Highly stable hexacoordinated nonoxidovanadium(IV) complexes of sterically constrained ligands: Syntheses, structure, and study of antiproliferative and insulin mimetic activity

Article abstract of DOI:10.1021/ic401866x

Three highly stable, hexacoordinated nonoxidovanadium(IV), V ^IV(L)₂, complexes (1-3) have been isolated and structurally characterized with tridentate aroylhydrazonates containing ONO donor atoms. All the complexes are stable in the open air in the solid state as well as in solution, a phenomenon rarely observed in nonoxidovanadium(IV) complexes. The complexes have good solubility in organic solvents, permitting electrochemical and various spectroscopic investigations. The existence of nonoxidovanadium(IV) complexes was confirmed by elemental analysis, ESI mass spectroscopy, cyclic voltammetry, EPR, and magnetic susceptibility measurements. X-ray crystallography showed the N₃O₃ donor set to define a trigonal prismatic geometry in each case. All the complexes show in vitro insulin mimetic activity against insulin responsive L6 myoblast cells, with complex 3 being the most potent, which is comparable to insulin at the complex concentration of 4 μM, while the others have moderate insulin mimetic activity. In addition, the in vitro antiproliferative activity of complexes 1-3 against the HeLa cell line was assayed. The cytotoxicity of the complexes is affected by the various functional groups attached to the bezoylhydrazone derivative and 2 showed considerable antiproliferative activity compared to the most commonly used chemotherapeutic drugs.

Full text of DOI:10.1021/ic401866x

Article
pubs.acs.org/IC
Highly Stable Hexacoordinated Nonoxidovanadium(IV) Complexes
of Sterically Constrained Ligands: Syntheses, Structure, and Study of
Antiproliferative and Insulin Mimetic Activity
Subhashree P. Dash,† Sagarika Pasayat,† Saswati Bhakat,† Satabdi Roy,† Rupam Dinda,*,†
Edward R. T. Tiekink,§ Subhadip Mukhopadhyay,∥ Sujit K. Bhutia,∥ Manasi R. Hardikar,⊥
Bimba N. Joshi,⊥ Yogesh P. Patil,‡ and M. Nethaji‡
†Department of Chemistry, National Institute of Technology, Rourkela 769008, Odisha, India
§Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
∥Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
⊥Biometry and Nutrition Group, Agharkar Research Institute, G.G. Agrakar Road, Pune 411004
‡Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India
S
* Supporting Information
ABSTRACT: Three highly stable, hexacoordinated nonoxidovanadium(IV),
VIV(L)2, complexes (1−3) have been isolated and structurally characterized with
tridentate aroylhydrazonates containing ONO donor atoms. All the complexes are
stable in the open air in the solid state as well as in solution, a phenomenon rarely
observed in nonoxidovanadium(IV) complexes. The complexes have good
solubility in organic solvents, permitting electrochemical and various spectroscopic
investigations. The existence of nonoxidovanadium(IV) complexes was confirmed
by elemental analysis, ESI mass spectroscopy, cyclic voltammetry, EPR, and
magnetic susceptibility measurements. X-ray crystallography showed the N3O3
donor set to define a trigonal prismatic geometry in each case. All the complexes
show in vitro insulin mimetic activity against insulin responsive L6 myoblast cells,
with complex 3 being the most potent, which is comparable to insulin at the
complex concentration of 4 μM, while the others have moderate insulin mimetic
activity. In addition, the in vitro antiproliferative activity of complexes 1−3 against the HeLa cell line was assayed. The
cytotoxicity of the complexes is affected by the various functional groups attached to the bezoylhydrazone derivative and 2
showed considerable antiproliferative activity compared to the most commonly used chemotherapeutic drugs.
compared to the uncomplexed VOSO4, further improvement
in ligand design is needed, focusing on identifying new
vanadium complexes with increased potency and decreased
toxicity.14
In the past few years, new metal complexes have been
identified as a very promising class of anticancer active
compounds.15−22 Some vanadium complexes, particularly,
peroxidovanadates(V) and bis(cyclopentadienyl)vanadium(IV)
complexes,23 have been found to possess antitumor activity.
Recently, some new types of oxidovanadium(IV) complexes,
INTRODUCTION
■
Vanadium attracts increasing interest in biochemistry.1,2 Of the
numerous reported effects of vanadium on organisms, its
stimulatory effect on the growth of algae and plants,3 the
inhibitory action of vanadate(V) on Na, K-ATPase,4 the
presence of vanadium at the active site of certain enzymes,
including haloperoxidases in sea algae and lichens5 and some
nitrogenases in nitrogen-fixing Azotobacter6 are especially worth
mentioning. Moreover, inorganic vanadyl and vanadate, as well
as some vanadium(IV) and (V) complexes, are potent insulin
mimics and as such may find use as alternatives to insulin in the
treatment of diabetes.7 The discovery of the in vivo insulin
mimesis per os of oxidovanadates(V),8 the oxidovanadium(IV)
precursor, vanadyl sulfate,9 and the much more potent
bis(maltolato)-oxidovanadium(IV) (BMOV)10 stimulates the
search for vanadium complexes which may have application in
the treatment of type II diabetes.11,12 Different approaches have
been attempted to develop more potent and orally active
vanadium-containing insulin-enhancing agents.13 Although the
said complexes have shown pharmacological advantages
mono(phenanthroline)oxidovanadium(IV) [VO(phen)-
24
(H2O)2]2+
and bis(1,10-phenanthroline)sulfatooxido-
vanadium(IV) [VO(SO4)(phen)2],25 were reported to exhibit
potent antitumor activity against the human nasopharyngeal
carcinoma-KB cell line and the clonogenic NALM-6 cell line,
respectively. Dong et al. have reported the cytotoxic activity of
some bis(phenanthroline)oxidovanadium(IV) complexes
Received: July 24, 2013
Published: December 4, 2013
© 2013 American Chemical Society
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against the human leukemic NALM-6 cell line.25 Noleto and
co-workers described the cytotoxic activity of some GALMAN-
A:VO2+/VO3+ and GALMAN-B:VO2+/VO3+ complexes against
HeLa cells.26 Very recently, Sasmal et al. have reported the
photocytotoxicity of the oxidovanadium(IV) complex [VO(L)-
(B)]Cl2, where L is bis(2-benzimidazolylmethyl)amine and B is
dipyrido[3,2-a:2′,3′-c]phenazine against the adenocarcinoma
A549 cell line.27
However, in contrast to the well-known vanadium(IV)/(V)
complexes containing VO2+ or VO3+ units,28 only very few
octahedral nonoxido VIV and VV complexes, the so-called “bare”
complexes, have been isolated and structurally characterized.29
Amavadin,30 a compound isolated from the mushroom Amanita
muscaria, has been shown to contain an octacoordinated V4+
ion31 without oxido ligands, but such nonoxido vanadium
species are still scarce.29
On the other hand, hydrazones, −NH−N=CRR′ (R and R′
= H, alkyl, aryl), are versatile ligands due to their applications in
the field of analytical32 and medicinal chemistry.33 Hydrazone
moieties are the most important pharmacophoric cores of
several anticancer, antiinflammatory, antinociceptive, and
antiplatelet drugs.34 In the context of the present study, it is
relevant to mention that although the chemistry of
oxidovanadium(IV)-aroylhydrazone complexes is well devel-
oped,35 far less information is available for model nonoxido
complexes,29a,p particularly concerning their biological proper-
ties.
We have been studying the chemistry of oxido−metal
complexe, including those of vanadium in O−N containing
donor environments36 along with electro generation of mixed-
valence divanadium(IV,V) complexes,36a,b and herein we report
the syntheses and X-ray crystal structures of three
nonoxidovanadium(IV) complexes containing aroylhydrazones
along with special reference to their insulin mimetic and
antiproliferative activities. These nonoxido VIV complexes were
fully characterized by various physicochemical techniques like
IR, EPR, ESI mass, electronic spectroscopy, magnetic
susceptibility studies, and electrochemical investigations.
temperature range fo 2−300 K with an applied field of 1 T.
Electrochemical data were collected using a PAR electro-
chemical analyzer and a PC-controlled potentiostat/galvanostat
(PAR 273A) at 298 K in a dry nitrogen atmosphere. Cyclic
voltammetry experiments were carried out with Pt working and
auxiliary electrodes, Ag/AgCl as the reference electrode, and
TEAP as the supporting electrolyte. X-band EPR measurements
were performed on a JEOL JES-FA 200 and Bruker EMX EPR
Spectrometer.
Synthesis of Ligands (H2L1−3). Schiff base ligands,
anthranylhydrazone of 2-hydroxy-1-acetonaphthone (H2L1),
salicylhydrazone of 2-hydroxy-1-acetonaphthone (H2L2), and
benzoylhydrazone of 2-hydroxy-1-acetonaphthone (H2L3) were
prepared by the condensation of 2-hydroxy-1-acetonapthone
and the respective acidhydrazide in equimolar ratio in ethanol
by a standard procedure.38 The resulting white compounds
were filtered, washed with ethanol, and dried over fused CaCl2.
Elemental analysis results, NMR (1H and 13C), and IR data for
all of these verified their preparation.
H2L1. Yield: 64%. Anal. Calcd. for C19H17N3O2: C, 71.46; H,
5.36; N, 13.16. Found: C, 71.48; H, 5.37; N, 13.14. IR (KBr
pellet, cm−1): 3473 ν(O−H); 3410 ν(NH2)s; 3329 ν(NH2)as;
1
3221 ν(NH); 1663 ν(CO); 1553 ν(CN). H NMR (400
MHz, DMSO-d6): δ 10.35 (s, 1H, naphthyl−OH), 9.17 (s, 1H,
NH), 7.91−6.23 (m, 10H, aromatic), 6.05 (s, 2H, NH2), 2.35
(s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): δ 153.98
(CO−N), 152.47 (NC(Me)), 152.36−113.59 (16C, aro-
matic), 24.15 (−CH3).
H2L2. Yield: 60%. Anal. Calcd. for C19H16N2O3: C, 71.24; H,
5.03; N, 8.74. Found: C, 71.28; H, 5.01; N, 8.71. IR (KBr pellet,
cm−1): 3542 ν(O−H); 3113 ν(N−H); 1661 ν(CO); 1555
1
ν(CN). H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H,
phenyl−OH), 10.37 (s, 1H, NH), 10.21 (s, 1H, naphthyl−
OH), 7.94−6.69 (m, 10H, aromatic), 2.32 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): δ 161.19 (CO−N), 155.89 (N
C(Me)), 152.50−114.52 (16C, aromatic), 24.09 (−CH3).
H2L3. Yield: 58%. Anal. Calcd. for C19H16N2O2: C, 74.98; H,
5.29; N, 9.20. Found: C, 74.96; H, 5.32; N, 9.21. IR (KBr pellet,
cm−1): 3337 ν(O−H); 3071 ν(N−H); 1659 ν(CO); 1573
EXPERIMENTAL SECTION
■
1
ν(CN). H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H,
General Methods and Materials. All chemicals were
purchased from commercial sources and used without further
purification. [VO(acac)2] was prepared as described in the
literature.37 Reagent grade solvents were dried and distilled
prior to use. The L6 myoblast cell line derived from a rat was
procured from NCCS, Pune, India. Penicillin, streptomycin,
DMEM, fetal bovine serum, and insulin were purchased from
Invitrogen (San Diego, CA), and the glucose estimation kit was
purchased from Randox. MTT (3-[4,5-dimethylthiazol-2-yl]-
2,5-diphenyltetrazolium) and DAPI (4′,6-diamidino-2-phenyl-
indole dihydrochloride) were purchased from Sigma Aldrich
(St. Louis, MO). Minimal essential medium (MEM) was
purchased from Gibco, India. Elemental analyses were
performed on a Vario ELcube CHNS Elemental analyzer. IR
spectra were recorded on a Perkin-Elmer Spectrum RXI
naphthyl−OH), 9.55 (s, 1H, NH), 7.91−7.27 (m, 11H,
aromatic), 2.34 (s, 3H, CH3).13C NMR (100 MHz, DMSO-
d6): δ 153.71 (CO−N), 152.63 (NC(Me)), 152.12−113.74
(16C, aromatic), 24.30 (−CH3).
Synthesis of Complexes [VIV(L1−3)2] (1−3). A general
synthetic procedure taking [VO(acac)2] as representative metal
precursor is described below:
[VO(acac)2] (0.5 mmol) was added to a hot solution of the
appropriate ligand H2L1−3 (1.0 mmol) in EtOH (20 mL), and
the color changed instantly to greenish black. After 3 h of
stirring, red (1, 2) and dark green (3) crystals were obtained
from the reaction mixture, which were filtered off, washed
thoroughly with ethanol, and dried. Some crystals were of
diffraction quality and were used directly for X-ray structure
determination using single crystal X-ray diffractometer.
[VIV(L1)2] (1). Yield: 66%. Anal. Calcd. for C38H30N6O4V: C,
66.57; H, 4.41; N, 12.26. Found: C, 66.55; H, 4.37; N, 12.29. IR
(KBr pellet, cm−1): 3298 ν(NH2)s; 3043 ν(NH2)as; 1589
ν(CN); 1256 ν(C−O)enolic; 1048 ν(N−N). ESI-MS
(CH2Cl2): m/z 708.49 (53%, [M + Na]+); ESI-MS (CH3CN
+ CH2Cl2) (19:1): m/z 708.12 (100%, [M + Na]+); ESI-MS
(MeOH + DMF) (19:1): m/z 708.21 (100%, [M + Na]+).
1
spectrophotometer. H and 13C NMR spectra were recorded
on a Bruker Ultrashield 400 MHz spectrometer using SiMe4 as
an internal standard. Electronic spectra were recorded on a
Lamda25, PerkinElmer spectrophotometer. Mass spectra were
obtained on a SQ-300 MS instrument operating in ESI mode.
DC magnetic susceptibility measurements were carried out on a
Vibrating Sample magnetometer, PPMS (Physical Property
Measurement System, Quantum Design, U.S.A.) in the
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Scheme 1. Schematic Diagram of Various Pathways through Which the Hexacoordinated VIV(L)2 Nonoxidovanadium(IV)
Complexes Were Synthesized
Figure 1. Molecular structures of 1 (a), 2 (b), 3 (c) and overlay diagram of 1 (red image), 2 (green) and 3 (blue) drawn so that the V, O1 and O2
atoms are coincident (d).
[VIV(L2)2] (2). Yield: 65%. Anal. Calcd. for C38H28N4O6V: C,
66.37; H, 4.10; N, 8.15. Found: C, 66.40; H, 4.07; N, 8.17. IR
(KBr pellet, cm−1): 3427 ν(O−H); 1591 ν(CN); 1250
ν(C−O)enolic; 1047 ν(N−N). ESI-MS (CH2Cl2): m/z 710.10
(50%, [M + Na]+); ESI-MS (CH3CN + CH2Cl2) (19:1): m/z
710.10 (100%, [M + Na]+); ESI-MS (MeOH + DMF) (19:1):
m/z 710.20 (100%, [M + Na]+).
MS (CH3CN + CH2Cl2) (19:1): m/z 678.27 (100%, [M +
Na]+); ESI-MS (MeOH + DMF) (19:1): m/z 678.25 (100%,
[M + Na]+).
Alternatively, these complexes can also be synthesized from
the starting materials, like VCl3, VOSO4, and NH4VO3, as
shown in Scheme 1. The spectral data matched well with the
values reported above.
X-ray Crystallography. For all three complexes (1−3), the
black crystals were obtained from the reaction mixture. Single
crystal X-ray diffraction measurements were performed on a
Bruker SMART CCD diffractometer employing graphite-
[VIV(L3)2] (3). Yield: 68%. Anal. Calcd. for C38H28N4O4V: C,
69.62; H, 4.30; N, 8.54. Found: C, 69.58; H, 4.31; N, 8.57. IR
(KBr pellet, cm−1): 1598 ν(CN); 1243 ν(C−O)enolic; 1046
ν(N−N). ESI-MS (CH2Cl2): m/z 655.25 (90.27%, [M]+); ESI-
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Table 1. Crystal Data and Refinement Details for 1−3
parameter
1
2
3
formula
C38H30N6O4V
685.62
C38H28N4O6V
687.58
C38H28N4O4V
655.58
formula weight
crystal habit, color
cryst size, mm
cryst syst
rectangle, red
0.06 × 0.07 × 0.17
monoclinic
P21/n
block, red
0.07 × 0.11 × 0.13
monoclinic
P21/n
hexagon, dark green
0.05 × 0.16 × 0.26
monoclinic
P21/c
space group
a, Å
14.608(6)
14.846(6)
14.976(6)
97.704(8)
3219(2)
4
14.711(4)
14.697(4)
15.068(4)
96.590(4)
3236.3(15)
4
13.807(7)
23.851(12)
10.249(5)
106.571(10)
3235(3)
4
b, Å
c, Å
β, °
V, Å3
Z
density, g/cm3 (calculated)
μ, cm−1
1.415
1.411
1.346
0.361
0.362
0.354
reflns collected
independent reflns
reflns with I ≥ 2σ(I)
R (observed data)
a in wghting scheme
Rw (all data)
largest diff. peak and hole e Å−3
CCDC deposition number
36 356
35 724
26 859
7362
7419
7320
3686
3887
2745
0.062
0.071
0.074
0.058
0.065
0.064
0.158
0.174
0.196
0.33 and −0.28
928 538
0.34 and −0.28
928 539
0.30 and −0.38
928 540
monochromated Mo Kα radiation (λ = 0.71073) so that θmax
=
and 4 μM of vanadium complexes (1−3) and VO(acac)2 for 4
h. The insulin (2 μM) was taken as positive control.43 The
residual glucose in the buffer aliquots remaining in each well
after 4 h was estimated using the hexokiase method by Randox
autoanalyzer.
27.5°. Data collection and reduction were by standard
methods,39 and absorption corrections were applied based on
multiple scans.40 The structures were solved by direct
methods41 and refined by full-matrix least-squares on F2.41 All
non-hydrogen atoms were refined anisotropically, C-bound
hydrogen atoms were included in the riding model
approximation, and O−H and N−H H atoms were refined
with the distance constraint 0.82 0.01 and 0.86 0.01 Å,
respectively. In the final cycles of each refinement, a weighting
Cytotoxic Assay. Human HeLa cervical cells were obtained
from the National Centre of Cell Science (NCCS), Pune, India,
and were maintained in minimal essential medium supple-
mented with 10% fetal bovine serum, penicillin−streptomycin
solution and incubated at 37 °C in 5% CO2 and 95%
humidified incubator. HeLa cells were harvested from
maintenance cultures in logarithmic phase, after counting in a
hemocytometer using trypan blue solution. The cell concen-
tration was adjusted to 5 × 104 cells/ml, and the cells were
plated in a 96-well flat bottom culture plate and incubated for
72 h with various concentrations of the test complexes, which
were dissolved in a 90% (v/v) DMF solution. The effect of the
drugs on the cancer cell viability was studied using the MTT
dye reduction assay by measuring the optical density at 595 nm
using a microplate reader spectrophotometer (Perkin-Elmer
2030).44 The DMF solutions that were used to dissolve the
drugs were also used in the control group treatment.
Nuclear Staining. Nuclear staining using the DAPI stain
was performed according to the method previously described.45
Briefly, HeLa cells either treated or untreated with test
compounds were smeared on a clean glass slide, cells were
fixed with 3.7% formaldehyde for 15 min, permeabilized with
0.1% Triton X-100, and stained with 1 μg/mL DAPI for 5 min
at 37 °C. The cells were then washed with PBS and examined
by fluorescence microscopy (Olympus IX 71) to ascertain any
condensation or fragmentation of the nuclei, indicating cells
undergoing apoptosis.
2
2
scheme of the form w = 1/[σ2(Fo ) + aP2], where P = (Fo
+
2Fc2)/3, was introduced. The final difference maps were
featureless. Molecular structure diagrams presented in Figure 1
were drawn with ORTEP-3 for Windows42a at the 50%
probability level, the overlay diagram in Figure 1d was drawn
with QMol,42b while remaining crystallographic diagrams were
drawn with DIAMOND.42c A summary of crystal data and
refinement details for 1−3 is provided in Table 1.
Crystallographic data in CIF format for the structures have
been deposited in the Cambridge Crystallographic Data
Centre; CCDC 928 538 for 1, CCDC 928 539 for 2, and
CCDC 928 540 for 3. This data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223−336−033; or e-
mail: deposit@ccdc.cam.ac.uk.
In Vitro Insulin Mimetic Activity. L6 myoblasts were
cultured in DMEM containing 10% FBS, penicillin (100 U/
ml), and streptomycin (100 μg/mL) in a humidified 5% CO2
incubator at 37◦C. To differentiate myotubes, the myoblast
cells (5 × 104) were seeded in 24-well plates in DMEM
containing 2% FBS. The myoblast cells (5 × 104) were grown
for 11 days in 0.4 mL of 2% FBS/DMEM to allow the
formation of myotubes. The medium was changed every 2 days.
On the 11th day, the cells were washed and incubated in Kreb’s
bicarbonate buffer (KRBB) for 2 h. Myotubes were then further
cultured in KRBB containing 25 mM glucose along with 1, 2,
RESULT AND DISSCUSSION
■
Synthesis. Scheme 1 presents the various pathways through
which the nonoxido vanadium(IV) hexacoordinated [VIV(L)2]
complexes were obtained. Reactions of aroylhydrazones
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(H2L1−3) with [VO(acac)2] or VOSO4 in acetonitrile or
ethanol lead to the formation of monomeric bis(tridentate)−
vanadium(IV) complexes [VIV(L1−3)2] (1−3). The reactions
are clean, affording large quantities of pure crystalline products
in good yield (∼ 70%). These compounds are highly soluble in
CH2Cl2, DMF, and DMSO and sparingly soluble in MeOH,
EtOH, and CH3CN.
Table 2. Selected Geometric Parameters (Å, °) for 1−3
parameter
1
2
3
coordination
geometry
V−O1
1.903(2)
1.919(2)
1.903(3)
V−O2
1.895(2)
1.902(2)
1.906(3)
V−O3
1.891(2)
1.908(2)
1.894(3)
Alternatively, these nonoxido VIV complexes can also be
isolated directly by the reaction of aroylhydrazones with various
oxidovanadium(V) and vanadium(III) compounds as starting
materials. The formation of [VIV(L)2] complexes from
oxidovanadium(V), NH4VO3, and vanadium(III), VCl3, species
probably involves a one-step reduction from vanadium(V) to
vanadium(IV), and a one step oxidation from vanadium(III) to
vanadium(IV) in open air, respectively, followed by oxido
abstraction from the oxidovanadium(IV) species generated in
situ. It is noteworthy that the entire synthetic route above can
be carried out in laboratory grade ethanol or acetonitrile under
ambient conditions. The reactions do not require dry solvent,
the presence of base, or an inert atmosphere, which is unusual
compared to previous reports.29c,e,o,x,46
Complexes 1−3 are highly stable both in the solid state and
in solution. For example, a solution of 1 in different
coordinating or noncoordinating solvents does not give any
oxidized product (no color change, no oxido-VIV, no oxido-VV,
as confirmed by ESI mass, time dependent UV−vis, and EPR
spectroscopy) after exposure to aerial oxygen for 3−4 days or
even purging oxygen gas into its solution, a rather uncommon
observation for nonoxidovanadium(IV) complexes. Again, to
check the stability of these nonoxidovanadium(IV) species, all
three complexes (1-3) were dissolved and recovered back from
solvent mixture (MeOH + DMF) (9:1) after keeping three
days in solution. The isolated solid products were characterized
by different spectroscopic techniques (Figures S1−S3). The
results matched well regardless of having been recorded using
the original compound or the isolated compound from solvent.
The absence of a vanadium oxo (VO) peak in the IR
spectrum, no disappearance of low energy transition peaks in
UV−vis spectrum, and time-dependent EPR clearly discard the
formation of corresponding V(V) in solution. The stability of
the complexes may be due to the simultaneous removal of the
oxido group, complete charge neutralization as well as the
formation of six strong covalent bonds at the V4+ center from
the hard donor atoms N and O, which possibly precludes the
approach of a reagent species within the reaction sphere of the
well-protected V4+ center. Also, the rigidity and steric bulk of
the ligands do not permit the formation of the square pyramidal
pentacoordinated VVOL(OR) complex so familiar in vanadium
chemistry, in which the terminal oxygen is in an axial position
and the tridentate ligand occupies the equatorial plane.
V−O4
1.878(2)
1.888(2)
1.900(3)
V−N2
2.053(3)
2.058(3)
2.073(4)
V−N4
2.066(3)
2.081(3)
2.065(4)
O1−V−O2
O1−V−O3
O1−V−O4
O1−V−N2
O1−V−N4
O2−V−O3
O2−V−O4
O2−V−N2
O2−V−N4
O3−V−O4
O3−V−N2
O3−V−N4
O4−V−N2
O4−V−N4
N2−V−N4
hydrogen bonds
H···N1
126.48(10)
137.78(10)
87.33(10)
74.41(10)
86.84(10)
86.27(10)
84.47(9)
127.59(11)
136.73(11)
87.26(10)
74.75(11)
87.05(11)
86.23(10)
83.75(10)
81.27(11)
141.64(11)
126.99(11)
86.94(11)
74.65(11)
141.72(11)
81.96(11)
129.20(11)
126.66(13)
136.77(14)
87.06(14)
74.22(15)
86.86(15)
87.22(14)
83.87(13)
82.11(14)
142.77(14)
126.80(14)
86.92(14)
74.24(15)
142.62(14)
82.14(15)
127.47(15)
81.43(10)
143.32(10)
125.70(10)
87.21(10)
74.47(10)
143.13(10)
82.14(10)
127.22(10)
2.03(4)
1.91(4)
Y···N1
2.710(5) (Y =
N5)
2.626(4) (Y =
O5)
H···N3
Y···N3
2.10(4)
1.86(4)
2.716(4) (Y =
N6)
2.628(4) (Y =
O6)
Y−H···N1
Y−H···N3
135(3) (Y = N5) 147(4) (Y = O5)
128(3) (Y = N6) 153(4) (Y = O6)
intramolecular N−H···N hydrogen bonds between an amino-H
and noncoordinating azo N atoms, Table 2. The six-membered
chelate rings exhibit significantly greater deviations from
planarity and may to a first approximation be described as
having an envelope conformation with the V atom lying well
out of the plane (i.e., 0.963(3) Å) defined by the remaining five
atoms (rms deviation = 0.0949 Å); the equivalent parameters
for the O4 chelate ring are 0.904(3) and 0.1200 Å, respectively.
This distortion enables the V atom to exist within a N2O4
donor set that approximates a trigonal prism. In this
description, the two triangular faces are defined by the (O1,
O4, N4) and (O2, O3, N2) atoms. The dihedral angle between
the trigonal faces is 2.67(9)°, and the twist of one face relative
to the other is 13.5° (cf., 0° for an ideal trigonal prism and 60°
for an ideal octahedron). The structure of 2 is isostructural with
1 and presents very similar coordination geometry.
For the two five-membered rings in 2, the V atom lies
0.196(5) and 0.270(5) Å above the plane defined by the
remaining four atoms (rms deviation = 0.0033 and 0.0061 Å for
the O1 and O3 rings, respectively). The adjacent benzene ring
is approximately coplanar to the respective five-membered ring
forming dihedral angles of 1.81(17) and 4.88(17)°; this
arrangement enables intramolecular O−H···N hydrogen
bonding, Table 2. Significant distortions are again evident for
the six-membered chelate rings with the V atom lying 0.960(4)
Å out of the plane through the remaining five atoms of the O2
chelate ring (rms deviation = 0.0943 Å); the equivalent values
for the O4 chelate are 0.926(4) and 0.1181 Å, respectively. In
Structure Description. Crystals were obtained for each of
1−3, and their crystal structures were determined. Molecular
structures are illustrated in Figure 1, and selected geometric
parameters are collected in Table 2. In 1, the central V atom is
coordinated by two dinegative, NO2-coordinating hydrazone
ligands forming five-membered CN2OV and six-membered
C3NOV chelate rings. The five-membered rings have envelope
conformations with the V atom lying 0.215(5) and 0.301(5) Å
above the plane of the remaining atoms of the O1 and O3
chelate rings (rms deviation = 0.0061 Å for each). Each five-
membered ring is virtually coplanar to the attached benzene
ring (dihedral angles between least-squares planes = 4.17(16)
and 7.04(15)°, respectively), which allows for the formation of
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terms of coordination geometry, the dihedral angle between the
trigonal faces is 2.00(10)°, and the twist angle is 10.1°. While
not isostructural with 1 and 2, the structure of 3 presents all the
hallmarks just described with the exception of the intra-
molecular hydrogen bonding.
complexes (Figures S7−S10). The spectral data from CH2Cl2
are summarized in Table 3, and the representative spectrum is
Table 3. Electronic Spectra for 1−3 in CH2Cl2
complex
wavelength (nm) (εmax (M−1cm−1))
For the five-membered rings rings in 3, the V atom lies
0.215(6) and 0.252(7) Å out of the planes of the O1 (rms
deviation = 0.0087 Å) and O3 chelate (0.0139 Å) rings,
confirming the flattened envelope conformations. Despite the
lack of an intramolecular hydrogen bond, as for 1 and 2, the
adjacent five- and six-membered chelate and benzene rings are
coplanar forming dihedral angles of 4.9(3) and 10.4(3)°. For
the six-membered chelate rings, the V atom lies 0.975(4) Å out
of the plane of the remaining atoms (rms deviation = 0.1064 Å)
for the O2 chelate ring0.981(5) and 0.1064 Å for the O4
chelate ring. Finally, the dihedral angle between the trigonal
face is 2.85(12)°, and the twist angle is 10.0°.
[VIV(L1)2], 1
633 (16174), 509 (13278), 368 (52404), 325 (65737),
265 (80382), 229 (99234)
[VIV(L2)2], 2
[VIV(L3)2], 3
619 (13060), 507 (13770), 388 (48743), 312 (54808),
253 (89508), 229 (109781)
614 (10273), 501 (9508), 361 (29726), 319 (46775),
265 (56666), 229 (72568)
The overlap diagram, Figure 1d, where the V,O1,O2 atoms
have been superimposed, highlights the similarity in the
molecular structures of 1−3, there being only minor differences
in the orientations of the peripheral substituents. This
homogeneity is reflected in the geometric parameters collated
in Table 2, with no significant differences apparent in the bond
lengths about the three V atoms. In the same way, no trends are
discerned from the bond angles, indicating that the amino (1)
and hydroxyl (2) groups do not exert an influence on the
molecular structure even though they form intramolecular
hydrogen bonds with the noncoordinating azo N atoms.
In the crystal structure of 1, no specific intermolecular
contacts were identified as being significant employing the
distance criteria established in PLATON,47 implying the second
amino-H atom does not form a significant intermolecular
contact. As shown in Figure S4, molecules are arranged in rows
along the b-axis and are surrounded by molecules forming
hydrophobic contacts. In isostructural 2, a similar packing is
observed, but in this case a C−H···π, edge-to-face interaction is
formed between methyl-H and the C1-benzene ring of centro
symmetrically related molecules to form dimeric aggregates (for
details see Figure S5). As for 1, no specific intermolecular
interactions are noted in the crystal structure of 3 (Figure S6).
A macroscopic difference in the global crystal packing is
apparent as molecules in 3 can be described as aggregating in
the bc-plane with the flat layers stacking along the a-axis. By
contrast, molecules in each of 1 and 2 aggregate in a zigzag
pattern parallel to the ab-plane and stack along the c-axis.
Figure 2. UV−vis spectra of 1 (1.83 × 10−5 M) in CH2Cl2 .
shown in Figure 2. There are two bands in the 633−501 nm
range, among which, the lowest-energy transition band around
633−614 nm is situated in the d−d transition region, but the
intensity (εmax, 16174−10273 M−1cm−1) of this band appears
too large for a pure d−d transition, for which the intensity is
generally very low for vanadium(IV) complexes. The high
intensity of these two bands (633−501 nm) and analogy with
other “bare” vanadium(IV) complexes29a−c,e,j,h,o,p,x suggest that
these transitions are most reasonably assigned as ligand-to-
metal charge transfer in origin. The other bands in the higher
energy absorptions (388−229 nm) are likely to be due to
ligand centered transitions.36b In 1 and 2, the bands are slightly
red-shifted relative to 3, presumably a consequence of the
electron-releasing −NH2 and −OH substituent on the ligands
in 1 and 2, respectively.29n
IR Spectroscopy. The IR data of all the ligands (H2L1−3
)
and their corresponding metal complexes (1−3) are given in
the the Experimental Section. All the ligands possess a band in
the region of 3542−3337 cm−1 due to aromatic −OH present
in the naphthalene moiety, which is absent in the
corresponding metal complexes due to the coordination.
However, the presence of a band at 3427 cm−1 in the case of
complex 2 is due to the −OH group attached to the benzene
nucleus of the ligand H2L2. Disappearance of bands for −NH
and −CO and appearance of bands in the range of 1256−
1243 cm−1 indicates the enolization of these two groups
forming a −NC−O− type of bond. Absence of ν(VO)
bands in the range of 1035−935 cm−1 clearly indicate the
nonoxido nature of the complex.48
1
NMR Spectroscopy. H and 13C NMR of the ligands
(H2L1−3) are recorded in DMSO-d6, and the data are given in
the Experimental Section. The spectra of the free ligands
(H2L1−3) exhibit a resonance in the range of δ = 10.35−10.21
ppm due to naphthyl −OH, δ = 10.37−9.17 ppm due to −NH,
and δ = 2.35−2.32 ppm due to −CH3 protons, respectively. All
the aromatic protons of the ligands are clearly observed in the
expected region, δ = 7.94−6.23 ppm.36a,b
From the 13C NMR spectra, it is observed that signals for
(CO−N) and (NC(Me)) carbon resonate in the downfield
region in the range of δ = 161.19−153.71 ppm and δ =
155.89−152.47 ppm, respectively, whereas the carbon due to
the methyl groups (−CH3) are found in the upfield region (δ =
UV Spectroscopy. Electronic spectra of the complexes 1−3
were recorded in CH2Cl2, DMF, and different mixture solvents
like H2O + DMF (19:1) and MeOH + DMF (19:1). In all
solutions, the spectral features are quite similar for all three
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24.30−24.09 ppm). Furthermore appearance of signals in the
range of δ = 152.50−113.59 ppm due to aromatic carbon
confirm the formation of the ligands.49
for a compound with spin 1/2 per formula unit, suggesting that
complexes are monomeric with no or very weak antiferro-
magnetic interaction between V atoms (intermolecular
coupling).52,53
ESI Mass Spectroscopy. ESI mass spectra of the
complexes 1−3 have been recorded in dichloromethane
solution. Mass spectral analysis for 3 shows the characteristic
molecular ion peak (M+) at m/z 655.25, whereas for
compounds 1 and 2, ESI-MS peaks are observed at m/z
708.49 [(M + Na)+] and 710.10 [(M + Na)+], respectively. The
ESI mass spectra have also been recorded from different solvent
mixtures like CH3CN + CH2Cl2 (19:1) and MeOH + DMF
(19:1). The results matched well regardless of having been
recorded in solutions with coordinating or noncoordinating
solvents (Figures S11−S12). The ESI mass data are
summarized in the Experimental Section.
Electrochemical Properties. The electrochemical proper-
ties of 1−3 have been examined in CH2Cl2 solution (0.1 M
TEAP) by cyclic voltammetry using a Pt working electrode, Pt
auxiliary electrode, and an Ag/AgCl reference electrode. The
voltammogram pattern is similar for 1−3, which includes both
an oxidation and a reduction process corresponding to one
electron transfer. The potential data are listed in Table 4, and
EPR Spectroscopy. X-band EPR spectra of 1−3 were
recorded in CH2Cl2 solution in the frozen state (77 K). The
data are listed in Table 5. A representative frozen solution
spectrum for 3 is shown in Figure 4, which reveals well-resolved
axial anisotropy with 8-line hyperfine structure, characteristic of
a mononuclear vanadium complex with nuclear spin (51V, I =
7/2).54 Corresponding spin-Hamiltonian parameters (g||,
1.948−1.945; A||, 129.43 × 10−4 cm−1−126.94 × 10−4 cm−1;
g⊥, 1.996−1.983; A⊥, 42.4 × 10−4 cm−1−40.8 × 10−4 cm−1) are
typical of trigonal prismatic oxidovanadium(IV) complexes
under comparable ON-containing donor environments.29a,o
Analysis of the EPR spectra of vanadium(IV) complexes
showed that the anisotropic hyperfine parameters of six-
coordinate complexes35g,54 have significantly lower values
compared to the corresponding values obtained with the five-
coordinated complexes,35e,f,36a,55 as is observed in the present
case. The EPR spectra have also been recorded from DMF
solution, and the results matches well with the original
spectrum reported above (Figure S14).
a
Table 4. Cyclic Voltammetric Results for 1−3 at 298 K
In Vitro Insulin Mimetic Activity. Vanadium compounds
are known to have an insulin mimetic effect.56 In this study, 1−
3 were tested for their insulin mimetic potential in an in vitro
glucose uptake assay. In L6 myotubes, a cell line of skeletal
muscle origin, glucose uptake in response to insulin stimulation
plays a key role in whole body glucose homeostasis. Glucose
transporter (GLUT) 4 is the major glucose transporter of
muscle exquisitely regulated by insulin through post-transla-
tional events.57 The L6 myotubes differentiated from the L6
myoblast have the ability to respond to insulin via insulin
receptor signaling and translocation of Glut 4 to the plasma
membrane. The hyperglycemic condition was created in cell
culture by incubating the cells in 25 mM glucose. In the present
experiment, 3 at 4 μM had a glucose uptake comparable to 2
μM insulin, taken as the positive control (Figure 5). The other
two complexes (1 and 2) have moderate insulin mimetic
activity, and VO(acac)2 showed negligible activity at the
concentrations tested. In the case of 3, the enhancement of the
insulin mimetic activity, with respect to 1 and 2, might be
related to their different structural characteristics, specifically,
the lack of hydrogen bonding functionality in 3. As 3 showed
glucose uptake stimulating activity in the myotubes comparable
to that of insulin, it is likely that 3 mimics insulin action via
complex
Ea1/2 (V)
ΔEaP (mV)
Ec1/2 (V)
ΔEcP (mV)
[VIV(L1)2], 1
[VIV(L2)2], 2
[VIV(L3)2], 3
1.10
1.11
1.09
300
340
280
− 0.54
− 0.55
− 0.53
240
270
220
a
In CH2Cl2 at a scan rate of 100 mV s−1. E1/2 = (Epa + Epc)/2, where
Epa and Epc are anodic and cathodic peak potentials vs Ag/AgCl,
respectively. ΔEP = Epa − Epc.
Figure 3 depicts a representative voltammogram of 3. In the
anodic region, complexes show a quasi-reversible single
electron wave (Figure 3a) at E1/2 values within the potential
window of 1.11 to 1.09 V, which is assigned to the oxidation of
the metal, V(IV)/V(V).50 In the cathodic region, V(IV) is
reduced to V(III), which shows a quasi-reversible single
electron wave (Figure 3b) at E1/2 values within the potential
window of −0.55 to −0.53 V.51
Magnetic Properties. Magnetic susceptibility data for 1−3
were collected over the temperature range of 2−300 K in an
applied magnetic field of 1 T, and a representative temperature
dependence of the magnetic susceptibility is shown in Figure
S13. At 300 K, 1−3 have effective magnetic moments (μeff) of
1.64, 1.66, and 1.68 μB, respectively. These results are typical
Figure 3. Cyclic voltammogram of 3 showing (a) oxidation (V(IV) →V(V)) and (b) reduction (V(IV) →V(III)) of the vanadium(IV) center.
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a
Table 5. X-Band EPR Data for Complexes 1−3 at 77 K
complex
g||
g⊥
gav
A||(10−4 cm−1
)
A⊥(10−4 cm−1
)
Aav (10−4 cm−1
)
[VIV(L1)2], 1
[VIV(L2)2], 2
[VIV(L3)2], 3
1.947
1.945
1.948
1.983
1.991
1.996
1.971
1.975
1.980
128.25
129.43
126.94
41.8
42.4
40.8
70.61
71.41
69.51
a
gav= 1/3 (2 g⊥ + g||). Aav= 1/3(2A⊥ + A||).
through the lipid layer of the cell membrane.59,60 The present
results are consistent with the observation that metal complexes
can exhibit greater biological activities than the free ligand.20a
Comparing the activity of three complexes, the cytotoxicity
follows the order of 2 > 3 > 1, which is reflected from their IC50
values with dose dependency illustrated in Figure 6. It is
remarkable that 2, containing the ortho-hydroxy group, is most
active suggesting that the electron-withdrawing and releasing
nature of the ortho-substituent may exert an influence over
antiproliferative activity. Specifically, 2 was most cytotoxic, a
result correlated with the presence of the electron-withdrawing
hydroxyl group. On the other hand, the presence of an
electron-donating substituent (−NH2) in the ligand core of 1
diminishes cytotoxicity, which is reflected in its IC50 value. For
complex 3, the value is between because of not having an
electron-withdrawing or a releasing group in the ligand. Very
recently, the antiproliferative activity of some oxidovanadium-
(IV) compounds has been reported by Yamaguchi et al. using
the similar technique against U937 cells, and the present results
are in accordance with the reported values.61
Figure 4. Frozen solution X-band EPR spectrum (77 K) in CH2Cl2 of
complex 3. Instrument settings: power, − 0.009 dB; modulation, 100
kHz; sweep center, 2500 G; sweep time, 120 s; sweep width, 2500 G.
Nuclear Staining Assay. To investigate the apoptotic
potential of test compounds in HeLa cells, DAPI staining was
performed. Chromatin condensation during the process of
apoptosis (type I programmed cell death) is a characterizing
marker of nuclear alteration. HeLa cells were treated with 25,
20, and 35 μM of 1, 2, and 3, respectively, that is, at doses less
than their respective IC50 values. The cells were incubated for
24 h before DAPI nuclear staining. Cells were examined under
fluorescent microscope fitted with a DAPI filter. Control cells
(treated with 90% DMF) hardly showed any sort of
condensation in comparison to the treated cells (see Figure
7). All images taken in grayscale demonstrate the brightly
condensed chromatin bodies and the nuclear blebbings, as
marked by arrows in Figure 7. Besides showing nuclear change,
the treated cells exhibited a shrinking morphology, which is
another important hallmark of apoptosis.
Figure 5. Effect of vanadium complexes (1−3) on glucose uptake in
cultured L6 myotubes under high glucose conditions (25 mM
Glucose). Three concentrations (1 μM, 2 μM and 4 μM) were tested
for each complex. The data are indicated as mean SEM (n = 3).
Student’s t-test was used where bars with asterisk show a significant
difference (*P < 0.05) with respect to the untreated control.
CONCLUSION
insulin receptor signaling with translocation of Glut 4 to the
plasma membrane.
■
The following are the salient observations and findings of this
work: (a) Three aroylhydrazone ligands, possessing a rigid,
bulky 2-hydroxy-1-acetonaphthone core and a selection of
anthranil-, salicyl- and benzoyl-hydrazide arms have been
synthesized and utilized in the synthesis of the corresponding
vanadium complexes. As expected, monomeric, hexacoordi-
nated and bis(tridentate)-vanadium(IV) [VIV(L)2] complexes
were isolated; these do not contain an oxido-group. Stability of
the complexes are related to the simultaneous oxido removal
and complete charge neutralization as well as the formation of
six strong covalent bonds at the V4+ center from the hard donor
atoms N and O. (b) The importance of the structural and
electronic effects arising from the incorporation of a bulky 2-
hydroxy-1-acetonaphthone group in the ketone part of
aroylhydrazones that can stabilize six-coordinate
nonoxidovanadium(IV) complexes has been highlighted,
which can be compared with our earlier work on
Inhibition of Cancer Cell Viability. In the present study,
antiproliferative efficacy of 1−3 was assayed by determining the
viability of HeLa cells using the MTT assay. The ligands H2L1−3
and VO(acac)2 gave high IC50 values of >200 μM, whereas 1−3
gave values in the range of 41−22 μM. In contrast, cisplatin,
gefitinib, gemcitabine, 5-fluorouracil, and vinorelbine, the most
commonly used chemotherapeutic drugs, are comparably
effective in HeLa cells with an IC50 value of 13, 20, 35, 40,
and 48 μM, respectively, under similar experimental con-
ditions.58 The significant decrease in the inhibitory concen-
tration for the ligand compared to the metal complex clearly
indicates that incorporation of vanadium in the ligand
environment has a marked effect on cytotoxicity. A possible
explanation is that by coordination, the polarity of the ligand
and the central metal ion are reduced through the charge
equilibration, which favors permeation of the complexes
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Figure 6. Effect of 1, 2, and 3 on cell viability and growth: Hela cells were treated with different concentrations of the test compound for 72h, and
then cell viability was measured by MTT assay. Data reported as the mean SD for n = 6 and compared against PBS control by using a Student’s t-
test. (*significant compared to PBS control).
Figure 7. Study of apoptosis by morphological changes in nuclei of HeLa cells: After treatment, HeLa cells from the control and treatment group
were fixed with 3.7% formaldehyde for 15 min, permeabilized with 0.1% Triton X-100, and stained with 1 μg/mL DAPI for 5 min at 37 °C. The cells
were then washed with PBS and examined by fluorescence microscopy (Olympus IX 71) (200×). Arrows show the morphological changes in the
nuclei of HeLa cells observed on applying drug (1−3) in comparison to control.
oxidovanadium(V) with ligand-containing ONO donor atom-
state and in solution, being resistant to exposure to aerial
oxygen for 3−4 days and even purging oxygen into their
s.36a,b (c) Complexes 1−3 are highly stable both in the solid
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solutions, a rather unusual phenomenon for “bare” vanadium-
(IV) or nonoxidovanadium(IV) complexes. (d) EPR and
magnetic susceptibility data provide reference values for typical
V(IV) sites. Electrochemical results suggest that the electro-
chemical oxidations and reductions are not ligand-centered but
metal-centered, generating VV and VIII species, respectively. (e)
All the complexes show in vitro insulin mimetic activity against
insulin responsive L6 myoblast cells, with complex 3 being the
most potent, which is comparable to insulin at the complex
concentration of 4 μM, while the others have moderate insulin
mimetic activity. In addition, the in vitro antiproliferative
activity of complexes 1−3 against the HeLa cell line was
assayed. The cytotoxicity of the complexes is affected by the
various functional groups attached to the bezoylhydrazone
derivative, and 2 showed considerable antiproliferative activity.
It is worth noting that although the structure and chemistry of
few nonoxidovanadium(IV) hydrazone complexes has been
recently described,29a,p the suitability of these and the related
nonoxidovanadium(IV) complexes in the study of vanadium
insulin mimesis and antiproliferative activity has not been
previously described.
2011). R. D. thanks Prof. M. Chaudhury and Prof. M. R.
Maurya for fruitful discussion and Prof. S. K. Chattopadhyay for
discussion and electrochemical study. R. D. also thanks Dr. T.
K. Maji for the magneto chemistry and Dr. T. K. Paine, and Dr.
P. Sen for EPR analysis. The Ministry of Higher Education
(Malaysia) and the University of Malaya (UM) is thanked for
funding crystal engineering studies through the High-Impact
Research scheme (UM.C/HIR-MOHE/SC/03).
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ASSOCIATED CONTENT
* Supporting Information
■
S
IR spectra of complex 1 and isolated compound 1′ (Figure S1),
UV−vis spectra of compound 2′ in CH2Cl2 as solvent (Figure
S2), ESI mass spectra of isolated compound 1′ [A] in (CH3CN
+ CH2Cl2 (19:1); [B] in (MeOH + DMF) (19:1) (Figure S3),
view in projection down the b-axis of the unit cell contents of 1
(Figure S4), view in projection down the b-axis of the unit cell
contents of 2 (Figure S5), view in projection down the c-axis of
the unit cell contents of 3 (Figure S6), time-dependent UV−vis
spectra of complex 2 in DMF as solvent (Figure S7), time-
dependent UV−vis spectra of complex 3 in DMF as solvent
(Figure S8), time-dependent UV−vis spectra of complex 2 in
solvent mixture (H2O + DMF) (19:1) (Figure S9), time-
dependent UV−vis spectra of complex 3 in solvent mixture
(MeOH + DMF) (19:1) (Figure S10), ESI mass spectra of
complex 3 (CH3CN + CH2Cl2) (19:1) (Figure S11), ESI mass
spectra of complex 3 (MeOH + DMF) (19:1) (Figure S12),
temperature dependence of the magnetic susceptibility of
complex 3 (Figure S13), time-dependent frozen solution X-
band EPR spectrum (77 K) of complex 3 in DMF at 0.5 h
interval. (Figure S14). This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: rupamdinda@nitrkl.ac.in.
■
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors thank the reviewers for their comments and
suggestions, which were helpful in preparing the revised version
of the manuscript. Funding for this research was provided by
Department of Science and Technology, Government of India
(Grants SR/FT/CS-016/2008 and SR/WOS-A/CS-145/
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