Synthesis, characterization, and cytotoxic and antimicrobial activities of mixed-ligand hydrazone complexes of variable valence VO: Z + (z = 2, 3)

Article abstract of DOI:10.1039/c9nj04171k

Two sets of mixed-ligand complexes were synthesized and characterized, namely, [V^IVO(L^1-4)(phen)] (1-4) and [V^VO(L^1-4)(hq)] (5-8) incorporating 2-aminobenzoylhydrazone of 2-hydroxyacetophenone (H₂L

Full text of DOI:10.1039/c9nj04171k

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Synthesis, characterization, and cytotoxic and
antimicrobial activities of mixed-ligand hydrazone
complexes of variable valence VOz+ (z = 2, 3)†
Cite this: New J. Chem., 2019,
43, 16714
b
Nirmalendu Biswas,a Sachinath Bera,b Nayim Sepay,
Titas Kumar Mukhopadhyay,c Krishnendu Acharya,d Sandipta Ghosh,d
Swarnali Acharyya,e Anup Kumar Biswas,f Michael G. B. Drewg and
a
Tapas Ghosh
*
Two sets of mixed-ligand complexes were synthesized and characterized, namely, [VIVO(L1–4)(phen)] (1–4)
and [VVO(L1–4)(hq)] (5–8) incorporating 2-aminobenzoylhydrazone of 2-hydroxyacetophenone (H2L1),
2-hydroxy-5-methylacetophenone (H2L2), 2-hydroxy-5-methoxyacetophenone (H2L3) and 5-chloro-2-
hydroxyacetophenone (H2L4) as primary ligands together with 1,10-phenanthroline (phen) and 8-hydroxy-
quinoline (Hhq) as co-ligands. The complexes were characterized by elemental analyses, magnetic susceptibility
measurements and various spectroscopic techniques. The structures of complexes 2, 5 and 8 were determined
by single crystal X-ray diffractometry. This study indicates that the co-ligands have remarkable effects on the
selective stabilization of the oxidation state of vanadium because the neutral N,N donor phen ligand stabilizes
the +IV state, while the monobasic OÀ,N donor hqÀ ligand stabilizes the +V state. Substituents on the aryloxy
ring also had significant effects on the electronic properties of vanadium in the resulting complexes. The E1/2
values of all the complexes and the lmax values for the LMCT transitions of pentavalent complexes 5–8 exhibited
linear relationships with the Hammett parameter of the substituent. The complexes exhibited promising
cytotoxic activity against lung cancer cells. Interestingly, complexes 2, 3 and 4 (with IC50 values of ca. 2.5 mM)
exhibited cytotoxic activity comparable to that found for the widely used cisplatin (also with an IC50 value of
2.5 mM). Nuclear staining experiments suggest that the complexes kill the cells through apoptosis, which is
further substantiated by molecular docking studies. These complexes also exhibited potential antimicrobial
activity against Escherichia coli, Bacillus subtilis, Staphylococcus aureus and Salmonella typhimurium.
Received 11th August 2019,
Accepted 1st October 2019
DOI: 10.1039/c9nj04171k
rsc.li/njc
coordination chemistry.1 In its two higher (+IV and +V) oxida-
tion states, vanadium is oxophilic and forms a variety of oxido
1. Introduction
Vanadium is an important trace bio-element with a variety species, viz., VO2+, VO3+, (OV-m-O-VO)3+/4+ [i.e., (V2O3)3+/4+] and
+
of oxidation states, ranging from ÀIII to +V and has rich VO2 involving extremely strong and inert VRO bonds.2,3
a Post Graduate Department of Chemistry, Ramakrishna Mission Vivekananda Centenary College, Rahara, Kolkata-700118, India. E-mail: ictg_64@yahoo.co.in
b Department of Chemistry, Jadavpur University, Kolkata 700032, India
c Department of Spectroscopy, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
d Department of Botany, University of Calcutta, 35, Ballygunge Circular Road, Kolkata-700019, India
e Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
f Herbert Irving Comprehensive Cancer Centre, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
g Department of Chemistry, The University of Reading, PO Box 224, Whiteknights, Reading, RG6 6AD, UK
† Electronic supplementary information (ESI) available: Molecular structure of 2 with ellipsoids at 30% probability. The intramolecular hydrogen bond is shown as a
dotted line (Fig. S1), overlay of the electronic spectra of complexes 1–4 in CH2Cl2 solution (Fig. S2), overlay of the electronic spectra of complexes 5–8 in CH2Cl2 solution
(Fig. S3), 51V NMR of complexes 5–8 in CDCl3 solution at 298 K (Fig. S4), X-band EPR spectra of complexes 1, 3 and 4 (black, experimental; red, simulated) in CH2Cl2
solution at (a) 300 K and (b) 77 K (Fig. S5–S7 respectively), schematic diagram of selected frontier orbitals for complexes 1–8 in their ground state geometries (Fig. S8),
cytotoxic activity of the H2L1–4 ligands (Fig. S9), cytotoxic activity of [VIVO(aa)2] (Fig. S10), cytotoxic activity of 1,10-phenanthroline and 8-hydroxyquinoline (Fig. S11), two
dimensional representations of binding sites interacting with the molecules of (a) 3 and (b) 6 (Fig. S12), dose–response curves for the antimicrobial activity of complex 2
(Fig. S13), dose–response curves for the antimicrobial activity of complex 5 (Fig. S14), calculated geometrical parameters for complexes 1–4 (Table S1), calculated
geometrical parameters for complexes 5–8 (Table S2). LD50 on a lung cancer cell line and binding energies of compounds 1–8 with Bcl2 protein (Table S3). CCDC
1887600–1887602. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9nj04171k
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Of them, the oxidovanadium ion represents the most stable 1,10-phenanthroline (phen, a neutral NN donor) and 8-hydroxy-
diatomic cation and dominates the chemistry of vanadium. The quinoline (Hhq, a monobasic ON donor) have been used. It
selective stabilization of these two states (namely, +IV and +V) has been found that starting from a tetravalent precursor
in a complex depends on the basicity of the donor moieties of [VIVO(aa)2] [where aaÀ represents the monoanionic form of
the ligand and the pH of the reaction medium. Vanadium has acetylacetone (Haa)] in the presence of phen, the H2L1–4 ligands
several effects on organisms; the following properties are yielded the tetravalent complexes [VIVO(L1–4)(phen)] (1–4), while
remarkable: (i) a stimulatory effect on the growth of algae and the pentavalent complexes [VVO(L1–4)(hq)] (5–8) were obtained
plants,4 (ii) the inhibitory action of vanadate(V) on Na,K-ATPase,5 in the presence of Hhq. These types of tetravalent and penta-
(iii) the involvement of vanadate in the regulation of phosphate valent mixed-ligand complexes are very rare particularly in the
metabolism in human organisms,6 (iv) the presence of vanadium presence of hydrazone ligands.11,15–17 These complexes were
at the active site of certain enzymes, including haloperoxidases in characterized by elemental analyses and by various spectro-
sea algae and lichens and some nitrogenases in the nitrogen-fixing scopic techniques, namely, IR, UV-vis, 1H NMR, 51V NMR
Azotobacter.7 It has been observed that vanadium complexes have and ESR, and also by magnetic susceptibility measurements.
a wide range of therapeutic potentials, e.g., insulin enhancing,8 Complexes 2, 5 and 8 were structurally characterized by X-ray
antiamoebic9 and antitumor10 activities. During the last ten years crystallography. To the best of our knowledge, complex 2
or so, our group has been working on the chemistry of vanadium11 represents the first structurally characterized complex contain-
utilizing different types of hydrazone ligands which, being derived ing hydrazone as the primary ligand and phen as the auxiliary
from the condensation of aliphatic/aromatic acid hydrazides with ligand. The electrochemical behaviour of these complexes was
aliphatic/aromatic carbonyl compounds, are versatile multidentate studied by cyclic voltammetry. The complexes were screened for
O,N donor ligands and have a wide range of applications in cytotoxic activity against lung cancer cells and antimicrobial
the fields of analytical12 and medicinal13 chemistry. Hydrazone activity against four pathogenic bacterial strains.
moieties provide important pharmaceutical cores for several anti-
cancer, anti-inflammatory and anti-platelet drugs.14 Moreover,
such types of hydrazone ligands contain O/N donor atoms which
are essential in stabilizing the +IV and +V states of vanadium due
to their hard acidic nature.
2. Experimental and computational
2.1 Materials and methods
2-Hydroxyacetophenone,
2-hydroxy-5-methylacetophenone,
The electronic properties of a metal ion in a complex can be
tuned by changing the co-ordination environment around the
metal ion and this can be done by two ways in a mixed-ligand
system: (i) by making substitutions on either or both of the
coordinated ligands or (ii) by changing one ligand, so varying
basicity. From this perspective, we have used a family of
hydrazone ligands which are derived by the condensation of
2-aminobenzoylhydrazide with 2-hydroxyacetophenone and its
5-substituted derivatives (H2L1–4, general abbreviation H2L,
Scheme 1) with a view to studying the effect of substituents on
2-hydroxy-5-methoxyacetophenone and 5-chloro-2-hydroxyaceto-
phenone were obtained from Aldrich. 2-Aminobenzoylhydrazide
was purchased from E. Merck. Acetylacetone and vanadyl sulphate
pentahydrate were obtained from Loba Chemical Company (India).
[VIVO(aa)2] was prepared by a previously reported method.18 All
other reagents were of A. R. grade obtained from commercial
sources and used without further purification.
2.2 Synthesis of H2L1–4 ligands
the electronic properties of the metal. In addition, to study the These ligands were synthesised in good yield by refluxing
effect of auxiliary ligands on the oxidation state of vanadium 2-aminobenzoylhydrazide with the respective 2-hydroxyaceto-
in the presence of the above mentioned hydrazone ligands phenone in an equimolar ratio in methanol as described
Scheme 1 Hydrazone ligands used in this study.
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elsewhere.19 Elemental analyses, 1H NMR, IR and mass spectral solution (20 mL) of H2L1 (0.27 g, 1.00 mmol) dropwise with
data confirmed their identity.
stirring. The reaction mixture was then heated under reflux for
2 h. After cooling the reaction mixture to room temperature, a
methanolic solution (10 mL) of Hhq (0.145 g, 1.00 mmol) was
2.3 Synthesis of [VIVO(L1–4)(phen)] (1–4) complexes
2.3.1 [VIVO(L1)(phen)] (1). To a methanolic solution (20 mL) added dropwise with continuous stirring. Immediately the
of [VIVO(aa)2] (0.265 g, 1.00 mmol) was added a warm methanolic brown solution turned violet. The shiny black microcrystalline
solution (20 mL) of H2L1 (0.27 g, 1.00 mmol) dropwise with product obtained after stirring the reaction mixture for 1 h at
stirring. The reaction mixture was then heated under reflux for room temperature was filtered, washed with methanol and
2 h. After cooling the reaction mixture to room temperature, a dried over silica gel. Yield: 0.44 g (92% based on [VIVO(aa)2]).
methanolic solution (10 mL) of phen (0.180 g, 1.00 mmol) was Anal. calcd for C24H19N4O4V: C, 60.25%; H, 3.97%; N, 11.71%.
added dropwise with continuous stirring. Immediately the Found: C, 60.11%; H, 3.88%; N, 11.65%. FT-IR bands (KBr
brown solution turned orange. The reaction mixture was then pellet, cmÀ1): 3422 (N–H), 1615, 1595 (CQNazomethine), 1368
stirred at room temperature for 1 h. A shiny orange-red micro- (C–Ophenolic), 1252 (C–Oenolic), 1035 (N–N), 954 (VRO). UV-Vis
crystalline product was obtained after stirring the reaction (CH2Cl2) [lmax, nm (e, MÀ1 cmÀ1)]: 545 (4320), 329 (9490).
mixture for 1 h at room temperature, and was filtered, washed 1H NMR (400 MHz, CDCl3, 298 K, d/ppm, J/Hz): 6.59 (d, 1H,
with methanol and dried over silica gel. Yield: 0.41 g (79% based H-3, J = 8.0), 7.65 (t, 1H, H-4, J = 8.0), 7.24–7.26 (m, 3H, H-5,
on [VIVO(aa)2]). Anal. calcd for C27H21N5O3V: C, 63.03%; H, H-11, H-20), 7.83 (d, 1H, H-6, J = 8.0), 7.09 (t, 1H, H-12, J = 8.0),
4.08%; N, 13.62%. Found: C, 62.91%; H, 4.21%; N, 13.55%. 6.47 (t, 1H, H-13, J = 8.0), 7.45–7.50 (m, 2H, H-14, H-17), 2.97
FT-IR bands (KBr pellet, cmÀ1): 3360 (N–H), 1614, 1597 (s, 3H, 3 Â H-15), 7.95 (d, 1H, H-16, J = 4.0), 8.13 (d, 1H, H-18,
(CQNazomethine), 1371 (C–Ophenolic), 1244 (C–Oenolic), 1013 (N–N), J = 8.0), 7.02 (t, 1H, H-21, J = 8.0), 6.93 (d, 1H, H-22, J = 8.0).
958 (VRO). UV-Vis (CH2Cl2) [lmax, nm (e, MÀ1 cmÀ1)]: 851 (40), 51V NMR (400 MHz, 293 K, d/ppm): À480.32. ESI-MS (positive)
755 (40), 410 (12 380), 321 (12 230). ESI-MS (positive) in CH3CN: in CH3CN: 479.09 (M + H+; 479.37), 501.08 (M + Na+; 501.37),
515.39 (M + H+; actual mass = 515.44), 537.39 (M + Na+; 537.44). 517.05 (M + K+; 517.37).
2.3.2 [VIVO(L2)(phen)] (2). This compound was prepared
2.4.2 [VVO(L2)(hq)] (6). This compound was prepared fol-
following an identical procedure to that described for com- lowing an identical method to that described for compound 5
pound 1 using the ligand H2L2 instead of H2L1. Yield: 0.40 g using the ligand H2L2 instead of H2L1. Yield: 0.42 g (85%).
(76%). Anal. calcd for C28H23N5O3V: C, 63.64%; H, 4.36%; N, Anal. calcd for C25H21N4O4V: C, 60.97%; H, 4.27%; N, 11.38%.
13.25%. Found: C, 63.45%; H, 4.46%; N, 13.14%. FT-IR bands Found: C, 60.82%; H, 4.32%; N, 11.34%. FT-IR bands (KBr
(KBr pellet, cmÀ1): 3358 (N–H), 1615, 1586 (CQNazomethine), pellet, cmÀ1): 3480 (N–H), 1616, 1575 (CQNazomethine), 1363
1371 (C–Ophenolic), 1262 (C–Oenolic), 1043 (N–N), 959 (VRO). (C–Ophenolic), 1256 (C–Oenolic), 1031 (N–N), 968 (VRO). UV-Vis
UV-Vis (CH2Cl2) [lmax, nm (e, MÀ1 cmÀ1)]: 842 (30), 774 (30), (CH2Cl2) [lmax, nm (e, MÀ1 cmÀ1)]: 540 (8940), 330 (20 820).
409 (13 630), 322 (15 720). ESI-MS (positive) in CH3CN: 528.96 1H NMR (400 MHz, CDCl3, 298 K, d/ppm, J/Hz): 6.59 (d, 1H, H-3,
(M + H+; 529.45), 550.94 (M + Na+; 551.45).
J = 8.0), 7.49 (dd, 1H, H-4, J = 8.0, 1.2), 7.61 (d, 1H, H-6, J = 1.2),
2.3.3 [VIVO(L3)(phen)] (3). This compound was prepared 7.29 (dd, 1H, H-11, J = 8.0, 4.0), 7.21–7.25 (m, 2H, H-12, H-17),
following an identical method to that described for compound 6.46 (t, 1H, H-13, J = 8.0), 7.65 (d, 1H, H-14, J = 8.0), 2.94 (s, 3 Â
1 using the ligand H2L3 instead of H2L1. Yield: 0.39 g (73%). H-15), 7.93 (d, 1H, H-16, J = 4.0), 8.12 (dd, 1H, H-18, J = 8.0, 1.2),
Anal. calcd for C28H23N5O4V: C, 61.76%; H, 4.23%; N, 12.87%. 7.44–7.46 (m, 1H, H-20), 7.08 (t, 1H, H-21, J = 8.0, 1.0), 6.83 (d,
Found: C, 61.62%; H, 4.30%; N, 12.79%. FT-IR bands (KBr 1H, H-22, J = 8.0), 2.42 (s, 3H, 3 Â H-25). 51V NMR (400 MHz,
pellet, cmÀ1): 3399 (N–H), 1616, 1585 (CQNazomethine), 1365 293 K, d/ppm): À475.76. ESI-MS (positive) in CH3CN: 493.11
(C–Ophenolic), 1260 (C–Oenolic), 1027 (N–N), 956 (VRO). UV-Vis (M + H+; 493.41), 515.09 (M + Na+; 515.41), 531.13 (M + K+; 531.41).
(CH2Cl2) [lmax, nm (e, MÀ1 cmÀ1)]: 840 (30), 724 (30), 406 (8530),
2.4.3 [VVO(L3)(hq)] (7). This compound was prepared fol-
322 (16 670). ESI-MS (positive) in CH3CN: 545.06 (M + H+; 545.46). lowing an identical method to that described for compound 5
2.3.4 [VIVO(L4)(phen)] (4). This compound was prepared using the ligand H2L3 instead of H2L1. Yield: 0.41 g (82%). Anal.
following an identical method to that described for compound calcd for C25H21N4O5V: C, 59.05%; H, 4.13%; N, 11.02%. Found:
1 using the ligand H2L4 instead of H2L1. Yield: 0.44 g (79%). C, 58.92%; H, 4.26%; N, 10.92%. FT-IR bands (KBr pellet, cmÀ1):
Anal. calcd for C27H20N5O3ClV: C, 59.13%; H, 3.65%; N, 3566 (N–H), 1616, 1565 (CQNazomethine), 1374 (C–Ophenolic),
12.77%. Found: C, 58.91%; H, 3.76%; N, 12.66%. FT-IR bands 1258 (C–Oenolic), 1044 (N–N), 955 (VRO). UV-Vis (CH2Cl2) [lmax
,
(KBr pellet, cmÀ1): 3374 (N–H), 1614, 1592 (CQNazomethine), nm (e, MÀ1 cmÀ1)]: 536 (11 140), 329 (30 830). 1H NMR (400 MHz,
1372 (C–Ophenolic), 1259 (C–Oenolic), 1038 (N–N), 958 (VRO). CDCl3, 298 K, d/ppm, J/Hz): 6.87 (d, 1H, H-3, J = 8.0), 6.59 (dd,
UV-Vis (CH2Cl2) [lmax, nm (e, MÀ1 cmÀ1)]: 864 (40), 720 (30), 1H, H-4, J = 8.0, J = 1.2), 7.29 (d, 1H, H-6, J = 1.2), 7.23–7.25 (m,
418 (17 510), 324 (16 920). ESI-MS (positive) in CH3CN: 549.08 2H, H-11, H-17), 7.65 (t, 1H, H-12, J = 8.0), 6.47 (dt, 1H, H-13, J =
(M+; 548.88), 571.07 (M + Na+; 571.88), 587.04 (M + K+; 587.88). 8.0, 1.2), 7.45–7.50 (m, 2H, H-14, H-21), 2.95 (s, 3H, 3 Â H-15),
7.94 (dd, 1H, H-16, J = 4.0, 1.2), 8.13 (dd, 1H, H-18, J = 8.0, 1.2),
2.4 Synthesis of [VVO(L1–4)(hq)] (5–8) complexes
7.06–7.11 (m, 2H, H-20, H-22), 3.86 (s, 3H, 3 Â H-25). 51V NMR
2.4.1 [VVO(L1)(hq)] (5). To a methanolic solution (20 mL) of (400 MHz, 293 K, d/ppm): À468.91. ESI-MS (positive) in CH3CN:
[VIVO(aa)2] (0.265 g, 1.00 mmol) was added a warm methanolic 509.19 (M + H+; 509.41), 531.18 (M + Na+; 531.41).
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2.4.4 [VVO(L4)(hq)] (8). This compound was prepared fol- 51V NMR spectra of the complexes in CDCl3 were recorded at
lowing an identical method to that described for compound 5 293 K using a Bruker AM 300L 400 MHz superconducting FT
using the ligand H2L4 instead of H2L1. Yield: 0.46 g (89%). Anal. NMR spectrophotometer. The 51V NMR spectra were referenced
calcd for C24H18ClN4O4V: C, 56.25%; H, 3.51%; N, 10.94%. to VOCl3 (0 ppm) as an external reference. The UV-vis spectra
Found: C, 56.10%; H, 3.39%; N, 10.87%. FT-IR bands (KBr were recorded on a Shimadzu UV-1700 spectrophotometer.
pellet, cmÀ1): 3445 (N–H), 1616, 1590 (CQNazomethine), 1375 Electrochemical measurements were performed at 298 K in CH2Cl2
(C–Ophenolic), 1256 (C–Oenolic), 1024 (N–N), 975 (VRO). UV-Vis solution for ca. 1 Â 10À3 mol dmÀ3 using tetrabutylammonium
(CH2Cl2) [lmax, nm (e, MÀ1 cmÀ1)]: 550 (6420), 332 (16 220). hexafluorophosphate (TBAHP) as supporting electrolyte under
1H NMR (400 MHz, CDCl3, 298 K, d/ppm, J/Hz): 6.60 (d, 1H, H-3, a dry N2 atmosphere on a BASi Epsilon-EC electroanalytical
J = 8.0), 7.39 (dd, 1H, H-4, J = 8.0, 1.2), 7.77 (d, 1H, H-6, J = 1.2), instrument. A BASi platinum working electrode, a platinum
7.27–7.29 (m, 1H, H-11), 7.66 (t, 1H, H-12, J = 8.0), 6.47 (t, 1H, auxiliary electrode and a Ag/AgCl electrode were used for
H-13, J = 8.0), 7.48–7.52 (m, 2H, H-14, H-20), 2.94 (s, 3H, 3 Â measurements. The redox potential data are referenced to a
H-15), 7.94 (d, 1H, H-16, J = 4.0), 7.23 (d, 1H, H-17, J = 8.0), 8.15 ferricenium/ferrocene, Fc+/Fc, couple.
(d, 1H, H-18, J = 8.0), 7.10 (dt, 1H, H-21, J = 8.0, 1.2), 6.87 (d,
1H, H-22, J = 8.0). 51V NMR (400 MHz, 293 K, d/ppm): À475.11.
2.6 Crystallographic data collection and refinement
ESI-MS (positive) in CH3CN: 512.89 (M+; 512.81), 535.85 X-ray quality single crystals of three complexes, namely, 2, 5
(M + Na+; 535.81), 551.82 (M + K+; 551.81).
and 8, were obtained by the slow evaporation of the
solvent CH3OH of the respective reaction mixture at room
temperature. X-ray data were measured with MoKa radiation
2.5 Physical measurements
Elemental analyses were performed on a PerkinElmer 2400 (l = 0.71069 Å) at 100(2) K for 2 and 8 and at 150(2) K for 5 using
CHN analyzer. IR spectra (as KBr pellets) were recorded on a an Oxford Diffraction X-Calibur CCD system. Data reduction for
Shimadzu FT-IR spectrophotometer, IR Affinity-1. Magnetic these three complexes 2, 5 and 8 were carried out with
susceptibilities were measured at 298 K using a PAR model the CrysAlis program.21 Structures were solved using direct
155 vibrating sample magnetometer fitted with a Walker Scien- methods with the Shelxs97 program.22 The non-hydrogen
tific L75 FBAL magnet using Hg[Co(SCN)4] as the calibrant. atoms were refined with anisotropic thermal parameters. The
Diamagnetic corrections were made using Pascal’s constants hydrogen atoms bonded to carbon were included in geometric
to obtain wcMorr and the resulting meff value was reported. The positions, and given thermal parameters equivalent to 1.2 times
ESI-MS spectra in positive ion mode were measured on a those of the atom to which they were attached, while those
Micromass QTOF YA 263 mass spectrometer. The X-band EPR bonded to nitrogen were located in difference Fourier maps
spectra of complexes 1–4 were recorded on a Magnettech GmbH and refined with distance constraints. Absorption corrections
MiniScope MS400 spectrometer (equipped with temperature were carried out using the ABSPACK program23 and structures
controller TC H03), where the microwave frequency was mea- were refined on F2 using the Shelxl16/6 program.24 Crystal-
sured with an FC400 frequency counter. Tetracyanoethene (tcne) lographic data are collected in Table 1. CCDC 1887600–1887602
(g = 2.0027) was used to calibrate the EPR spectra. The EPR contain the crystallographic data for complexes 2, 5 and 8
1
spectra were simulated using Easy Spin20 software. The H and respectively.†
Table 1 Summary of X-ray crystallographic data for complexes 2, 5 and 8
2
5
8
Empirical formula
Formula weight
C28H23N5O3V
528.45
C24H19N4O4V
478.37
C24H18ClN4O4V
512.81
Crystal colour
Crystal system
Temperature/K
Space group
Red
Triclinic
100(2)
Black
Black
Monoclinic
100(2)
Triclinic
150(2)
%
P1
P1
P21/n
a/Å
b/Å
c/Å
a/1
b/1
g/1
10.2716(10)
10.6456(9)
12.1344(9)
81.817(7)
70.266(8)
82.082(7)
1230.48(18)
2
7.8475(6)
10.8678(9)
14.0113(12)
68.768(8)
77.151(7)
72.756(7)
1054.86(16)
2
12.6574(4)
7.6841(2)
22.0915(7)
(90)
91.060(3)
(90)
2148.27(11)
4
1.586
V/Å3
Z
r
calc/g cmÀ3
1.426
0.444
1.506
0.511
m/mmÀ1
0.628
F(000)
546
5834/3/673
0.971
0.0621, 0.1198
0.0856, 0.1349
0.368, À0.378
492
4712/3/305
1.012
0.0441, 0.0985
0.0559, 0.1041
0.782, À0.395
1048
3795/0/309
1.091
0.0354, 0.0920
0.0411, 0.0967
0.348, À0.385
Data/restraints/parameters
Goodness-of-fit on F2
R indices, [I 4 2s(I)] R1, wR2
R indices (all data): R1, wR2
Residual electron density (e ÅÀ3
)
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2.7 DFT calculations
DAPI solution was aspirated, cells were washed three times with
1Â PBS, mounted with mounting medium, which held cover
slips in place and examined by fluorescence microscopy using a
Leica DM IL LED microscope at a 40Â objective.
The geometries of compounds 1–8 were optimized in the gas
phase with the Gaussian 09 (revision B. 01) software25 using the
6-31+G(d,p) basis set26 and the B3LYP functional27 for non-
metallic atoms and the LANL2DZ28 effective core potential for
vanadium. Starting models were obtained from the crystal
structures where possible or derived from them. TD-DFT calcu-
lations were also done using these basis sets.
2.10 Method for molecular docking studies
The DFT optimized structures of complexes 1–8 were used in
docking. The coordinates of the Bcl-2 protein (PDB: 4LVT) were
obtained from the Protein Data Bank for docking studies.
Molecular docking studies for these complexes were carried
out using AutoDock 4.2.33 In these studies, the conformations
of the complexes were allowed to change but that of the Bcl-2
protein was fixed. The data obtained from docking were examined
with the PyMOL (http://pymol.sourceforget.net/) software.34
Discovery Studio 4.1 Client and Chimera 1.10.1rc were used
for visualization effects.
2.8 Cytotoxicity assays
The cytotoxicities of these complexes were determined using a
PromegaCellTiter 96s AQueous One Solution Cell Proliferation
Assay kit (Cat # G3580) containing a tetrazolium complex
following the manufacturer’s instructions. Briefly, 10 000 HARA
cells (human squamous cell lung carcinoma cell line), kindly
provided by Dr Haruo Iguchi,29 Clinical Research Institute,
National Hospital Organization Shikoku Cancer Center, 2.11 Method for antimicrobial activity
Matsuyama, Japan, were plated in 100 mL RPMI growth medium
Staphylococcus aureus MTCC Code 96, Bacillus subtilis MTCC
(supplemented with 10% fetal bovine serum and penicillin–
streptomycin) per well in 96 well plates. After overnight incuba-
tion at 37 1C in a CO2 incubator with 5% CO2, the complexes
were added to cells at various concentrations with 200 mL serum-
free growth medium per well. Each concentration was used in
duplicate wells. All the complexes were dissolved in 100% DMSO
and diluted in the growth media to provide various concentra-
tions. After 72 h incubation, the medium was carefully aspirated
from the wells and 100 mL serum-free colourless growth medium
was added to each well. Then, 20 mL of CellTiter 96 AQueous One
Solution Reagent was added into each well of the 96-well assay
plate. After 1 hour incubation at 37 1C in a CO2 incubator, the
amount of soluble formazan was determined by absorbance at
450 nm. As NADPH or NADH, produced by dehydrogenase
enzymes in metabolically active cells, reduces an MTS tetrazo-
lium compound to a coloured formazan product that is soluble
in tissue culture medium,30,31 the amount of formazan produced
is directly proportional to the number of living cells in culture.
Viability is measured by the number of viable cells (percent
of untreated control cells) for each concentration, expressed as
the percent of viable cells in untreated control wells, which
was arbitrarily assigned 100% viability, and represented as the
Code 736, Salmonella typhimurium MTCC Code 98 and Escherichia
coli MTCC Code 68 were obtained from MTCC, Institute of
Microbial Technology, Chandigarh, India. Antibacterial effects
were assessed by microdilution methods.35 Briefly, the four
investigating bacteria were cultured overnight in nutrient broth
and the cell densities were estimated at 1 Â 105 CFUs mlÀ1
separately. Reactions were performed in a 96 well plate con-
sisting of standard commercially available nutrient broth (NB)
which was obtained from HIMEDIA (200 mL), inoculum (20 mL)
and different dilutions of test samples. Following 24 h incuba-
tion at 37 1C, 40 mL (0.2 mg mlÀ1) iodonitrotetrazolium chloride
(INT) was added to each well and incubated for another 30 min.
Each set was done in triplicate. IC50, the concentration at which
50% growth of bacteria is inhibited in comparison with positive
control, was calculated from the calibration curve prepared
using percentages of inhibition against concentrations in mM.
Streptomycin was used as a standard drug.
3. Results and discussion
3.1 Synthesis
standard error of the mean (SEM) of the triplicate wells for each The mixed-ligand oxidovanadium(IV) complexes [VIVO(L1–4)(phen)]
concentration used in this assay.
(1–4) and oxidovanadium(V) complexes [VVO(L1–4)(hq)] (5–8) incor-
porating 1,10-phenanthroline (phen) and 8-hydroxyquinoline
(Hhq), respectively, as auxiliary ligands have been prepared by
the reaction of [VIVO(aa)2] with equimolar amounts of the respec-
2.9 Method of nuclear staining for apoptosis assay
We used a microscopic method to detect apoptotic nuclei using
a nucleic acid staining dye, 4,6-diamidino-2-phenylindole (DAPI).
We followed the procedure as described by Dash et al.,32 in
which HARA cells were plated on glass chamber slides (Lab-TekII
Chamber slides, Nunc) and then grown for 24 hours before
being treated with these complexes or left untreated (non-
apoptotic control). After 48 hours of treatment, cells were fixed
with 3.7% formaldehyde for 15 minutes. Subsequently, they were
washed three times with 1Â phosphate buffered saline (PBS),
permeabilized with 0.1% Triton X-100 and stained with 1 mg mlÀ1
DAPI (prepared in 1Â PBS) for 5 minutes at 37 1C. After the
tive H2L (where H2L represents the general abbreviation of H2L1–4
)
followed by addition of equivalent amounts of the respective
auxiliary ligands in methanol under aerobic conditions. The aerial
dioxygen most likely acts as an oxidizing agent for the formation
of the +V state of vanadium in complexes 5–8. The formation
reactions may be represented by the following eqn (1) and (2):
[VIVO(aa)2] + H2L + phen - [VIVO(L)(phen)] + 2Haa
(1)
2[VIVO(aa)2] + 2H2L + 2Hhq + 1/2O2 - 2[VVO(L)(hq)]
+ 4Haa + H2O
(2)
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Table 2 Selected bond lengths (Å) and bond angles (1) in complex 2
3.2 Description of the crystal structures
3.2.1 Description of the structure of 2. Crystals of complex 2
belong to the triclinic crystal system, in the non-centro-
symmetric space group P1, in which the asymmetric unit
consists of two molecules (Fig. S1, ESI†), called A and B, which
have similar geometries and closely matching dimensions. For
clarity, only molecule A is shown in Fig. 1. Each molecule is
composed of a central vanadium ion in a distorted octahedral
environment surrounded by one tridentate dinegative hydra-
zone ligand bound in a meridional manner (mer-ONO donor
set in the enol form), one symmetrical bidentate neutral 1,10-
phenanthroline (phen; N,N donor set) spanning equatorial and
axial positions along with an oxido ion at the other axial
position, indicating the +IV oxidation state of vanadium (also
confirmed by magnetic susceptibility measurements and EPR
spectral analysis, vide infra). Selected bond lengths and bond
angles in the metal coordination spheres of A and B molecules
are compared in Table 2. There are also two other potential
donor sites in the coordinated hydrazone ligand, viz., amine-N3
and the other imine-N2 which are not coordinated due to non-
planarity with the former three donor sites. However, in both
molecules, the two hydrogen atoms of amine-N3 form donor
hydrogen bonds, intermolecular to N2 and intramolecular to
O1 with the dimensions listed in Table 3. In the distorted
octahedral environment around the metal, one phenolic-O, O1,
one amide-O, O2 (in the enol form), and one imine-N, N1, of the
doubly deprotonated meridionally disposed (L2)2À ligand along
with one of the two pyridine nitrogens N5 of the phen ligand
constitute the equatorial plane with r.m.s. deviations of 0.007
and 0.002 Å from which the vanadium atom is displaced by
0.384(4) and 0.388(3) Å towards the axial terminal O3 in mole-
cules A and B respectively. The second axial position is occupied
by the other pyridine nitrogen N4 of phen, thus binding this
symmetrical ligand to metal asymmetrically. This hydrazone
Complex
2A
2B
Bond lengths, Å
V–O1
V–O2
V–O3
V–N1
V–N4
V–N5
1.942(6)
1.971(6)
1.606(7)
2.067(8)
2.251(8)
2.118(7)
1.947(6)
1.991(6)
1.607(6)
2.070(7)
2.322(8)
2.136(7)
Bond angles, deg
O3–V–O2
O3–V–O1
O3–V–N4
O3–V–N5
O3–V–N1
O2–V–N4
O2–V–N5
O2–V–N1
O1–V–O2
O1–V–N4
O1–V–N5
O1–V–N1
N5–V–N4
N1–V–N4
N1–V–N5
102.4(3)
101.0(3)
167.2(3)
94.1(3)
107.5(3)
79.5(3)
90.0(3)
78.2(3)
154.9(3)
79.8(2)
97.3(3)
86.2(3)
73.1(3)
85.3(3)
157.0(3)
101.0(3)
102.9(3)
168.1(3)
94.8(3)
106.3(3)
79.2(3)
92.2(3)
78.1(3)
154.2(2)
79.5(3)
95.4(3)
85.9(3)
73.3(3)
85.5(3)
158.1(3)
ligand generates a six-membered ring and a five-membered
chelate ring at the vanadium center, with the corresponding
bite angles being 86.2(3)1 and 78.2(3)1 for A and 85.9(3)1 and
78.1(3)1 for B respectively. The atoms in the five-membered ring
are closely coplanar with r.m.s. deviations of 0.010 and 0.013 Å,
respectively, for A and B, while the six-membered ring is folded.
The C–O, C–N and N–N bond lengths in the five-membered
chelate ring are consistent with the enolate form of the amide.
The atoms in the third chelate ring, [V1–N4–C27–C28–N5],
formed by phen are also approximately coplanar (with r.m.s.
deviations of 0.027 and 0.009 Å) with bite angles of 73.1(3)1 and
73.3(3)1, respectively, and this plane is almost perpendicular to
the equatorial plane intersecting at angles 88.9(2)1 and 89.7(2)1
respectively. The shortest and longest bonds formed by the metal
atom are the two axial bonds formed by the terminal oxido group
VRO3 and the axial-N (V–N4), with the latter being lengthened
due to the trans influence of the oxido atom. It is to be noted
that such type of asymmetric binding of the phen ligand is
also observed with other ONO donor ligand environments.36 The
three vanadium–oxygen bond lengths in the complex follow
the order: oxido o phenolato o amide, which is probably due
to the order of O - V p-bonding.
3.2.2 Description of the structures of 5 and 8. Crystals of
%
complex 5 belong to the triclinic system with space group P1,
while complex 8 belongs to the monoclinic crystal system with
the P21/n space group. The molecular structures of 5 and 8 are
displayed in Fig. 2 and 3 respectively.
Like complex 2, complexes 5 and 8 also consist of a neutral
unit composed of a central vanadium ion in a distorted
octahedral environment surrounded by one tridentate dinega-
tive hydrazone ligand bound in a meridional manner (mer-ONO
donor set in the enol form), one bidentate mononegative
8-hydroxyquinoline (hqÀ; OÀ,N donor set, in contrast to 2,
Fig. 1 Molecular structure of 2, molecule A, with ellipsoids at 30% prob-
ability. The structure of molecule B is equivalent. The intramolecular
hydrogen bond is shown as a dotted line.
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Table 3 Dimensions of hydrogen bonds (distances, Å, angles (deg)) in complex 2
D–HÁ Á ÁA
d(D–H)
d(HÁ Á ÁA)
d(DÁ Á ÁA)
+(DHA)
Symmetry element
N3A–HN3AÁ Á ÁN2A
N3A–HN3BÁ Á ÁO1B
N3B–HN3CÁ Á ÁO1A
N3B–HN3DÁ Á ÁN2B
0.86(2)
0.87(2)
0.86(2)
0.86(2)
1.99(5)
2.44(7)
2.12(3)
2.00(5)
2.684(10)
2.994(9)
2.952(10)
2.664(10)
136(6)
122(7)
164(7)
133(6)
1 + x, y À 1, z À 1
Table 4 Selected bond lengths (Å) and angles (1) in complexes 5 and 8
Complex
5
8
Bond lengths, Å
V–O1
V–O2
V–O3
V–O4
V–N1
V–N4
1.8212(16)
1.9316(15)
1.6015(16)
1.8508(14)
2.1077(17)
2.3235(18)
1.8281(17)
1.9338(16)
1.5896(16)
1.8536(15)
2.099(2)
2.383(2)
Bond angles, deg
O3–V–O1
O3–V–O4
O1–V–O4
O3–V–O2
O1–V–O2
O4–V–O2
O3–V–N1
O1–V–N1
O4–V–N1
O2–V–N1
O3–V–N4
O1–V–N4
O4–V–N4
O2–V–N4
N1–V–N4
99.69(8)
98.99(7)
103.88(7)
97.44(7)
155.29(7)
90.80(6)
100.83(7)
83.74(7)
157.23(7)
75.63(6)
174.86(8)
83.96(7)
76.53(6)
80.24(6)
83.11(6)
101.48(8)
98.40(7)
101.81(7)
98.64(8)
152.07(7)
94.14(7)
95.64(8)
83.15(7)
163.81(7)
75.75(7)
173.87(8)
80.51(7)
75.49(6)
81.51(7)
90.35(7)
Fig. 2 Molecular structure of 5 with ellipsoids at 30% probability. The
intramolecular hydrogen bond is shown as a dotted line.
(viz., the amine-N3 and the other imine-N2) which are non-
planar to the bonded three donor sites are not bonded to the
metal. However, in 5, N3 forms two donor hydrogen bonds; one
is intramolecular to N2 and the other is intermolecular to the
terminal oxygen O3(1 À x, 1 À y, Àz), thus forming a centro-
symmetric dimer. A similar arrangement is found in 8 with an
intramolecular hydrogen bond to N2 and an intermolecular
hydrogen bond to O3(2 À x, Ày, Àz). It will be noted that in 8,
unlike in 5, the same hydrogen atom is involved in both bonds,
with the second hydrogen not involved. The detailed dimen-
sions of these H-bonds are given in Table 5. In both structures,
the vanadium atom is bonded to four oxygen atoms and two
nitrogen atoms to form a distorted octahedral geometry. One
phenolate O1, one amide O2 (in the enol form) and the imine
nitrogen N1 of the doubly deprotonated meridionally disposed
(L)2À ligand along with the phenolic oxygen O4 of the deproto-
nated 8-hydroxyquinoline (hqÀ) constitute the equatorial plane
with r.m.s. deviations of 0.035 and 0.045 Å, from which the
vanadium atom is displaced by 0.307(1) and 0.288(1) Å towards
Fig. 3 Molecular structure of 8 with ellipsoids at 30% probability. The
intramolecular hydrogen bond is shown as a dotted line.
which contains a neutral bidentate N,N donor set) spanning the terminal O3 atom in the two structures respectively. The
equatorial and axial positions along with an oxido ion at the second axial position is occupied by the pyridine nitrogen N4 of
other axial position indicating the +V oxidation state (cf. the +IV hqÀ. These hydrazone ligands generate a six-membered ring
oxidation state in 2) of vanadium (also confirmed by magnetic and a five-membered chelate ring at the vanadium centre, with
susceptibility measurements, vide infra). Selected bond-lengths the corresponding bite angles being 75.63(6) and 75.76(7)1 in 5
and bond angles in the two metal coordination spheres are and 8 respectively. The atoms in the five-membered ring are
compared in Table 4. The remaining two potential donor sites closely coplanar with r.m.s. deviations of 0.042 and 0.023 Å,
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indicating a 109–122 cmÀ1 shift to a higher wave number upon
complexation due to the diminished repulsion between the lone
pairs of adjacent nitrogen atoms. A sharp band observed in the
3085–3445 cmÀ1 region is likely to be associated with the
intramolecularly H-bonded phenolic O–H group.
Table 5 Dimensions of hydrogen bonds (distances, Å; angles (deg)) in 5
and 8
D–HÁ Á ÁA
d(D–H) d(HÁ Á ÁA) d(DÁ Á ÁA) +(DHA) Symmetry element
5
N3–H3AÁ Á ÁO3 0.84(2) 2.20(2) 3.019(2) 165(2) 1 À x, 1 À y, Àz
N3–H3BÁ Á ÁN2 0.86(2) 2.09(2) 2.702(3) 128(2)
8
3.4 UV-Visible spectra of the complexes
N3–HN3BÁ Á ÁN2 0.83(2) 2.12(2) 2.725(3) 130(2)
Electronic spectra of complexes 1–8 were recorded in CH2Cl2
solution. The tetravalent complexes 1–4 display two ligand-field
transitions in the near IR-visible region: one near 840–864 nm
and other around the 720–774 nm region (Table 6) due to the
dxy - dxz,yz and dxy - dx2Ày2 transitions respectively.3b The
expected third transition due to the dxy - dz2 transition is
probably masked by the strong charge transfer band at higher
energies. The strong absorption at around 406–418 nm may be
due to the charge transfer of the type O(phenolic) - V4+. The
intra-ligand p - p* transition (of the CQN bond) is observed
near 320 nm (Fig. S2, ESI†). Complexes 5–8 display two intense
transitions in the 300–800 nm region: one in the 536–550 nm
region (Fig. S3, ESI†) and the other in the 329–332 nm region.
These transitions arise due to the ligand to metal charge transfer
(LMCT) transitions and the intra-ligand p - p* transition (of the
CQN bond) respectively. The LMCT transitions are expected as
they are observed in similar types of complexes.11
N3–HN3BÁ Á ÁO3 0.83(2) 2.47(2) 2.941(3) 117(2) 2 À x, Ày, Àz
respectively, while the six-membered ring is folded. The C–O,
C–N, and N–N bond lengths of the five-membered chelate ring
are consistent with the enolate form of the amide. The atoms in
the third chelate ring formed by the hqÀ are also approximately
coplanar (with r.m.s. deviations of 0.043 and 0.021 Å) with bite
angles of 76.53(6) and 75.49(6)1, respectively, and this plane is
almost perpendicular to the equatorial plane intersecting at
angles of 86.05(5) and 88.22(4)1 in 5 and 8 respectively. As in
complex 2, the shortest and longest bonds are formed by
the two axial atoms the terminal oxido group [i.e., VRO3]
and V–N4, which is lengthened due to the trans influence of the
oxido atom. The VRO3 (oxido), V–O1 (phenolato) and V–O2
(amido/enolato) bond lengths are well within the range
reported for VO3+ complexes, with carbonic acid hydrazide
ligands and hqÀ co-ligands.11a,f,g,j,k As a consequence of O - V
p-bonding, these four vanadium–oxygen bond lengths in the
complexes are in the order: oxido o phenolato o amide.
However, as expected, the two phenolate bonds, namely, V–O1
[1.8212(16) in 5; 1.8281(17) in 8] and V-O4 [1.8508(14) in 5;
1.8536(15) in 8], are not similar.
For complexes 5–8, the lmax values for the LMCT transitions
exhibited a linear relationship (eqn (3)) (Fig. 4) with the Hammett
parameter (s) value of the substituents with an r value of 1.00.
3.3 IR spectra of the complexes
The characteristic ligand bands in the regions 1628–1668,
2918–3059 and 3444–3477 cmÀ1 due to CQO, N–H and O–H
stretches, respectively, are not observed in their corresponding
vanadium complexes, indicating the transformation of the
CQO and N–H groups to the enolic form and their subsequent
coordination to vanadium through the deprotonation of
the phenolic and enolic hydrogens. A new band appearing in
the 1244–1262 cmÀ1 region in the complexes was assigned to the
C–O (enolate) mode. The strong band near 1565–1597 cmÀ1 is
attributed to the CQN bond, while the VRO stretching bands
are observed in the 954–968 cmÀ1 region, indicating a hexa-
coordinated environment around the metal centre.11,15–17 The
N–N band was observed in the 1013–1044 cmÀ1 region,
Fig. 4 Plot of lmax versus the Hammett constant (s) for complexes 5–8.
Table 6 Electronic spectral and electrochemical data at 298 K of complexes 1–8 in CH2Cl2 solution
Complex
l
max, nm (e, dm3 MÀ1 cmÀ1
)
E1/2 (V) (DE) (mV)
[VIVO(L1)(phen)] (1)
[VIVO(L2)(phen)] (2)
[VIVO(L3)(phen)] (3)
[VIVO(L4)(phen)] (4)
[VVO(L1)(hq)] (5)
[VVO(L2)(hq)] (6)
[VVO(L3)(hq)] (7)
[VVO(L4)(hq)] (8)
851 (40), 755 (40), 410 (12 380), 321 (12 230)
842 (30), 774 (30), 409 (13 630), 322 (15 720)
840 (30), 724 (30), 406 (8530), 322 (16 670)
864 (40), 720 (30), 418 (17 510), 324 (16 920)
545 (4320), 329 (9490)
540 (8940), 330 (20 820)
536 (11 140), 329 (30 830)
0.65 (330)
0.62 (360)
0.59 (500)
0.71 (220)
À0.16 (120)
À0.18 (120)
À0.19 (184)
À0.14 (250)
550 (6420), 332 (16 200)
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The relationship indicates that the dependence of the lmax
value on the substituent is 27.55 nm.
UV-vis: lmax (nm) = 544.19 + 27.55 Â s
(3)
3.5 Electrochemical properties of the complexes
The electrochemical properties of complexes 1–8 were examined
in CH2Cl2 solution (0.1 M TBAHP) by cyclic voltammetry using a
Pt working electrode, a Pt auxiliary electrode and a Ag/AgCl
reference electrode and are listed in Table 6. The tetravalent
complexes 1–4 exhibit quasi-reversible one electron oxidation
peaks in the 0.59 to 0.71 V region, while the pentavalent
complexes 5–8 display quasi-reversible one-electron reduction
peaks in the À0.14 to À0.19 V region. Representative spectra of
complexes 1 and 8 are displayed in Fig. 5 and 6 respectively.
Analysis of the E1/2 values of these two set of complexes indicates
that they decrease with the increasing electron donating property
of para substituents and the reverse is true for electron with-
drawing substituents. Plots of the E1/2 values of complexes 1–4
and 5–8 versus the s values of the respective substituents give
the following linear relationships (eqn (4) and (5) respectively,
Fig. 7 and 8) with an r value of 1.0.
Fig. 7 Plot of E1/2 versus the Hammett constant (s) for complexes 1–4.
Fig. 8 Plot of E1/2 versus the Hammett constant (s) for complexes 5–8.
CV: E1/2 (V) = 0.654 + 0.23 Â s
CV: E1/2 (V) = À0.162 + 0.10 Â s
(4)
(5)
3.6 1H NMR spectra of the ligands and complexes 5–8
Fig. 5 Cyclic voltammogram of complex 1 in CH2Cl2 solution.
1
The H NMR spectra of the ligands were recorded in DMSO-d6
solvent, while those of complexes 5–8 were recorded in CDCl3
solvent. The data are given in the Experimental section. The
phenolic O–H group of the acetophenone moiety of the free
hydrazone ligand exhibits resonance in the d 12.63–13.23 ppm
region. However, this signal is not observed in complexes 5–8,
suggesting that the phenolic OH group of the acetophenone
moiety is involved in bonding to vanadium through deprotona-
tion. All the aromatic protons of the complexes are observed in
the d 6.59–8.15 ppm region.
3.7 51V NMR spectra of complexes 5–8
Like the 1H NMR spectra, the 51V NMR spectra of the pentavalent
complexes 5–8 (recorded in CDCl3 solution at room temperature)
may also be used to examine the stability of these pentavalent
complexes in solution. The 51V NMR spectra of these complexes
are displayed in Fig. S4 (ESI†). One sharp signal is obtained in
Fig. 6 Cyclic voltammogram of complex 8 in CH2Cl2 solution.
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each of the four complexes 5–8, respectively, at À480.32,
À475.76, À468.91 and À475.11 ppm, suggesting that these
complexes are stable in solution.
3.8 Magnetic properties of the complexes
The magnetic susceptibilities of all the complexes were mea-
sured at room temperature. The data indicate that complexes
1–4 are paramagnetic [the effective magnetic moments (meff
)
values are B1.70 mB, Table 7], while the other complexes 5–8 are
diamagnetic, suggesting the +IV (in 1–4) and +V (in 5–8)
oxidation states of vanadium. The meff values for complexes 1–4
are typical for one unpaired electron per formula unit, suggesting
that these complexes are monomeric with very weak or no anti-
ferromagnetic interactions between the V atoms of the neigh-
bouring molecules.
3.9 EPR spectra of complexes 1–4
The X-band EPR spectra of the tetravalent complexes 1–4 were
recorded in CH2Cl2 solution at 300 K and 77 K. The data are
listed in Table 7 and a representative spectrum for 2 is shown in
Fig. 9 and those for 1, 3 and 4 are shown in Fig. S5–S7 (ESI†). At
300 K, a typical eight-line spectral pattern (Fig. 9a) is obtained
with giso B 2.00 and Aiso B 95 Â 10À4 cmÀ1, and at 77 K, a well-
resolved axial anisotropy with an 8-line hyperfine structure
(Fig. 9b), characteristic of a mononuclear vanadium complex
with nuclear spin (51V, I = 7/2), is obtained. The spin-
Hamiltonian parameters (g8, g>, A8 and A>) are comparable
with similar types of V(IV) complexes having identical geome-
trical structures. The g8 o g> and A8 c A> relationships are
characteristic of an axially compressed d1xy configuration.11,15,37
Fig. 9 X-band EPR spectra of complex 2 (black, experimental; red,
simulated) in CH2Cl2 solution at (a) 300 K and (b) 77 K.
3.10 Computational study
The DFT optimized geometrical parameters of complexes 2, 5
and 8 (Tables S1 and S2, ESI†) are in reasonable agreement with
the values obtained from X-ray crystallographic data (Tables 2
and 4) and the DFT optimized structures of all the complexes
are shown in Fig. 10. The MOs of selected frontier orbitals of
the complexes in their ground state optimized geometries are
shown in Fig. S8 (ESI†). The vertical excitation energies and
oscillator strengths (f) of excited states obtained from TD-DFT
calculations are given in Table 8. A comparison of the calcu-
lated data in Table 8 with the experimental data in Table 6
indicates that for the tetravalent complexes 1–4, with the
exception of the transition near 850 nm, all the other three
observed transitions are predicted theoretically, while for the
pentavalent complexes 5–8, the observed two transitions are
predicted by DFT calculations.
3.11 Study of cytotoxic activity of 1–8 complexes on lung
cancer cell line
We tested the cytotoxic activity of these vanadium complexes on
a lung cancer cell line (HARA cells) using cisplatin as a positive
control. We chose the HARA cell line to test cytotoxicity because
it is sensitive to metal complexes such as cisplatin and carbo-
platin which are used for the treatment of lung cancer. In this
cytotoxicity assay, different complexes show a wide range of
toxicities in a dose dependent manner (Fig. 11 and Table S3,
ESI†). For example, in the series of mixed-ligand oxidovanadium(IV)
complexes 1–4, the IC50 values of complexes 2, 3 and 4 are around
2.5 mM similar to that found for cisplatin, while that for complex 1
is 7.5 mM. In the case of mixed-ligand oxidovanadium(V) complexes
5–8, the IC50 values of complexes 5, 6 and 8 are ca. 12.5, 5 and 5 mM,
Table 7
m
eff values at room temperature and EPR spectral parameters [g and A (Â10À4 cmÀ1)] of complexes 1–4 in CH2Cl2 solution at 300 K and 77 K
Complex
meff (BM)
giso
Aiso
Line width (mT)
g8
g>
gav
A8
A>
Aav
Line width (mT)
[VIVO(L1)(phen)] (1)
[VIVO(L2)(phen)] (2)
[VIVO(L3)(phen)] (3)
[VIVO(L4)(phen)] (4)
1.65
1.69
1.68
1.70
1.978
1.977
1.978
1.977
94.55
94.92
94.20
95.27
1.8
1.8
1.8
1.9
1.95
1.96
1.95
1.96
1.99
1.99
1.99
1.99
1.977
1.981
1.977
1.981
171.27
169.49
170.92
169.13
57.12
55.31
55.32
55.31
95.17
93.37
93.85
93.25
2.3
2.1
2.0
2.1
Limits of error in g values: Æ0.01 and in A values: Æ3 Â 104 cmÀ1
.
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Fig. 10 DFT optimized structures of complexes 1–8.
Table 8 Vertical excitation energies (Ecal), oscillator strengths (fcal) and
types of excitations of the excited states obtained from TD-DFT calcula-
tions of 1–8
Complex
Ecal/nm
fcal
Excitation
1
747.24
419.60
354.37
0.0006
0.1355
0.0131
HOMO - LUMO+2 (0.61233)
HOMOÀ2 - LUMO+2 (0.52862)
HOMOÀ2 - LUMO+3 (0.64620)
HOMOÀ3 - LUMO+2 (0.81462)
HOMOÀ1 - LUMO (0.65134)
HOMOÀ2 - LUMO+2 (0.53202)
HOMOÀ2 - LUMO+3 (0.64363)
HOMOÀ2 - LUMO+1 (0.89699)
HOMOÀ2 - LUMO+2 (0.49323)
HOMOÀ2 - LUMO+3 (0.62565)
HOMO - LUMO+1 (0.68691)
HOMO - LUMO+4 (0.46513)
HOMOÀ2 - LUMO+2 (0.42752)
HOMOÀ2 - LUMO+3 (0.67409)
HOMO - LUMO+1 (0.56039)
HOMOÀ1 - LUMO (0.49992)
HOMOÀ3 - LUMO (0.79485)
HOMOÀ2 - LUMO (0.66657)
HOMOÀ3 - LUMO+2 (0.44942)
HOMOÀ4 - LUMO (0.24404)
HOMOÀ2 - LUMO (0.64910)
HOMOÀ3 - LUMO+2 (0.36927)
HOMOÀ1 - LUMO+3 (0.41043)
HOMOÀ3 - LUMO (0.50831)
HOMOÀ2 - LUMO (0.46231)
HOMOÀ2 - LUMO+4 (0.63490)
HOMOÀ2 - LUMO (0.68313)
HOMOÀ8 - LUMO (0.45235)
HOMOÀ7 - LUMO (0.42766)
2
3
4
750.18
427.12
358.36
0.0007
0.0847
0.0155
749.85
469.07
364.62
0.0007
0.0723
0.0149
744.83
436.78
363.88
0.0007
0.1820
0.0123
5
6
510.37
341.46
510.42
0.2442
0.0934
0.2290
346.65
517.21
0.0677
0.1161
7
8
Fig. 11 Cytotoxic activity of complexes 1–8 and comparison with
cisplatin.
327.78
513.5
336.35
0.0423
0.2568
0.0423
the tetravalent complexes 1–4. We also investigated the mecha-
nism of cytotoxicity of these complexes using complexes 1 and 5
respectively, while for complex 7 the value is 25 mM. It is as representative samples (Fig. 12). We used nuclear staining of
noteworthy that the free H2L1–4 ligands and [VIVO(aa)2] show treated and untreated cells using DAPI, a DNA binding dye.
practically no toxicity (Fig. S9 and S10 respectively, ESI†), Cells treated with complexes 1 and 5 show distinct chromatin
while the phen (IC50 B 50 mM) and Hhq (IC50 B 100 mM) condensation and fragmentation, a distinct characteristic of
ligands exhibit appreciably low toxicity (Fig. S11, ESI†) than all apoptosis. Fig. 12 shows the experimental proof of cell death
the complexes described here. It is to be noted that these treated with these complexes through apoptosis. Although
complexes are stable under the experimental conditions as complexes 1–4 belong to the same class of mixed-ligand
suggested by the spectral studies. It is noteworthy that in oxidovanadium(IV) complexes, complexes 2–4 are potentially
general these pentavalent complexes 5–8 are less toxic than more toxic than complex 1. Similarly, complexes 5–8 also
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effective as cisplatin in killing human lung cancer cells and
may be potential therapeutic candidates for the treatment of
lung cancer.
3.12 Docking study
Simultaneous over-expression and under-expression of, respec-
tively, anti-apoptotic and pro-apoptotic genes is the cause of
cancer. The Bcl-2 protein is a result of expression of the anti-
apoptotic gene.38 Therefore, a high concentration of the Bcl-2
protein in cells decreases the levels of Bax and Bak proteins due
to complex formation. This Bax protein is very important to
cell apoptosis through the settlement of integrity of the
external surfaces of mitochondria, which liberates pro-apoptotic
signalling factors that can initiate the activation of caspase-9 and
caspase-3 genes. So, blocking of the Bax binding site (BH3)
[Fig. 13(a)] of the Bcl-2 protein by some small molecules frees
Bax for apoptosis.
Fig. 12 Experimental proof of lung cancer cell death treated with com-
plexes 1 and 5.
Molecular docking is a very important theoretical study used
to find the binding site of a protein where a small molecule
prefers to bind with the lowest energy.39 To understand the
belong to the same class of mixed-ligand oxidovanadium(V) mechanism of anti-lung cancer activity on HARA cells of the
complexes, but complexes 5, 6 and 8 show potent toxicity, vanadium complexes, a docking study of all the vanadium
whereas complex 7 shows almost no toxicity in the concen- complexes 1–8 with the Bcl-2 protein (PDB: 4LVT) has been done.
tration range used in this experiment. It is evident from this The docking study shows that all the oxidovanadium(IV) complexes,
study that some of the complexes have the ability to kill lung namely [VIVO(L1–4)(phen)] (1–4), show greater activity than the
cancer cells effectively, and in fact, complexes 2–4 are equally oxidovanadium(V) complexes, namely [VVO(L1–4)(hq)] (5–8) as
Fig. 13 (a) BH3 binding site of Bcl-2 protein, (b) binding site of compound 3, (c) mode of interactions and amino acids of Bcl-2 interacting with 3,
(d) binding site of compound 6, (e) mode of interactions of 6 with amino acids of Bcl-2, and (f) overlay of all the structures of complexes 1–8 inside
the BH3 site.
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shown in Table S3 (ESI†). In the docking study, compounds 3
and 6 were found to be best in their corresponding class in
agreement with the experimental anticancer study. Compounds
2 and 4 also exhibit comparable binding energy with compound
3 and we found that complex 8 has a similar binding energy
with the Bcl2 protein to complex 6 (Table S3 and Fig. S11c–e,
ESI†). In fact, it is clear from Table S3 (ESI†) that the binding
energies of the complexes with the Bcl-2 protein follow the
experimental cytotoxicity order and the tetravalent complexes
2–4 are somewhat more toxic than the pentavalent complexes
5–8. Two different pockets of the hydrophobic core of BH3 are
the favoured binding sites of both the compounds [Fig. 13(b)
and (d)]. Amino acid residues Tyr108, Phe112, Met115, Gln118,
Leu119, Arg129, Val133, Leu137, and Ala194 are found in the
vicinity of the bound compound 3, whereas Arg146, Val148,
Phe198, Ala100, Phe104, Arg107, and Tyr108 residues are pre-
sent in the binding pocket for compound 8 [Fig. 13(c) and (e)].
Several non-covalent interactions including van der Waals
interactions, hydrogen bonding, carbon hydrogen bonding,
p-donor hydrogen bonding, p-sulphur, p–p staking, p–p T
shaped and p-alkyl interactions are the binding forces for 3
[Fig. 13(c) and Fig. S12(a), ESI†]. However, van der Waals, p–p T
shaped, p-alkyl and hydrophobic interactions play important
roles for the binding of 6 [Fig. 13(e) and Fig. S12(b), ESI†]. It is
interesting to note that all of these compounds prefer to bind at
the BH3 binding site [Fig. 13(f)]. Therefore, these compounds
effectively generate the signal of death and may initiate apop-
tosis by inhibiting the Bcl-2 from binding with Bax.
Fig. 14 Antimicrobial activity of complexes 1–4 and comparison with
streptomycin.
Fig. 15 Antimicrobial activity of complexes 5–8 and comparison with
streptomycin.
3.13 Antimicrobial activity study
activity (Fig. 14 and 15). The concentration of the stock solutions
In this study, the synthesized complexes 1–8 along with the for all the complexes was 1 mM in 100% dimethyl sulfoxide
reference compound (streptomycin) and the ligands used in (DMSO). Besides this, the dose–response curves for the anti-
this study, namely, H2L1–4, phen and Hhq, were tested microbial activity of complexes 2 and 5 are shown in Fig. S12 and
for in vitro antibacterial activity40–43 against four pathogenic S13 (ESI†) respectively. For Gram negative Escherichia coli, the
bacterial strains (Gram negative Escherichia coli, Gram positive antibacterial activity follows the order: 2 4 4 4 3 4 1, whereas
Bacillus subtilis, Gram positive Staphylococcus aureus and Gram for Gram positive Staphylococcus aureus and Gram negative
negative Salmonella typhimurium) by the microdilution method. Salmonella typhimurium, the antibacterial activity follows the
The results listed in Table 9 show that almost all the test order: 2 4 3 4 4 41. For Gram positive Bacillus subtilis, the
compounds (except for 3 for Bacillus subtilis and 8 for Gram antibacterial activity follows the order: 2 4 4 4 1, with 3 being
negative Escherichia coli) showed good to excellent antibacterial inactive. Similarly, a scrutiny of the IC50 values indicates that
Table 9 IC50 values of complexes 1–8, streptomycin (a standard drug) and the phen and Hhq ligands against Escherichia coli, Bacillus subtilis,
Staphylococcus aureus and Salmonella typhimurium
IC50 (mM) Æ SD
Gram negative
Escherichia coli
Gram positive
Bacillus subtilis
Gram positive
Staphylococcus aureus
Gram negative
Salmonella typhimurium
Complex
1
2
3
4
5
6
7
8
44.74 Æ 1.49
15.18 Æ 1.56
30.33 Æ 0.49
27.37 Æ 1.43
94.14 Æ 1.07
52.84 Æ 1.78
60.03 Æ 0.57
—
53.5 Æ 1.04
16.09 Æ 0.87
—
60.31 Æ 1.09
25.7 Æ 0.76
32.17 Æ 1.05
53.83 Æ 1.21
82.63 Æ 0.65
31.5 Æ 1.08
83.66 Æ 1.14
52.73 Æ 0.48
10.81 Æ 0.164
55.00 Æ 1.17
62.50 Æ 1.02
39.88 Æ 0.67
11.2 Æ 0.82
28.49 Æ 0.49
33.39 Æ 1.01
34.51 Æ 0.79
23.37 Æ 0.68
41.33 Æ 1.07
31.25 Æ 0.91
8.75 Æ 0.02
31.93 Æ 0.49
16.67 Æ 1.65
20.32 Æ 1.08
54.13 Æ 0.98
34.17 Æ 1.10
9.62 Æ 0.009
63.88 Æ 2.04
78.50 Æ 1.69
Streptomycin
phen
Hhq
9.3 Æ 0.11
46.50 Æ 1.89
63.51 Æ 2.88
103.27 Æ 2.89
131.03 Æ 2.13
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complex 6 showed higher antimicrobial activity followed by 8, 5 Conflicts of interest
and 7 towards Gram positive Staphylococcus aureus and Gram
There are no conflicts to declare.
negative Salmonella typhimurium. For Gram negative Escherichia
coli, complex 8 is inactive, whereas 6 is the most active, and for
Gram positive Bacillus subtilis, the order is: 5 4 6 4 8 4 7. From
the IC50 values of these complexes it is clear that most anti-
Acknowledgements
We thank the University Grants Commission (New Delhi, India)
for financial assistance (F.PSW-172/09-10). We are thankful
to our College authority for providing research facilities. We
gratefully acknowledge DST-FIST for instrumental help at the
Ramakrishna Mission Vivekananda Centenary College, Rahara.
We also thank EPSRC and the University of Reading for funds
for the X-Calibur system. We are also grateful to Dr Ayan Datta,
Department of Spectroscopy, Indian Association for the Cultiva-
tion of Science, Jadavpur, Kolkata, India, for his support in DFT
calculation. We also thank Dr P. Ghosh, Ramakrishna Mission
Residential College, Narendrapur, Kolkata, India, for instrumental
help for electrochemical study. S. B. (PDF/2016/001935) is thank-
ful to SERB, India, for the fellowships.
microbial activity is found when the substituent at the para
position in the aromatic ring is methyl. Among the eight com-
plexes studied here, complex 2 exhibited excellent antibacterial
activity as indicated by its low IC50 values ranging between 11.2
and 25.7 mM [whereas the IC50 values for streptomycin (standard
drug) are 9.3 against Escherichia coli, 9.62 against Bacillus subtilis,
10.81 against Staphylococcus aureus and 8.75 against Salmonella
typhimurium]. It should be noted that the H2L1–4 ligands did not
exhibit any such antibacterial activity even at high concentra-
tions, whereas phen and Hhq displayed antibacterial activity
against the above-mentioned four pathogenic bacteria. However,
it is evident from the IC50 values (Table 9) that the phen and Hhq
ligands are significantly less toxic than most of our reported
complexes. It is also to be noted that DMSO did not affect the
bacterial growth.
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