Fluorene-based chemodosimeter for "turn-on" sensing of cyanide by hampering ESIPT and live cell imaging

Article abstract of DOI:10.1039/c4tb00388h

A new salicylaldehyde appended fluorene-based chemodosimeter (FSal) has been designed by taking consideration of the special nucleophilicity of cyanide ion. FSal shows selective affinity towards CN^- over other anions (namely F^-, Br^-, NO₃^-, ClO ₄^-, N₃^-, H₂PO ₄^-, AcO^-, I^-, Cl^-, and NO₂^-) through turn-on fluorescence with a minimum detection limit of 0.06 ppm. The turn-on fluorescence of the FSal-CN complex resulting from hampering ESIPT is also supported by DFT and TDDFT calculations. Biological compatibility and live cell imaging of this unique probe have also been explored.

Full text of DOI:10.1039/c4tb00388h

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PAPER
Fluorene-based chemodosimeter for “turn-on”
sensing of cyanide by hampering ESIPT and live cell
imaging†
Cite this: J. Mater. Chem. B, 2014, 2,
4733
Manas Kumar Bera,a Chanchal Chakraborty,a Pradeep Kumar Singh,b Chandan Sahu,c
c
b
c
a
*
Kaushik Sen, Samir Maji, Abhijit Kumar Das and Sudip Malik
A new salicylaldehyde appended fluorene-based chemodosimeter (FSal) has been designed by taking
consideration of the special nucleophilicity of cyanide ion. FSal shows selective affinity towards CNꢀ
over other anions (namely Fꢀ, Brꢀ, NO3ꢀ, ClO4ꢀ, N3ꢀ, H2PO4ꢀ, AcOꢀ, Iꢀ, Clꢀ, and NO2ꢀ) through turn-
on fluorescence with a minimum detection limit of 0.06 ppm. The turn-on fluorescence of the FSal–CN
complex resulting from hampering ESIPT is also supported by DFT and TDDFT calculations. Biological
compatibility and live cell imaging of this unique probe have also been explored.
Received 10th March 2014
Accepted 23rd April 2014
DOI: 10.1039/c4tb00388h
www.rsc.org/MaterialsB
Fluorescent chemosensors have many advantages, including
high sensitivity, low operational cost, ease of detection and
1. Introduction
suitability as diagnostic tools for biological concerns.8–13 There
are several methods for the selective detection of CNꢀ, which
include cyanide addition to ZnII-porphyrin,14 a polymer–CuII-
complex,15 CdSe quantum dots,16 and organoboron deriva-
tives.17 Hydrogen-bonding interactions,18 luminescent lifetime
measurements,19 and deprotonation techniques20 have also
been adopted for this purpose. However, there is growing
interest to develop a chemodosimetric probe for CNꢀ to
circumvent the interference from other anions and this
approach is based on an irreversible reaction of the strong
nucleophile, CNꢀ, which has been used in cyanohydrin reac-
tions.21 The carbonyl centers, which are ortho with respect to a
hydroxyl group, act as strong electrophiles due to the resonance-
assisted hydrogen bonds (RAHBs) introduced by Gilli et al.22 and
the nucleophilic addition to the carbonyl centers become very
facile.23
The cyanide anion (CNꢀ) is one of the most deadly poisons to
mammals,1,2 although it is extensively used in industrial
processes, including heap leaching of gold from ore, metal-
lurgy, and electroplating. It is also used in bers and the resin
industry.3 Despite safeguards and stringent norms set by
different regulatory bodies, the accidental release of cyanide
can contaminate drinking water and become a serious threat to
the environment.4 Environmental implications may be caused
by some food plants like cassava and also by some Rosaceae
such as apricot seeds (and also almonds, apples, cherries,
plums, pears etc.) which produce cyanogenic glycosides during
natural defense mechanisms. The glycosides are hydrolyzed by
enzymes upon injury or stress to produce HCN.5 Furthermore,
the release of cyanide into the environment, with potentially
dangerous effects, is an added source of concern.6 In living cells,
cyanide binds with the Fe3+ in heme units, and affects the
oxygen supply. The active site of cytochrome c is inactivated by
CNꢀ and blocks the electron transport chain. As a result,
cellular respiration is inhibited.7 All the above factors demand
the development of a receptor for CNꢀ sensing in aqueous as
well as in cellular environments.
Keeping the above in perspective, we have designed and
synthesized a novel chemodosimetric probe FSal (Scheme 1) to
detect CNꢀ based on uorene as a color reporting group and
salicylaldehyde as an electrophile for the employment of an
intramolecular hydrogen bond with a phenolic proton. We have
also synthesized two model compounds FBal and FMBal
according to Scheme 1 to support the sensing mechanism. To
date, various chemosensors24 which have been reported for
CNꢀ, suffer from several limitations such as a high detection
limit, interference of other anions like Fꢀ or AcOꢀ and high
temperature. In this circumstance, it is a challenge for us to
fabricate a unique chemodosimetric system which can detect
CNꢀ from an aqueous solution without being affecting by other
anions and at levels lower than the permissible level for cyanide
(0.2 ppm) in drinking water set by the Environment Protection
Agency (EPA).25 To the best of our knowledge, this is the rst
aPolymer Science Unit, Indian Association for the Cultivation of Science, 2A & 2B Raja
S. C. Mullick Road, Jadavpur, Kolkata – 700032, India. E-mail: psusm2@iacs.res.in
bDepartment of Spectroscopy, Indian Association for the Cultivation of Science, 2A & 2B
Raja S. C. Mullick Road, Jadavpur, Kolkata – 700032, India
cDepartment of Biosciences and Bioengineering, Indian Institute of Technology
Bombay, Mumbai, Maharashtra, India 400076
† Electronic supplementary information (ESI) available: Detailed NMR spectra,
MALDI-TOF mass spectra for all compounds, UV-Vis spectra, PL spectra, and
details of theoretical calculations and biological studies. See DOI:
10.1039/c4tb00388h
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cyanide as tetrabutylammonium salt) were prepared in deion-
ized water. The experiments were done by taking 2 mL probe
solution followed by addition of an aqueous solution of
different anions. Aer addition of the anion solution, the
resulting solution was shaken well and its spectra were recorded
aer 5 min. For emission spectra, measurement slits were 5/5.
2.4 Synthesis
9,9-Dioctyluorene-2,7-bis(trimethylene boronates) (2). Into
a solution of 2,7-dibromo-9,9-dioctyluorene 1 (2 g, 3.6 mmol)
in anhydrous THF (30 mL), n-BuLi (1.6 M in hexane, 6.7 mL,
10.8 mmol) was added dropwise at ꢀ78 ꢁC. The reaction mixture
was stirred for 2 h prior to the addition of trimethyl borate
(4 mL, 36 mmol) in one portion. The mixture was warmed to
room temperature, stirred overnight and was poured into
crushed ice containing HCl (2 M) while stirring. The mixture
was extracted with ether and the combined extracts were evap-
orated to give a yellowish liquid (diboronic acid). Then the
mixture was reuxed with 1,3-propanediol (0.63 mL, 8.71 mmol)
in 40 mL toluene for 10 h. Aer the workup, the crude product
was puried by column chromatography (with silica gel and
petroleum ether–ethyl acetate (4 : 1) as the eluent) to afford a
yellowish liquid (1.36 g, 68% yield). 1H-NMR (300 MHz, CDCl3):
d (ppm) 7.78–7.62 (m, 4H), 7.32 (m, 2H), 4.20 (t, 8H), 2.10 (m,
4H), 1.99 (m, 4H), 1.27–1.03 (m, 20H), 0.84 (t, 6H), 0.60 (m, 4H).
13C-NMR (300 MHz, CDCl3): d (ppm) 150.4, 143.6, 132.6, 127.7,
127.3, 120.9, 62.7, 55.0, 40.6, 31.9, 30.1, 29.8, 29.3, 27.5, 23.8,
22.7, 14.2. Elemental analysis for C35H52B2O4 (%) calculated: C
75.28, H 9.39; found: C 75.55, H 9.30. MALDI-TOF (m/z):
calculated: 558.4, found: 558.3.
Scheme 1 Synthesis of the fluorene-based probe, FSal, and two
model compounds, FBal and FMBal.
report where a salicylaldehyde appended uorene-based che-
modosimeter has been used for the detection of CNꢀ from water
with high selectivity and a low detection limit (0.06 ppm). Again,
this novel probe is biocompatible which is an added advantage
for live cell applications.
2. Experimental
2.1 Materials
2,7-Dibromo-9,9-dioctyluorene, 3-bromobenzaldehyde, n-BuLi,
tri-methylborate, 5-bromosalicylaldehyde, 1,3-propanediol,
Pd(PPh3)4, and tetrabutylammonium cyanide (TBACN) were
from Sigma-Aldrich Co. Ltd. and the rest were from Merck India
Pvt. Ltd. All the reagents were used without further purication,
and all the experiments were performed at room temperature
(25 ꢁC). All the solvents used for the synthesis were from Merck
India Pvt. Ltd. and were used aer distillation under N2. For
spectral detection, the HPLC grade CH3CN solvent was used,
whereas deionized water (obtained from the Millipore Milli-Q
system, 18 MU) was used to prepare the salt solutions.
9,9-Dioctyluorene-2,7-bis-(5-salicylaldehyde) (FSal). 9,9-
Dioctyluorene-2,7-bis(trimethylene boronate) (2) (0.558 g, 1.0
mmol), 5-bromosalicylaldehyde (0.4 g, 2.0 mmol) and Pd(PPh3)4
(0.008 g) were added to a mixture of 15 mL THF and aqueous 2
M Na2CO3 (7 mL) under a nitrogen atmosphere. The mixture
ꢁ
was vigorously stirred at 90 C for 24 h. Aer the mixture was
cooled to room temperature, it was poured into 100 mL
deionized water. The aqueous layer was extracted with
dichloromethane three times. The combined organic layers
were washed with water and dried over sodium sulfate. Aer
vacuum evaporation of the solvent, the residue was puried by
column chromatography (with silica gel and DCM–petroleum
ether as the eluent) to give a yellowish liquid (0.378 g, 60%
2.2 Characterization
All the compounds were characterized by 1H-NMR, 13C-NMR
and matrix-assisted laser desorption ionization time-of-ight
(MALDI-TOF) techniques. The NMR spectra were acquired on
300 and 500 MHz Bruker DPX spectrometers using CDCl3 as the
solvent and TMS as the standard reference at room tempera-
ture, with the chemical shi given in parts per million. UV-Vis
spectra of all the samples were recorded with a Hewlett–Packard
UV-Vis spectrophotometer (model 8453). Photoluminescence
studies of solutions were recorded with a Horiba Jobin Yvon
Fluoromax 3 spectrometer at an excitation wavelength of
360 nm. MALDI-TOF was carried out with a Bruker Daltonics
FLEX-PC using dithranol as a matrix.
1
yield). H-NMR (500 MHz, CDCl3): d (ppm) 11.03 (s, 2H), 10.03
(s, 2H), 7.87–7.77 (m, 6H), 7.56–7.51 (m, 4H), 7.13–7.10 (d, 2H),
2.08–2.02 (m, 4H), 1.33–0.71 (m, 30H). 13C-NMR (500 MHz,
CDCl3): d (ppm) 196.8, 161.0, 152.0, 140.1, 138.4, 136.0, 133.9,
131.9, 125.7, 121.0, 120.9, 120.4, 118.2, 55.5, 40.6, 32.0, 30.0,
29.8, 29.5, 23.9, 22.8, 14.2. Elemental analysis calculated (%) for
C
43H50O4: C 81.90, H 7.93; found: C 81.63, H 8.05. MALDI-TOF
(m/z): calculated: 630.8, found: 630.4.
9,9-Dioctyluorene-2,7-bis-(3-bromobenzaldehyde) (FBal).
9,9-Dioctyluorene-2,7-bis(trimethylene boronate) (2) (0.279 g,
2.3 Preparation of test solution, absorption and emission
measurements
For spectroscopic measurements, the FSal, FBal and FMBal 0.5 mmol), 3-bromobenzaldehyde (0.185 g, 1.0 mmol) and
solutions (5 mM) were prepared in CH3CN separately. The stock Pd(PPh3)4 (0.006 g) were added to a mixture of 10 mL THF and
solutions of the anions (2 mM) as their potassium salt (only aqueous 2 M Na2CO3 (4 mL) under a nitrogen atmosphere. The
4734 | J. Mater. Chem. B, 2014, 2, 4733–4739
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mixture was vigorously stirred at 90 ꢁC for 24 h. Aer the
mixture was cooled to room temperature, it was poured into 100
mL deionized water. The aqueous layer was extracted with
dichloromethane three times. The combined organic layers
were washed with water and dried over sodium sulfate. Aer
vacuum evaporation of the solvent, the residue was puried by
column chromatography (with silica gel and DCM–petroleum
ether as the eluent) to give a yellowish liquid (0.194 g, 65%
yield). 1H-NMR (500 MHz, CDCl3): d (ppm) 10.13 (s, 2H), 8.19 (s,
2H), 7.96–7.94 (d, 2H), 7.89–7.81 (dd, 4H), 7.67–7.61 (m, 6H),
2.09–2.05 (m, 4H), 1.33–0.70 (m, 30H). 13C-NMR (500 MHz,
CDCl3): d (ppm) 192.5, 152.1, 142.6, 140.6, 138.8, 137.0, 133.2,
129.6, 128.8, 128.1, 126.3, 121.5, 120.5, 55.6, 40.4, 32.0, 30.3,
29.8, 29.4, 23.9, 22.7, 14.1. Elemental analysis for C43H50O2 (%)
calculated: C 86.24, H 8.42; found: C 85.81, H 8.47. MALDI-TOF
(m/z): calculated: 598.8, found: 598.4.
9,9-Dioctyluorene-2,7-bis-(5-bromo-2 methoxybenzaldehyde)
(FMBal). Powdered K2CO3 (0.066 g, 0.48 mmol, 3 equiv.) was
added to a solution of 9,9-dioctyluorene-2,7-bis-(5-salicylalde-
hyde) (0.1 g, 0.16 mmol) in dry DMF (4 mL) under N2 and the
mixture was stirred at room temperature for 15 min. MeI
(0.068 g, 0.48 mmol, 3 equiv.) was added dropwise and the
reaction mixture was stirred at room temperature for 12 hours.
It was then quenched with water (50 mL) and the solution was
extracted with EtOAc (4 ꢂ 25 mL). The combined organic layers
were washed with water, and brine, dried over sodium sulfate
and concentrated. The residue was puried by column chro-
matography (with silica gel, EtOAc–petroleum ether as the
eluent) to give a white solid (0.094 g, 90% yield). 1H-NMR
(500 MHz, CDCl3): d (ppm) 10.55 (s, 2H), 8.16–8.15 (d, 2H), 7.90–
7.86 (dd, 2H), 7.77–7.47 (d, 2H), 7.58–7.53 (m, 4H), 7.12–7.09 (d,
2H), 4.00 (s, 6H), 2.06–2.01 (m, 4H), 1.25–0.75 (m, 30H). 13C-
NMR (500 MHz, CDCl3): d (ppm) 190.0, 161.3, 151.9, 140.1,
138.5, 134.6, 134.4, 126.8, 125.7, 125.0, 121.0, 120.2, 112.2, 56.0,
Fig. 1 (a) The fluorogenic response of FSal (5 mM in CH3CN) with
26 equiv. of CNꢀ and 50 equiv. of other anions in H2O. (b) The
absorption spectra of FSal (5 mM in CH3CN) upon addition of 5 equiv. of
55.5, 40.5, 31.8, 30.1, 29.8, 29.3, 23.9, 22.7, 14.1. Elemental CNꢀ and 10 equiv. of other anions in H2O. (c) The emission spectra of
FSal (5 mM in CH3CN) upon addition of CNꢀ (26 equiv.) and an excess
of other anions (50 equiv.) in H2O. Excitation at 329 nm (slit 5/5).
analysis for C45H54O4 (%) calculated: C 82.03, H 8.26; found: C
81.67, H 7.94. MALDI-TOF (m/z): calculated: 658.9, found: 658.4.
3. Results and discussion
excess at 10 equiv.) does not affect the absorption maximum.
Starting from 2,7-dibromo-9,9-dioctyluorene, followed by However, a low intensity broad peak is prominent in the
boronate ester formation and subsequent reaction with the 400–450 nm region aer addition of CNꢀ to FSal and a visible
aldehyde compounds, we have synthesized a uorene-based colour change (from colourless to yellow; Fig. S13 in the ESI†) is
salicylaldehyde containing probe (FSal) and two model observed, indicating the formation of a FSal–CN complex.
compounds (FBal and FMBal) according to Scheme 1. All
To explain the colorimetric response of FSal, we have per-
compounds are soluble in all common organic solvents like formed density functional theory (DFT) calculations on FSal and
CH3CN, DMSO, chloroform, tetrahydrofuran, methanol etc. its product, FSal–CN.26 Geometry optimization was carried out
FSal shows an absorption maximum at 329 nm (p–p*) along at the B3LYP/6-31 G(d) level27 and optimized geometries were
with a shoulder at 308 nm and an emission maximum at considered for single-point time dependent DFT (TD-DFT)
380 nm (lex ¼ 329 nm), along with a low intensity broad peak calculations at the B3LYP/TZVP level.28 The lowest energy
from 520–640 nm in the CH3CN solvent (Fig. 1b and c). The geometries of FSal and FSal–CN, corresponding to a H transfer
ꢀ
ability of FSal to complex with other anions (Fꢀ, Brꢀ, NO3
,
from phenolic oxygen to formyl oxygen, are shown in Fig. 2a and
ClO4ꢀ, N3ꢀ, H2PO4ꢀ, AcOꢀ, Iꢀ, Clꢀ, NO2ꢀ) has been explored b. This proton transfer has also been validated by 1H NMR
1
with the help of UV-Vis absorption and emission spectrometry. studies (Fig. 3). H NMR titrations were performed in CDCl3,
Upon addition of only 5 equivalents of CNꢀ, the absorption with 0.016 mmol of FSal dissolved in 0.5 mL of CDCl3. TBACN
peak of FSal (5 mM) shows a red shi of 14 nm (Fig. 1b) with a was dissolved in CDCl3 and added to the NMR tube via a
decrease in intensity, whereas the addition of other anions (in syringe, followed by shaking for 5 minutes. The results revealed
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aer addition of CNꢀ to FSal, the low intensity broad peak
appears in the 400–450 nm region, which is for the charge-
transfer band from the negatively charged quinone part to the
uorene moiety (Fig. 2e and f). This transition, calculated at
410 nm with an oscillator strength f ¼ 1.51, corresponds to the
HOMO–LUMO transition (Tables ST1 and ST2 in the ESI†).
The uorescence response of FSal (5 mM in CH3CN) was
studied with the addition of different anions (CNꢀ 26 equiv. and
an excess of other anions at 50 equiv. in H2O). The emission
maximum of FSal is shied to 520 nm aer the addition of CNꢀ
with a 9 fold increase in intensity, whereas the addition of other
anions does not lead to any signicant changes (Fig. 1c). Due to
excited state intramolecular proton transfer (ESIPT), which
opens routes for nonradiative deactivation, FSal is a weak
emitter in acetonitrile.29 Aer the addition of CNꢀ, the formyl
group of FSal generates a cyanoalkoxide anion (deprotonated
cyanohydrine) that exchanges the phenolic proton. This process
hampers the ESIPT and results in a strong emission.29 ESIPT is a
photoinduced procedure in which a proton jumps across the
intramolecular hydrogen bond (IMHB) from a proton donor
group to a proton acceptor group, and was rst described by
Weller.30 The sensing mechanism for FSal with CNꢀ is shown in
(Fig. 4a). To test the sensing mechanism through ESIPT, two
model compounds have been synthesized (FBal and FMBal). As
FBal has no phenolic-OH group and FMBal has a methyl pro-
tected phenolic-OH group, the possibility of ESIPT is minimized
Fig. 2 (a and b) The optimized geometry of FSal and the FSal–CN
complex. The HOMO and LUMO diagrams of FSal (c and d) and FSal–
CN (e and f).
Fig. 3 The partial 1H NMR spectra of FSal in the presence of different
concentrations of CNꢀ ions in CDCl3.
that aer the addition of CNꢀ to FSal, the aldehyde proton is
shied upeld (from d ¼ 10.03 ppm to d ¼ 5.6 ppm) in CDCl3 at
room temperature, indicating the formation of cyanohydrin due
to the nucleophilic attack of CNꢀ on the formyl group of FSal. As
a result, a negative charge has moved to the phenolic oxygen to
generate a partial quinonoid structure in which the negative
charge is delocalized over the conjugated system.
The TD-DFT calculation for FSal also indicates that the peak
at 329 nm is due to a p–p* transition (Fig. 2c and d, HOMO–
Fig. 4 (a) A scheme of the sensing mechanism of FSal for CNꢀ. (b)
LUMO+2 at 338 nm with an oscillator strength f ¼ 1.45) and Representative emission spectra of three probes (5 mM in CH3CN).
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(Fig. 4b). FBal and FMBal produce absorbance maxima at 327 (Fig. 5b). The intensity of the peak at 520 nm gradually increases
and 330 nm and emission maxima at 452 and 466 nm (Fig. S14– up to 26 equiv. of CNꢀ. A plot of I/I0 (where I is the intensity at
S18†) respectively. Even under UV irradiation (lex ¼ 365 nm), 520 nm for the FSal–CN complex and I0 is the intensity of FSal at
the solutions of these two moieties show strong emission.
565 nm) against [CNꢀ] reveals that the curve is linearly tted
The selectivity of FSal has been further demonstrated by from 0 to 5 equiv. of CNꢀ (Fig. 5c), from which we estimate a
observing a visual greenish yellow uorescent color only for detection limit of 0.06 ppm.31 This limit of detection is much
CNꢀ (Fig. 1a) under a 365 nm UV lamp. However, FBal and lower than the limit (0.2 ppm) set by the EPA for drinking water.
FMBal have no affinity towards CNꢀ (Fig. S19 in the ESI†). From the Job's plot32 (Fig. 5d) the binding ratio of FSal and CNꢀ
Competitive uorescence studies were performed in order to is found to be 1 : 2.
elucidate the effectiveness of FSal under harsh conditions. The
To demonstrate the application of CNꢀ sensing in cells, we
uorescence spectra of FSal (5 mM, in CH3CN) were recorded rst tested whether this sensor (FSal) possessed any cytotoxicity.
aer addition of the CNꢀ anion (25 equiv. in H2O) in the pres- To elucidate this possibility, the cytotoxicity of FSal was per-
ence of an excess of other anions (100 equiv. in H2O, Fig. S20 in formed using a MTT assay33 for SH-SY5Y neuronal cells (Fig. 6a)
the ESI†). A representative bar plot (Fig. 5a), showing the uo- with a wide range of FSal concentrations. Details of the exper-
rescence response of individual anions (red bars) as well as the iments are given in the ESI.† FSal does not show any signicant
selective sensing of cyanide by FSal in the presence of an excess cytotoxicity in SH-SY5Y cells. To further demonstrate the CNꢀ
of other anions (green bars), reveals the retention of the activity sensing potential of this novel sensor in cells, internalization of
of FSal in different environments.
FSal was investigated by incubating it with cells. Aer washing,
A titration experiment was carried out by taking FSal (5 mM in the cells were treated with CNꢀ. Aer CNꢀ treatment (3 mM), as
CH3CN) with gradual addition of an aqueous solution of CNꢀ shown in (Fig. 6c), a successful response is found to CNꢀ in the
Fig. 5 (a) A bar plot of the fluorescence response for individual anions (red bars) and the selectivity response towards CNꢀ in the presence of an
excess of other anions (100 equiv.) (green bars). (b) The fluorescence titration profile of FSal (5 mM in CH3CN) with CNꢀ (0–26 equiv.) in H2O. (c) A
plot of I/I0 vs. the [CNꢀ] fluorescence titration spectra. Inset: an extension of (c) for cyanide concentrations at 0–8 equiv. (d) A Job's plot for the
stoichiometry determination of FSal to CNꢀ indicating a 1 : 2 ratio of FSal to CNꢀ, observed from the emission spectra.
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Fig. 6 (a) A MTT assay for FSal. (b) Fluorescence imaging of SH-SY5Y
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Conclusion
In summary, we have designed and synthesized a salicylalde-
hyde-appended uorene-based chemodosimeter (FSal) which
has been recognized as a CNꢀ sensor with high selectivity and a
very low detection limit (0.06 ppm which is much below the
permissible level (0.2 ppm) of drinking water) for the rst time.
TD-DFT calculations support the proposed mechanism. Our
designed probe is biocompatible and in vitro cell imaging with
SH-SY5Y neuronal cells has been explored. Our designed probe
FSal is nontoxic and in vitro cell imaging provides a good
response aer the addition of CNꢀ. Hence, it can be employed
for real-life applications. Therefore, our compound will cover a
wide range of chemical and biological applications.
´
´
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Acknowledgements
M. K. B. acknowledges CSIR for nancial support. The authors
are thankful to the MALDI-TOF facility at IACS.
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