites or stoichiometry (n) and this was found to be one. could be better explained by the proposed first model, i.e.,
The value for log Kd was obtained from log([A–]) at binding of PPi to the ZnII centre of L1Zn through a stable
log[(F0 – Fx)/(Fx – Fα)] = 0. The solid line in the inset of six-membered chelate. Further experiments revealed that
Figure 2, C represents the best fit of the plot with a re- spectral patterns for L1Zn in the presence of 2 mol-equiv.
gression coefficient value of 0.998. The reciprocal of Kd is of PPi remained unchanged even in the presence of 10 mol-
–
the binding constant (Kb) and was evaluated from this plot equiv. of other anions (F–, Cl–, Br–, I–, NO3 , CH3COO–,
–
–
as (2.2Ϯ0.18)ϫ105 m–1. A similar 1:1 binding stoichiome- C6H5COO–, SO42–, HSO4 and H2PO4 ). This confirmed
try for PPi was also evaluated from the titration profile the specificity of L1Zn towards PPi in presence of these
(Figure S8). The binding constant was also determined for anions in an aq. HEPES buffer/CH3CN (1:4, v/v) medium.
H2PO4– in an aq. HEPES buffer/CH3CN (1:4, v/v) medium
and was found to be 98Ϯ0.8m–1 under identical conditions.
Stronger electrostatic interactions between the cationic
–
Zn2+ centre and HP2O73–, compared with H2PO4 , could
be attributed to the higher affinity of PPi towards the recep-
tor L1Zn. Independent interference studies revealed that
changes in fluorescence due to the addition of 5.0ϫ10–4
m
of PPi remained unaffected even in the presence of 10 mol-
–
equiv. of H2PO4 and other common anions mentioned
above. Thus, by probing the fluorescence output as the re-
sponse signal, L1Zn could be used as a fluorogenic sensor
molecule for biologically important pyrophosphate ions in
aq. HEPES buffer/CH3CN (1:4, v/v) medium. The small
blue shift in the absorption spectra for L1Zn on binding to
PPi can be explained by DFT calculations and is discussed
later.
Figure 3. Partial 31P NMR (CD3CN) spectra for PPi in the absence
In order to understand the nature of binding of the PPi
ion to the ZnII centre of L1Zn, we recorded the 31P NMR
spectrum (Figure 3) of the tetrabutylammonioum salt of
pyrophosphate in the absence and presence of 1.5 mol-
and presence of 1.5 equiv. of L1Zn.
In order to check the binding affinity of this ZnII-based
equiv. of L1Zn in CD3CN. 31P NMR spectra recorded for receptor unit towards other biologically important phos-
PPi suggest that both P atoms present in the PPi moiety phates (e.g. ATP, CTP, ADP and AMP) we needed to in-
are equivalent, however, on binding to the ZnII centre a crease the proportion of the water or HEPES buffer in the
pronounced upfield shift was observed for the Pα atom as composition of the mixed solvent. Optical (Figure 4, A) and
compared to that for the Pβ atom.[11c,11e] This observation fluorescence (Figure 4, B) spectral responses of L1Zn
may be explained using two different models. According to towards these anions, along with all other anions (F–, Cl–,
–
–
the first model, a strong ZnII–OPα and a much weaker Br–, I–, NO3 , CH3COO–, C6H5COO–, SO42–, HSO4 and
–
ZnII–OPβ binding accounts for the less appreciable upfield H2PO4 ) mentioned earlier, were checked in an aq. HEPES
shift for Pβ in the 31P NMR spectra; while for the second buffer/CH3CN (2:3, v/v) medium (pH = 7.4) (Figure 4).
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Figure 5. Fluorescence spectra of L1Zn (2.15ϫ10–5 m) in an aq.
HEPES buffer/CH3CN (2:3, v/v) (pH = 7.4) medium in the pres-
ence of varying (A) [AMP] = (0–1ϫ10–3 m) and (B) [ADP] = (0–
1ϫ10–3 m). Respective inset figures reveal the double-logarithmic
plot for the spectral changes at 379 nm.
Figure 4. (A) Absorption and (B) emission spectra of L1Zn
(2.15ϫ10–5 m) in the absence and presence of different anions
(8.0ϫ10–4 m) in an aq. HEPES buffer/CH3CN (2:3, v/v) medium
(pH = 7.4); inset: photographs of the quartz cuvette showing fluo-
rescence of (a) L1Zn and (b) L1Zn–AMP in an aq. HEPES buffer/
CH3CN (2:3, v/v) medium after exposing solutions to UV radia-
tion.
Thus, the observed relative binding affinity of L1Zn to-
No detectable change in the absorbance spectra of L1Zn wards three different nucleotides follows the order,
was evident on addition of these anionic analytes (Figure 4, AMP ϾKADP ϾKPPi ϾϾKATP. This could be best explained
K
A); however, emission spectral studies revealed detectable if one considers a shorter chain length of AMP, which al-
changes only for AMP and ADP (Figure 4, B). No other lows a more efficient π–π stacking interaction between the
anions including ATP, CTP and PPi could induce either a adenine moiety and the nearly planar terpyridine group of
negligible or very weak spectral change. Between AMP and the receptor fragment (L1Zn), as compared with that in the
ADP, emission spectral changes were more prominent for case of ADP or ATP. Such an explanation for the HgII/
AMP. This signifies that either very weak or negligible CuII-based receptor for preferential binding to GMP is re-
binding of other anions, except AMP and ADP, occurs at ported earlier.[21]
the ZnII centre of L1Zn. The observed preference for AMP/
A detailed literature survey on the receptors that could
ADP, compared to PPi in more polar aqueous/CH3CN (2:3, preferentially bind to AMP results in only a few reports.[22]
v/v) media could be explained if one considers the differ- In the first report, Kimura et al. have shown that different
ence in solvation energy of various phosphates in water me- protonated forms of azamacrocycles could bind ATP, ADP
3–
dia. Enthalpy of solvation for HP2O7 in water is reported and AMP through hydrogen bond formation involving the
to be much higher than the related monophosphate (for anionic OPhosphate of the respective nucleotide and the
–
–
1
H2PO4 , ΔH = 76 kcal/mol) or diphosphate (H3P2O7 , ΔH (H)N+Macrocycle, which could be probed only by H NMR
3–
= 87 kcal/mol) and thus HP2O7 prefers to remain in the spectroscopic studies.[22a] While the second one includes a
solvated form rather than being coordinated to the ZnII ZnII–dipicolylamine-based receptor that works on the dis-
centre in L1Zn.[19a,20] Thus, the increase in polarity of the placement mechanism utilizing the weaker ZnII–AMP bind-
solvent with an increase in the proportion of water is re- ing as compared with ZnII–catechol binding.[22b] A very re-
sponsible for the more extensive hydration of PPi as com- cent report has described the selective binding of the other
pared with AMP and ADP and thus loss of coordination monophosphate (5Ј-GMP) in a mixed organic–aqueous
by PPi to the ZnII centre in L1Zn in an aq. HEPES buffer/ (DMSO/H2O, 1:4, v/v) medium,[21a] where binding of the
CH3CN (2:3, v/v) medium. The relative affinities of AMP monophosphate caused a decrease in the luminescence in-
and ADP towards L1Zn were evaluated through systematic tensity and the binding constant was evaluated as
fluorescence titration profiles using 2.15ϫ10–5 m of L1Zn 1.2ϫ104 m–1. Thus, considering available literature reports,
and varying [ADP] of 0–1.0ϫ10–3 m or [AMP] of 0– selective binding achieved for AMP and ADP in mixed
9.97ϫ10–4 m; the respective sets of emission spectra with aqueous/CH3CN (2:3, v/v) is significant.
varying [AMP] and [ADP] are shown in Figure 5.
To understand the relative binding affinity of PPi, AMP
The affinity constant was evaluated from the plot of and ADP towards L1Zn and the possible role of solvation
log[(F0 – Fx)/(Fx – Fα)] vs. log([A]) (inset of Figure 5) using in affecting the relative binding affinities/preferences, along
Equation (2). Solid lines shown in the inset of Figure 5 and with the nature of the observed blue shift in the absorption
the regression coefficient data suggest the correctness of the spectra for L1Zn on coordination to PPi, DFT calculations
plots. For both the cases, a 1:1 binding stoichiometry was have been performed. The molecular electrostatic potential
3–
evident (n = 1) and the binding constants for AMP and (MESP) was calculated for HP2O7 and the monoanionic
ADP were
evaluated
as
(7.2Ϯ0.2)ϫ103 m–1 and form of AMP and ADP (salts used for studies and expected
(5.1Ϯ0.25)ϫ103 m–1, respectively, at 25 °C in an aq. to prevail at pH = 7.4) at the BLYP/6-31G** level in both
HEPES buffer/CH3CN (2:3 (v/v), pH = 7.4) medium. acetonitrile and aqueous phase (Figure 6). To simplify the
Affinity constants for PPi towards L1Zn were also evaluated MESP analysis, the most negative evaluated point (Vmin) in
and were found to be 121Ϯ7 m–1. No detectable change the electron-rich regions was obtained through topography
in the fluorescence spectral pattern for ATP/CTP calculations. The calculated Vmin for HP2O73– in acetonitrile
prevented the evaluation of the respective binding affinities. is much higher (–368.3 kcal/mol) than the monoanionic
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ZnII–2,2Ј:6Ј,2ЈЈ-Terpyridine-Based Complex
forms of AMP (–200.8 kcal/mol) and ADP (–135.5 kcal/
mol). A similar trend was also observed in the aqueous
phase (HP2O73–, –369.6 kcal/mol; AMP, –200.8 kcal/mol;
ADP, –136.2 kcal/mol). Thus, the MESP analysis suggests
3–
that HP2O7 should bind strongly to L1Zn compared to
3–
AMP and ADP. To compare the binding ability of HP2O7
and AMP towards L1Zn, calculations were performed using
the GGA/BLYP/DNP method in both acetonitrile and
3–
water. The calculated binding energy for HP2O7
is
13.2 kcal/mol higher than AMP in acetonitrile. However, in
a solvent with high polarity (water) the difference in bind-
ing energy is only 7.2 kcal/mol, which is 6.0 kcal/mol lower
than the difference in the binding energy calculated in ace-
tonitrile.
Figure 7. The frontier molecular orbitals involved in the electronic
transition for (A) L1Zn and (B) L1Zn–[HP2O73–] calculated from
the GGA/BLYP/DNP method in an acetonitrile medium [colour
code, gray: carbon; red: oxygen; pink: phosphorus; blue: nitrogen;
white: hydrogen].
Figure 6. The MESP isosurfaces of (A) HP2O73–, (B) monoanionic
AMP and (C) monoanionic ADP generated with the isosurface
value of 1.25 kcal/mol in acetonitrile. The position of Vmin is shown
in red [colour code, gray: carbon, red: oxygen, yellow: phosphorus,
white: hydrogen].
Conclusions
In this work we have described a new ZnII-based receptor
molecule that could bind reversibly with various biolo-
gically important phosphate ions. In an aq. HEPES buffer/
CH3CN (1:4, v/v) medium (pH 7.4) L1Zn was found to bind
PPi in the presence of an excess of other common anions,
This reveals that the increase in polarity of solvent de-
creases the binding affinity of HP2O7 towards L1Zn. This
coupled with higher solvation energy for PPi could actually
account for either very weak or a lack of any affinity of
PPi for L1Zn in an aq. HEPES buffer/CH3CN [2:3 (v/v)]
medium.
3–
–
2–
like F–, Cl–, Br–, I–, NO3 , CH3COO–, C6H5COO–, SO4
,
–
–
HSO4 and H2PO4 ; while in the more polar solvent envi-
ronment with a higher proportion of aqueous solution, e.g.
an aq. HEPES buffer/CH3CN (2:3, v/v) medium, this recep-
tor showed specificity towards AMP/ADP, as compared
with ATP and PPi. Solvation of these anions play a crucial
role and relative binding affinity changes for these anions
with the increase in the proportion of the protic solvent like
water in the solvent mixture. DFT calculations have been
performed to rationalize the observed preferences of this
ZnII-based receptor towards these phosphate ions.
Further, to understand the shift in absorption spectra of
3–
L1Zn on binding with the HP2O7 ion, calculations were
performed using the GGA/BLYP/DNP method in both ace-
tonitrile and water. The HOMO–LUMO of L1Zn generated
from DFT calculations in acetonitrile as the solvent are
given in Figure 7 (A). The corresponding orbitals generated
3–
for the complex L1Zn–HP2O7 are given in Figure 7 (B).
For L1Zn the HOMO is largely located on the coumarin
moiety, whereas the LUMO is largely located on the ZnII-
bound terpyridine group. This suggests that for the absorp-
tion spectra, intrercomponent charge transfer predomi-
nantly happens from coumarin to the ZnII-bound terpyrid-
Experimental Section
ine group. The calculated energy for this electronic transi- Materials and Methods: The chemicals such as 2-acetylpyridine, 4-
methylbenzaldehyde, ethyl acetoacetate, N-bromosuccinimide
(NBS), dibenzoyl peroxide, tetrabutylammonium salts of various
anions, different nucleotides (adenosine 5Ј-monophosphate mono-
hydrate, adenosine 5Ј-diphosphate sodium salt, adenosine 5Ј-tri-
phosphate disodium monohydrate and cytidine 5Ј-triphosphate dis-
odium salt monohydrate) were obtained from Sigma–Aldrich and
were used as received without any further purification. All the
other reagents used were of reagent grade (S. D fine chemical, In-
dia) and were used as received. Pyridasyl pyridinium iodide salt,
(E)-3-(4ЈЈ-methylphenyl)-1-(pyrid-2Ј-yl)prop-2-enone, 4Ј-(p-methyl-
phenyl)-2,2Ј:6Ј,6ЈЈ-terpyridine, 4Ј-(p-methylphenyl)-2,2Ј:6Ј,6ЈЈ-ter-
tion is 2.169 eV; however, the energy for corresponding elec-
tronic transitions in L1Zn–HP2O7 is 2.541 eV. The higher
3–
transition energy in the latter case suggests the blue shift
of absorption spectra after binding with HP2O73–, which is
qualitatively in agreement with the experimental results. To
see the effect of polarity of solvent, calculations were also
performed in water at the same level of theory. The calcu-
lated results gave similar results (Figure S10) but with a
slightly less difference in transition energy compared to the
results obtained in acetonitrile.
Eur. J. Inorg. Chem. 2011, 3050–3058
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
3055

P. Das, A. Ghosh, M. K. Kesharwani, V. Ramu, B. Ganguly, A. Das
FULL PAPER
pyridine, 4Ј-[4-(bromomethyl)phenyl]-2,2Ј:6Ј,2ЈЈ-terpyridine and
L1, 7-hydroxy-4-methylcoumarin were synthesized following pre-
viously reported procedures.[23] Various analytical and spectro-
scopic data obtained for these intermediates provided necessary
supports for the proposed formulation and required purity (Sup-
porting Information). These were used without any further purifi-
cation. HPLC grade water (Fisher Scientific) was used as a solvent.
Acetonitrile and acetone were used for studies and were purified
through distillation following standard procedures prior to use. Ele-
mental analysis was conducted with a 4100 elemental analyzer.
FTIR spectra were recorded as KBr pellets with a Perkin–Elmer
is AMP or ADP) was used. Binding constants were calculated from
fluorescence intensities using the method described by Lehrer,
Fashman and Chipman et al.[24] According to this procedure fluo-
rescence intensities (F0, Fx and Fα) are related to the analyte con-
centration [A] through Equations (1) and (2), where F0 and Fα are
the relative fluorescence intensities at the initial point and satura-
tion point, respectively, and Fx is the fluorescence intensity at a
certain concentration of added analyte [A].
{F0 – Fx}/({Fx – Fα}) = ([A]n)/Kd
(1)
(2)
n
1
Spectra GX 2000 spectrometer. H and 31P NMR spectra were re-
log[{F0 – Fx}/({Fx – Fα}] = nlog[A] – nlogKd
corded with a Bruker 200 MHz (Avance-DPX 200)/500 MHz
(Bruker Avance II 500) FT spectrometer. Electronic spectra were
recorded with a Shimadzu UV-3101 PC spectrophotometer; while
fluorescence spectra as well as time-correlated single-photon count-
ing (TCSPC) studies were carried out using Edinburgh Instru-
ments, Model H5773-03, fitted with a blue-sensitive photomulti-
plier.
The binding constant Kb is obtained by plotting log[(F0 – Fx)/(Fx –
Fα)] vs. log[A]. The slope of the double-logarithmic plot obtained
from the experimental data is the number of binding sites or stoi-
chiometry (n); whereas the value of log([A]) at log[(F0 – Fx)/(Fx
–
Fα)] = 0 gives logKd. The reciprocal of Kd is the binding constant
Kb.
Spectrophotometric Study: An aqueous HEPES buffer solution was
used for maintaining a pH of 7.4. A 1.07ϫ10–4 m solution of L1Zn
in an aq. HEPES buffer/CH3CN (pH = 7.4) and two different
buffer solutions with different solvent proportions, aq. HEPES
buffer/CH3CN with 1:4 (v/v) and 2:3 (v/v), were used for studies.
These solutions were prepared, stored under dark conditions and
used for all spectroscopic studies after an appropriate dilution. A
1.0ϫ10–3 m solution of different polynucleotides and the tetrabu-
tylammonioum salt of the respective anions were prepared in the
same solvent mixture. Solutions of complex L1Zn were further di-
luted for optical spectral studies and the effective final concentra-
tion was adjusted to 2.15ϫ10–5 m; while the effective concentra-
tions of the different analyte (anions) was adjusted to 8.0ϫ10–4 m.
Computational Methodology: The calculations were performed
from a generalized gradient approximation (GGA)[25] using the
BLYP functional[26] integrated in the density functional program
DMol3 (version 4.1.2) of Accelrys Inc.[27] The physical wave func-
tions were expanded in terms of numerical basis sets. We used a
DNP double-numerical polarized basis set that is comparable to
the 6-31G** basis set. The conductor-like screening model (CO-
SMO) was employed for solvent calculations.[28] The molecular
electrostatic potential (MESP) was calculated using Equation (3),
where ZA is the charge on nucleus “A” located at distance RA and
ρ(rЈ) is the electron density.[29]
Luminescence Study: Two different standard solutions were used
for the luminescence titration studies. Different stock solutions of
L1Zn in an aq. HEPES buffer/CH3CN (1:4 (v/v), pH = 7.4) and
an aq. HEPES buffer/CH3CN (2:3 (v/v), pH = 7.4) medium were
(3)
In general, electron-dense regions are expected to show high nega-
tive MESP whereas electron deficient regions are characterized by
positive MESP.[30] The most negative valued point (Vmin) in elec-
tron-rich regions and the most positive values point (Vmax) can
prepared and stored in the dark. For all measurements, λext
=
315 nm was used (excitation and emission slit width of 3/3 nm).
The initial concentration of L1Zn for both stock solutions was
maintained at 1.07ϫ10–4 m. The first stock solution [aq. HEPES
buffer/CH3CN (1:4, v/v)] was used for recording the changes in the
spectral pattern for L1Zn in the presence of various added anions
be obtained from the MESP topography calculation.[31] Molecular
3–
electrostatic potentials (MESP) were calculated for HP2O7
,
monoanionic form of AMP and ADP at the BLYP/6-31G** level
in both an acetonitrile and water medium using the Gaussian 03
program.[32]
(F–, Cl–, Br–, I–, NO3 , CH3COO–, C6H5COO–, SO42–, HSO4 ,
–
–
HP2O73–, H2PO4 ) with an effective [L1Zn] = 2.15ϫ10–5 m. The
–
second stock solution [aq. HEPES buffer/CH3CN, 2:3 (v/v)] was
used to record spectra with PPi and the different nucleotides (ATP,
CTP, AMP, ADP), while the effective concentrations were
8.0ϫ10–4 m and 2.15ϫ10–5 m for the anionic analyte and L1Zn,
respectively.
Synthesis of L1: 4Ј-[4-(Bromomethyl)phenyl]-2,2Ј:6Ј,2ЈЈ-terpyridine
(0.51 g, 1.263 mmol), 7-hydroxy-4-methylcoumarin (0.222 g,
1.263 mmol), K2CO3 (0.262 g, 1.894 mmol) and 18-crown-6
(0.034 g, 0.1 equiv.) in dry acetone (100 mL) were refluxed under
a dinitrogen atmosphere with continuous stirring for 48 h in an
appropriate round-bottomed flask. The reaction mixture was then
cooled to room temperature and poured into ca. 80 mL water. A
precipitate was obtained and this was then filtered. The residue was
washed with ca. 50 mL water and dried over P2O5. The desired
product was further purified by column chromatography using sil-
ica gel as a stationary phase and CH3OH/CHCl3 (2:98, v/v) as the
Two different sets of fluorescence titrations were carried out. For
the first set of titrations a stock solution of the L1Zn [in an aq.
HEPES buffer/CH3CN (1:4, v/v) medium] was used after appropri-
ate dilution. Tetrabutylammonium (TBA) salts of the respective
anions ([A] = 1.0ϫ10–3 m; “A” stands for anion) were prepared in
the same solvent medium. All titration experiments were performed
using 2.15ϫ10–5
m solutions of complex L1Zn and varying eluent. The major fraction was collected and after drying under
[HP2O73–] (0–2.0ϫ10–4 m). The second set of titrations were carried
out using an aq. HEPES buffer/CH3CN (pH = 7.4) (2:3, v/v) solu-
tion, while maintaining [L1Zn] = 2.15ϫ10–5 m. A stock solution of
[A] = 2.0ϫ10–3 m for the respective nucleotides (ADP, AMP) was
prepared in an aq. HEPES buffer/CH3CN (pH = 7.4) (2:3, v/v)
medium. For this set of titrations a varying [A] (0–1.0ϫ10–3 m) (A
reduced pressure pure product was isolated as a white solid; yield
0.21 g, 44%. H NMR (500 MHz, CDCl3, 25 °C, TMS): δ = 8.74–
7.72 (m, 4 H, ArH), 8.68 (d, J = 8 Hz, 2 H, ArH), 7.94 (d, J =
8 Hz, 2 H, ArH), 7.91–7.87 (m, 2 H, ArH) 7.58 (d, J = 8 Hz, 2 H,
ArH), 7.52 (d, J = 9 Hz, 1 H, ArH), 7.37 (d, J = 7.5 Hz, 2 H,
ArH), 6.96 (d, J = 6 Hz, 1 H, ArH), 6.93 (s, 1 H, ArH), 6.18 (s, 1
1
3056
www.eurjic.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2011, 3050–3058

ZnII–2,2Ј:6Ј,2ЈЈ-Terpyridine-Based Complex
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H, ArH), 5.21 (s, 2 H, –CH2), 2.41 (s, 3 H, –CH3) ppm. FTIR
(KBr): νmax = 3051, 2924, 1727, 1611, 1387, 1266, 1145, 1069, 835,
˜
789 cm–1. ESI-Ms: (m/z) = 498.48 (M+, 15%), 521.45 (M+ + Na+,
100%). C32H23N3O3 (497.55): calcd. C 77.25, H 4.66, N 8.45; found
C 77.3, H 4.7, N 8.4.
[4]
L1Zn: L1 was found to have a limited solubility in methanol. Thus,
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CHCl3 (ca. 5 mL). Methanol (30 mL) was then added to this solu-
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sired compound was then allowed to precipitate in a pure form by
slow evaporation of the solvent at room temperature. The precipi-
tate thus obtained was filtered, washed with cold water and dried
over P2O5; yield 0.107 g, 70%. 1H NMR (200 MHz, CD3OD +
D2O, 25 °C, TMS): δ = 9.03 (s, 2 H, ArH), 8.82 (d, J = 7.8 Hz, 2
H, ArH), 8.24–8.16 (m, 4 H, ArH), 7.97 (m, 2 H, ArH), 7.88–7.79
(m, 4 H, ArH), 7.69 (d, J = 8.6 Hz, 1 H, ArH), 7.18 (d, J = 6.4 Hz,
1 H, ArH), 6.98 (s, 1 H, ArH), 6.62 (s, 1 H, ArH), 5.37 (s, 2 H,
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3
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5.1.
[8]
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Acknowledgments
Authors thank the Department of Science and Technology and
Council of Scientific and Industrial Research (CSIR), India for
supporting this research. P. D. and A. G. thank the CSIR for a
Sr. Research Fellowship. M. K. K. thanks the University Grants
Commission (UGC), New Delhi for a Sr. Research Fellowship.
V. R. thanks the Department of Bio Technology (DBT), India for
a research fellowship. A. D. thanks Dr. P. K. Ghosh, Director,
CSMCRI for his encouragement.
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P. Das, A. Ghosh, M. K. Kesharwani, V. Ramu, B. Ganguly, A. Das
FULL PAPER
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Received: February 4, 2011
Published Online: June 1, 2011
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