[VIVO]2+ complexes: Structure, unusual magnetic properties and cytotoxic effect

Article abstract of DOI:10.1016/j.ica.2018.05.013

The present investigation was carried out with the aim of synthesizing and characterizing five vanadium coordination compounds (6–10) with different Schiff bases (1 = N,N′-bis(salicylidene)-o-phenylenediamine, 2 = N,N′-bis(4-hydroxysalicylidene)-o-phenyle

Full text of DOI:10.1016/j.ica.2018.05.013

InorganicaChimicaActa480(2018)197–206
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Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Research paper
[VIVO]2+ complexes: Structure, unusual magnetic properties and cytotoxic
effect
L. Joshua Hernández-Beníteza, Pamela Jiménez-Cruza, Karla E. Cureño-Hernándeza,
Alejandro Solano-Peraltab, Marcos Flores-Álamob, Angelina Flores-Parrac, Isabel Gracia-Morad,
Silvia E. Castillo-Bluma,⁎
a
Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX 04510,
México
b
Unidad de Servicios de Apoyo a la Investigación y a la Industria, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán,
CDMX 04510, México
c
Departamento de Química, Centro de Investigación y de Estudios Avanzados, AP 14-740, CDMX 07000, México
Unidad de Investigación Preclínica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX 04510, México
d
A R T I C L E I N F O
A B S T R A C T
Keywords:
Cytotoxic activity
EPR spectroscopy
Magnetic properties
Oxidovanadium(IV) complexes
X-ray crystal structures
The present investigation was carried out with the aim of synthesizing and characterizing five vanadium co-
ordination compounds (6–10) with different Schiff bases (1 = N,N′-bis(salicylidene)-o-phenylenediamine,
2 = N,N′-bis(4-hydroxysalicylidene)-o-phenylenediamine,
3 = N,N′-bis(4-methoxysalicylidene)-o-phenylene-
diamine, 4 = N,N′-bis(3-hydroxysalicylidene)-o-phenylenediamine, 5 = N,N′-bis(3-methoxysalicylidene)-o-
phenylenediamine) and studying their cytotoxic properties. Based on their physical (magnetic susceptibility),
spectral (X-ray, electronic, IR, 1H NMR, 13C NMR, EPR and mass) and analytical (elemental analysis) results, the
structures of these Schiff bases and their respective oxidovanadium(IV) complexes were established. Crystal
structures of compounds 6 (Monoclinic, C 2/c, Z = 16) and 7–8 (Triclinic, P-1, Z = 2) had been determined by
X-ray diffraction and confirmed pentacoordination of vanadium(IV) with a slightly distorted square-pyramidal
geometry. Vanadium coordination compounds displayed low effective magnetic moments (0.85–0.89 BM) that
maybe due to the intermolecular hydrogen bonding and π-stacking interactions in the crystal arrangements.
Cytotoxic activity was evaluated on human tumor cell lines: 6–9 (HeLa = 0.443–1.502 μM) and 6–10 (HCT-
15 = 0.373–1.415 μM), with exception of 7. Cell growth inhibition revealed that regardless of the cancer cell
line type compounds 6 and 8 showed similar activity -possible effect due to the complex per se- giving new
insights into the structure–activity relationship for these complexes.
1. Introduction
conflicting risks in hypertension and heart diseases to regulation of
cancer and apoptosis [5].
Vanadium is a well-known metal of high importance in physiology,
environment and industry. It is a first-row transition metal with elec-
tronic configuration of [Ar]3d34s2 [1]. Its oxidation states span from
−1 to +5, being +3, +4 and +5 the most common. Elemental va-
nadium does not occur in nature and [VIVO]2+ ion is the most stable
[2]. The abundance of vanadium in the crust of the planet is relatively
high (c.a. 0.019%) and is the same case in sea water, where it is the
second transition metal more abundant; nevertheless, the interest on
the research of vanadium coordination compounds before 1980 was
scarce [3].
It is found in vanadium-dependent haloperoxidases and alternative
nitrogenases [1], its individual species show important effects in-
hibiting the function of many enzymes, e.g., phosphatases (protein
tyrosine phosphatases) [5a-5d], phosphorylases (Na+, K+-ATPases,
Ca2+-ATPases [5a-5d]) and ribonucleases [5c] and stimulating the
function of others, e.g., SOD (superoxide dismutase), CAT (catalase),
GSH-Px (phospholipid hydroperoxide glutathione peroxidase) and Mn-
SOD [5d]. Vanadium(V) is an analogue of phosphorus and thus an in-
hibitor against phosphorylases. Additionally, this metal shows toxicity
in large amounts but it is considered by some authors to be an essential
element for humans [6].
Vanadium coordination compounds may exhibit different biological
effects going from diabetes and lipid profile regulation [4,5],
The metal based compounds such as vanadium, titanium, copper,
⁎
Corresponding author.
E-mail address: blum@unam.mx (S.E. Castillo-Blum).
https://doi.org/10.1016/j.ica.2018.05.013
Received 28 February 2018; Received in revised form 11 May 2018; Accepted 13 May 2018
0020-1693/©2018ElsevierB.V.Allrightsreserved.

L.J. Hernández-Benítez et al.
InorganicaChimicaActa480(2018)197–206
detector (λMoKα = 0.71073 Å, monochromator: graphite) source
ruthenium, tin and rhodium have been reported as promising che-
motherapeutic drugs [7]. In addition, vanadium coordination com-
pounds have received considerable attention as antitumor agents
against murine tumors (leukemia, Ehrlich ascites tumor and mammary
adenocarcinoma) with insulin-like and antihyperlipidemic properties in
human body [8].
The structural features of Schiff bases are of interest in coordination
chemistry; these types of ligands have been used for the synthesis of
complexes with transition metal ions. The complexes display properties
which are useful for a wide range of applications, such as in pharma-
cology, catalysis and sensors [9,10]. It has already been reported that
tetradentate Schiff bases such as N,N′-bis(salicylidene)-o-phenylene-
diamine readily form complexes with vanadium salts yielding oxido-
vanadium complexes [10]. For these reasons, herein we report the
synthesis, characterization and evaluation of the potential cytotoxic
activity of five vanadium coordination compounds using Schiff bases as
N2O2 donor group.
equipped with a sealed X-ray source tube at 130 K.
Unit cell constants were determined with a set of 15/3 narrow
frame/runs (1° in ω) scans. A data set consisted of 1054, 528 and 856
frames of intensity collected for 6–8, respectively, with a frame width of
1° in ω, a counting time of 7 s/frame, and a crystal-to-detector distance
of 55.00 mm. The double pass method of scanning was used to exclude
any noise. The collected frames were integrated by using an orientation
matrix determined from the narrow frame scans. CrysAlisPro and
CrysAlis RED software packages [12] were used for data collection and
integration. Analysis of the integrated data did not reveal any decay.
Final cell constants were determined by a global refinement of 17744,
5160 and 4166 reflections (θ < 26.3°) for 6–8, respectively. Collected
data were corrected for absorbance by using analytical numeric ab-
sorption correction [12a] using a multifaceted crystal model based on
expressions upon the Laue symmetry using equivalent reflections.
Structure solution and refinement were carried out with the SHELXS-
2014 [12b] and SHELXL-2014 [12c]. WinGX v2014.1 software was
used to prepare material for publication [12d]. Full-matrix least-
squares refinement was carried out by minimising (Fo2–Fc2)2. All non-
hydrogen atoms were refined anisotropically. H atoms of the hydroxy
and water groups (H–O) were located at a difference map and refined
isotropically with Uiso(H) = 1.5 for H–O. H atoms attached to carbon
were placed in geometrically idealized positions and refined as riding
on their parent atoms, with CeH]0.95–0.99 Å and with Uiso
(H) = 1.2Ueq(C) for aromatic and methylene groups, and Uiso
(H) = 1.5Ueq(C) for methyl groups.
2. Experimental
2.1. Reagents and solvents
Chemicals were purchased from various commercial suppliers and
were used without further purification. All differently substituted 3,4-
salicylaldehydes, o-phenylenediamine, VO(acac)2, propylene glycol,
cisplatin and sulforhodamine B were obtained from Sigma-Aldrich and
solvents used for the synthesis and purification from J.T. Baker.
Details of the X-ray studies for compounds 6–8 are summarized in
Table 1 and selected bond lengths and angles parameters are listed in
Table 2. Crystallographic data have been deposited at the Cambridge
Crystallographic Data Center as Supplementary material number CCDC
1822762 (6), 1589634 (7) and 1589635 (8). Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK. e-mail: deposit@ccdc.cam.ac.uk.
2.2. Instrumentation
IR spectra in the range 4000–400 cm−1 were performed on a Perkin
Elmer FTIR/FIR Spectrum 400 spectrophotometer with a universal ATR
sampling accessory at room temperature. NMR spectra of the ligands
were recorded on
a Varian VNMRS (400 MHz) spectrometer in
DMSO‑d6. 1H and 13C chemical shifts were reported in ppm (δ) relative
to internal TMS (δH 0.00 ppm). Additionally, data from 2D-NMR ex-
periments COSY, HSQC and HMBC were used to get the unambiguous
assignment of the signals and thus the structural characterization of the
ligands. HRMS were obtained by LC/MSD TOF on an Agilent
Technologies instrument with ESI as ionization source using DMSO as
solvent. Electronic absorption spectra of DMSO solutions were re-
corded on a HP/Agilent 8453 UV-Visible spectrophotometer with a HP/
Agilent 89090A Peltier Temperature Controller. EPR spectra of powder
samples and DMSO solutions were performed under no-saturation
conditions on a Bruker Elexsys E-500 spectrometer using the X-band
(9.8 GHz) with 100 kHz modulation frequency. Measurements at room
temperature (295 K) of powder samples were recorded in 4 mm O.D.
quartz EPR tubes while fluid DMSO solutions in a 1 mm I.D. flat cell.
Determinations at 77 K were obtained with frozen DMSO solutions
using liquid nitrogen. The g- and A-values were calculated using the
microwave frequency and measuring the magnetic field and confirmed
by computer simulation with easyspin computational package in
Matlab [11], the instructions outlined above do not include second
order corrections. Elemental analyses were carried out on a Perkin
Elmer 2400 Series II CHNS/O analyzer using cysteine as internal stan-
dard. Magnetic susceptibility measurements at room temperature of
powder samples were performed on a Sherwood Scientific Magnetic
Susceptibility Balance using the Gouy method. Melting points were
measured in sealed capillaries on a Stuart SMP10/120 V/60 digital
melting point apparatus with three-digit LED display and are un-
corrected.
2.4. Cytotoxic activity
Human tumor (HeLa, cervix; HCT-15, colorectal) cell lines were
purchased from American Type Culture Collection (ATCC). HeLa was
propagated in Eagle’s Minimum Essential Medium (EMEM; ATCC) and
HCT-15 in Roswell Park Memorial Institute Medium (RPMI; Gibco,
Invitrogen corporation). In both cases, the cell culture media was
supplemented with 10% fetal bovine serum (FBS; Gibco, Invitrogen
corporation) without antibiotics.
Experiments were performed with cells within at least five passages
from each other. All cells were split when 70–80% confluence was
reached using 0.25% trypsin-PBS. Briefly, 2 × 104 cells/well were
plated in 96-well microplates with 100 µL of medium supplemented
with 10% FBS and allowed to attach, incubating at 37 °C and 5% CO2
for 24 h. At the end of the incubation period, the medium was aspirated
and the cells were exposed to coordination compounds in six different
concentrations (1000, 100, 10, 1, 0.1 and 0.01 µg/mL) for 24 h under
conditions previously described. The solutions of the compounds were
obtained by preparing a 10 mg/mL stock solution in DMSO followed by
decimal serial dilutions with propylene glycol. Cisplatin was used as
drug control. An important consideration is that compound 8 was not
evaluated at 1000 µg/mL but 500 µg/mL as highest concentration due
to its solubility.
Cell growth was determined according to the sulforhodamine B
(SRB) assay [13]. In vitro studies were done in triplicate and data are
expressed as mean
Daigger model ELx800 microplate reader and % cell growth of each
concentration of each compound was calculated as:
SE. Absorbance was measured at 490 nm in a
2.3. X-ray crystallographic structure determinations
%
growth = 100*[T/C]; being T the optical density of the treated wells
and C is the optical density of untreated wells. The concentration that
induces 50% of maximum inhibition of cell proliferation (IC50) was
Crystals of complexes 6–8 mounted on a glass fiber were studied
with an Oxford Diffraction Gemini “A” diffractometer with a CCD area
198

L.J. Hernández-Benítez et al.
InorganicaChimicaActa480(2018)197–206
Table 1
Crystal data and structure refinement parameters of complexes 6–8.
Identification code
6
7
8
Empirical formula
Formula weight
Crystal system
Space group
C20 H14 N2 O3
381.27
Monoclinic
C 2/c
V
C24 H26 N2 O7
505.41
Triclinic
P -1
V
C22 H20 N2 O6
459.34
Triclinic
P -1
V
Temperature (K)
Wavelength (Å)
130(2)
0.71073
130(2)
0.71073
130(2)
0.71073
Unit cell dimensions
a (Å)
b (Å)
c (Å)
α (°)
27.2851(9)
6.9278(2)
39.5380(15)
90
106.108(4)
90
7180.3(4)
16
1.411
8.3396(6)
11.5493(12)
12.9875(11)
100.558(8)
107.175(7)
96.368(7)
1156.62(18)
2
7.4958(7)
11.1969(11)
12.3066(8)
72.646(7)
89.869(7)
79.019(8)
966.18(15)
2
β (°)
γ (°)
Volume (Å3)
Z
ρcalc (gcm−3
)
1.451
0.477
526
1.579
0.559
474
μ (mm−1
F (0 0 0)
)
0.574
3120
Crystal size (mm)
θ range (°)
0.40 × 0.36 × 0.28
3.541–25.681
–32 ≤ h ≤ 32
−8 ≤ k ≤ 8
−47 ≤ l ≤ 47
80463
0.42 × 0.33 × 0.28
3.372–25.680
−10 ≤ h ≤ 10
−14 ≤ k ≤ 14
−15 ≤ l ≤ 15
22,717
0.37 × 0.14 × 0.05
3.429–30.143
−10 ≤ h ≤ 10
−14 ≤ k ≤ 15
−16 ≤ l ≤ 17
13,883
Index ranges
Reflections collected
Independent reflections [Rint
Completeness to θ = 26.3°
Data/restraints/parameters
Goodness-of-fit on F2
]
6562 [0.0669]
99.7%
6562/0/469
1.242
4374 [0.0721]
99.8%
4374/0/337
1.244
4947 [0.0351]
99.7%
4947/0/285
1.058
Final R, wR2 indexes
I ≥ 2 s (I)
0.0707, 0.1329
0.0739, 0.1343
0.540
0.0594, 0.1592
0.0815, 0.1814
1.130
0.0402, 0.0860
0.0574, 0.0976
0.356
All data
Δρ Maximum (eÅ−3
)
Δρ Minimun (eÅ−3
)
−0.567
−0.542
−0.378
Refinement method: Full-matrix least-squares on F2.
aldehyde in a 1:2 molar ratio by adapting a reported procedure [16].
Reagents were dissolved in anhydrous ethanol (50 mL) in a 100 mL flat-
bottomed flask, equipped with a reflux condenser and a magnetic
stirrer. Reactions were refluxed for 6 h. In all cases a translucent solu-
tion was observed. Subsequently, the solid products formed were fil-
tered off while the reaction mixture was still hot, purified with cold
anhydrous ethanol (3 × 10 mL) washes and vacuum-dried. Fig. 1 in-
dicates the assigned numbering for ligands characterization.
Table 2
Selected bond lengths (Å) and bond angles (°) for compounds 6–8.
Bond
6a
7
8
N(1)-V(1)/N(3)-V(2)
N(2)-V(1)/N(4)-V(2)
O(1)-V(1)/O(4)-V(2)
O(2)-V(1)/O(5)-V(2)
2.056(4)/2.062(4)
2.072(3)/2.076(3)
1.922(3)/1.927(3)
1.925(3)/1.930(3)
1.596(3)/1.601(3)
110.5(1)/110.2(1)
108.2(1)/108.4(1)
86.3(1)/85.8(1)
103.5(1)/104.9(1)
145.7(1)/144.7(1)
87.5(1)/87.4(1)
105.9(1)/105.9(1)
87.8(1)/87.4(1)
2.056(3)
2.052(2)
1.925(2)
1.918(2)
1.609(3)
107.8(1)
107.5(1)
86.1(1)
103.8(1)
88.0(1)
148.5(1)
108.8(1)
142.9(1)
87.9(1)
2.059(1)
2.051(2)
1.926(2)
1.930(1)
1.617(1)
109.78(6)
109.61(7)
83.54(6)
105.98(7)
144.04(6)
88.17(6)
106.65(7)
87.95(6)
143.53(6)
78.25(6)
O(3)-V(1)/O(6)-V(2)
O(3)-V(1)-O(1)/O(6)-V(2)-O(4)
O(3)-V(1)-O(2)/O(6)-V(2)-O(5)
O(1)-V(1)-O(2)/O(4)-V(2)-O(5)
O(3)-V(1)-N(2)/O(6)-V(2)-N(4)
O(1)-V(1)-N(2)/O(4)-V(2)-N(4)
O(2)-V(1)-N(2)/O(5)-V(2)-N(4)
O(3)-V(1)-N(1)/O(6)-V(2)-N(3)
O(1)-V(1)-N(1)/O(4)-V(2)-N(3)
O(2)-V(1)-N(1)/O(5)-V(2)-N(3)
N(2)-V(1)-N(1)/N(4)-V(2)-N(3)
2.5.1.1. N,N′-bis(salicylidene)-o-phenylenediamine (1). Reagents: 2-
Hidroxybenzaldehyde (2.441 g, 20 mmol) and o-phenylenediamine
(1.080 g, 10 mmol). Product: 2.945 g (9.3 mmol) of a yellow powder
was obtained after purification. Yield: 93%. Mp: 166–167 °C. Anal.
Calcd. for C20H16N2O2 (M = 316.4 gmol−1): C, 75.93; H, 5.10; N,
8.86%. Found: C, 75.86; H, 5.15; N, 9.11%. IR (ATR, υ cm−1): 3053
(CeH)arom, 1610 (C]N), 1584, 1560, 1480 (C]C)arom, 1190 (C-O).
145.3(1)/145.2(1)
78.6(1)/78.4(1)
78.5(1)
a
Values are given for the two independent molecules present in the asym-
metric unit of the crystal lattice.
determined using DoseResp sigmoidal fitting function in OriginPro
2016 [14] by plotting the percent of cell growth against the Log of the
drug concentration. Statistical analysis was performed by one-way
ANOVA followed by Dunnett’s multiple comparison test using
GraphPad Prism 5 software [15].
2.5. Synthesis
2.5.1. Ligands
General procedure. The salphen ligands (1–5) were prepared by the
condensation reaction of o-phenylenediamine with the respective
Fig. 1. Chemical structures of the Schiff base ligands employed.
199

L.J. Hernández-Benítez et al.
InorganicaChimicaActa480(2018)197–206
NMR (400 MHz, DMSO‑d6, 298 K) δ (ppm). 1H: 6.92–7.01 (m, 4H; H3,
H5), 7.38–7.48 (m, 6H; H10, H4, H9), 7.66 (dd, J = 8.2, 1.9 Hz, 2H; H6),
8.93 (s, 2H; H7), 12.93 (s, 2H; OH). 13C: 116.64 (C3), 119.05 (C5),
119.46 (C1), 119.72 (C9), 127.76 (C10), 132.42 (C6), 133.40 (C4),
142.23 (C8), 160.35 (C2), 164.00 (C7).
2.5.2. Vanadium complexes
General procedure. VO(acac)2 was added carefully in small portions
to a suspension of the appropriate ligand (1–5) in anhydrous ethanol
(50 mL) in a 1:1.1 molar ratio. An excess of ligand in each reaction was
used to ensure its maximum complexation. Reactions were magnetic
stirred for 24 h at RT in a 100 mL flat-bottomed flask. Reaction media
color changed from the ligand suspension color (yellow or orange) to
green (6–8) or khaki (9–10). The change of color was very fast in all
cases yielding a turbid reaction media. The solid products formed were
filtered off, purified with cold anhydrous ethanol (3 × 10 mL) washes
and vacuum-dried. Thereafter, vanadium complexes (6–10) were dried
at 100 °C for 24 h. Solubility data indicate the amount of vanadium
coordination compound in mg dissolved in a specific volume in μL of
DMSO. Sonication was sometimes used to promote an effective dis-
solution of the complexes.
2.5.1.2. N,N′-bis(4-hydroxysalicylidene)-o-phenylenediamine
(2). Reagents: 2,4-Dihydroxybenzaldehyde (2.768 g, 20 mmol) and o-
phenylenediamine (1.083 g, 10 mmol). Product: 2.860 g (8.2 mmol) of
a yellow powder was obtained after purification. Yield: 82%. Mp:
227–228 °C. Anal. Calcd. for C20H16N2O4 (M = 348.4 gmol−1): C,
68.96; H, 4.63; N, 8.04%. Found: C, 69.40; H, 4.44; N, 8.3%. IR (ATR,
υ cm−1): 3327 (O–H), 3057 (CeH)arom, 1608 (C]N), 1575, 1540,
1501, 1452 (C]C)arom, 1188 (C–O). NMR (400 MHz, DMSO‑d6, 298 K)
δ (ppm). 1H: 6.29 (d, J = 2.3 Hz, 2H; H3), 6.39 (dd, J = 8.5, 2.3 Hz, 2H;
H5), 7.29–7.34 (m, 2H; H10), 7.35–7.39 (m, 2H; H9), 7.43 (d,
J = 8.5 Hz, 2H; H6), 8.74 (s, 2H; H7), 10.27 (s, 2H; OH), 13.39 (s,
2H; OH). 13C: 102.41 (C3), 107.82 (C5), 112.28 (C1), 119.47 (C10),
127.01 (C9), 134.42 (C6), 142.01 (C8), 162.63 (C4), 162.89 (C7), 163.31
(C2).
2.5.2.1. N,N′-bis(salicylidene)-o-phenylenediamine vanadium(IV) oxide
complex (6). Reagents: VO(acac)2 (0.713 g, 2.7 mmol) and 1 (0.951 g,
3.0 mmol). Product: 0.980 g (2.57 mmol) of a green powder was
obtained after purification. Yield: 95%. Mp > 300 °C. Solubility:
soluble 1 in 100 parts of DMSO at 25 °C. Anal. Calcd. for VO
(C20H14N2O2) (M = 381.3 gmol−1): C, 63.00; H, 3.70; N, 7.35%.
Found: C, 62.84; H, 3.39; N, 7.49%. IR (ATR, υ cm−1): 3048
(CeH)arom, 1601 (C]N), 1577, 1531, 1459 (C]C)arom, 1190 (CeO),
981 (V]O). µeff 0.87 BM. TOF+, m/z calcd. For (M+H)+: 382.3.
Found: 382.1. UV/Vis (DMSO) λ (nm): 317, 399. Crystals were
obtained by vapor diffusion in acetone as solvent and ethanol as
precipitant at RT.
2.5.1.3. N,N′-bis(4-methoxysalicylidene)-o-phenylenediamine
(3). Reagents: 2-Hydroxy-4-methoxybenzaldehyde (3.052 g, 20 mmol)
and o-phenylenediamine (1.088 g, 10 mmol). Product: 3.129 g
(8.3 mmol) of a yellow crystalline compound was obtained after
purification. Yield: 83%. Mp: 174–175 °C. Anal. Calcd. for
C
22H20N2O4 (M = 376.4 gmol−1): C, 70.20; H, 5.36; N, 7.44%.
Found: C, 69.68; H, 5.26; N, 7.83%. IR (ATR, υ cm−1): 3059
(CeH)arom, 1607 (C]N), 1583, 1567, 1509, 1463 (C]C)arom, 1199
(C-O). NMR (400 MHz, DMSO‑d6, 298 K) δ (ppm). 1H: 3.80 (s, 6H;
OCH3), 6.49 (d, J = 2.4 Hz, 2H; H3), 6.54 (dd, J = 8.6, 2.5 Hz, 2H; H5),
7.32–7.36 (m, 2H; H9), 7.40–7.43 (m, 2H; H10), 7.54 (d, J = 8.6 Hz, 2H;
H6), 8.82 (s, 2H; H7), 13.51 (s, 2H; OH). 13C: 55.45 (OCH3), 100.82
(C3), 106.83 (C5), 113.16 (C1), 119.43 (C10), 127.22 (C9), 134.04 (C6),
141.69 (C8), 162.78 (C7), 163.54 (C4), 163.82 (C2).
2.5.2.2. N,N′-bis(4-hydroxysalicylidene)-o-phenylenediamine
vanadium
(IV) oxide complex (7). Reagents: VO(acac)2 (0.717 g, 2.7 mmol) and
2 (1.051 g, 3.0 mmol). Product: 0.945 g (2.29 mmol) of a green powder
was obtained after purification. Yield: 85%. Mp > 300 °C. Solubility:
soluble 1 in 75 parts of DMSO at 25 °C. Anal. Calcd. for VO
(C20H14N2O4) (M = 413.3 gmol−1): C, 58.12; H, 3.41; N, 6.79%.
Found: C, 57.35; H, 3.28; N, 6.79%. IR (ATR, υ cm−1): 3315 (O–H),
3062 (CeH)arom, 1597 (C]N), 1577, 1536, 1481, 1422 (C]C)arom
,
:
2.5.1.4. N,N′-bis(3-hydroxysalicylidene)-o-phenylenediamine
1121 (CeO), 985 (V]O). µeff 0.87 BM. TOF+ m/z calcd. for (M+H)+
(4). Reagents: 2,3-Dihydroxybenzaldehyde (2.770 g, 20 mmol) and o-
phenylenediamine (1.089 g, 10 mmol). Product: 2.931 g (8.4 mmol) of
a red–orange crystalline compound was obtained after purification.
Yield: 84%. Mp: 204–206 °C. Anal. Calcd. for C20H16N2O4 (M = 348.4
gmol−1): C, 68.96; H, 4.63; N, 8.04%. Found: C, 68.47; H, 4.37; N,
8.07%. IR (ATR, υ cm−1): 3463 (O–H), 3051 (CeH)arom, 1617 (C]N),
1580, 1544, 1522, 1467 (]C)arom, 1208 (CeO). NMR (400 MHz,
DMSO‑d6, 298 K) δ (ppm). 1H: 6.79 (t, J = 7.8 Hz, 2H; H5), 6.95 (dd,
J = 7.9, 1.6 Hz, 2H; H4), 7.12 (dd, J = 7.8, 1.6 Hz, 2H; H6), 7.39–7.44
(m, 4H; H10, H9), 8.88 (s, 2H; H7); 9.24 (s, 2H; OH), 12.90 (s, 2H; OH).
13C: 118.74 (C5), 119.11 (C4), 119.58 (C1), 119.96 (C9), 122.77 (C6),
127.70 (C10), 142.15 (C8), 145.62 (C3), 149.45 (C2), 164.74 (C7).
414.3. Found: 414.0. UV/Vis (DMSO) λ (nm): 331, 398. Crystals were
obtained by vapor diffusion in acetone as solvent and ethanol as
precipitant at RT.
2.5.2.3. N,N′-bis(4-methoxysalicylidene)-o-phenylenediamine vanadium
(IV) oxide complex (8). Reagents: VO(acac)2 (0.716 g, 2.7 mmol) and
3 (1.133 g, 3.0 mmol). Product: 1.006 g (2.28 mmol) of a green powder
was obtained after purification. Yield: 84%. Mp > 300 °C. Solubility:
soluble 1 in 200 parts of DMSO at 25 °C. Anal. Calcd. for VO
(C22H18N2O4) (M = 441.3 gmol−1): C, 59.87; H, 4.11; N, 6.34%.
Found: C, 59.96; H, 3.91; N, 6.64%. IR (ATR, υ cm−1): 3021
(CeH)arom, 1596 (C]N), 1574, 1521, 1490, 1455 (C]C)arom, 1200
(CeO), 979 (V]O). µeff 0.85 BM. TOF+ m/z calcd. for (M+H)+: 442.3.
Found: 442.1. UV/Vis (DMSO) λ (nm): 326, 393. Crystals were
obtained by slow solvent evaporation in CH3CN at RT.
2.5.1.5. N,N′-bis(3-methoxysalicylidene)-o-phenylenediamine
(5). Reagents: 2-Hydroxy-3-methoxybenzaldehyde (3.041 g, 20 mmol)
and o-phenylenediamine (1.080 g, 10 mmol). Product: 2.977 g
(7.9 mmol) of an orange crystalline compound was obtained after
purification. Yield: 79%. Mp: 172–173 °C. Anal. Calcd. for
2.5.2.4. N,N′-bis(3-hydroxysalicylidene)-o-phenylenediamine
vanadium
(IV) oxide complex (9). Reagents: VO(acac)2 (0.718 g, 2.7 mmol) and
4 (1.049 g, 3.0 mmol). Product: 1.037 g (2.51 mmol) of a khaki powder
was obtained after purification. Yield: 90%. Mp > 300 °C. Solubility:
C
22H20N2O4 (M = 376.4 gmol−1): C, 70.20; H, 5.36; N, 7.44%.
Found: C, 70.88; H, 5.36; N, 7.68%. IR (ATR, υ cm−1): 3058
(CeH)arom, 1609 (C]N), 1586, 1568, 1456 (C]C)arom, 1204 (CeO).
NMR (400 MHz, DMSO‑d6, 298 K) δ (ppm). 1H: 3.81 (s, 6H; OCH3),
6.90 (t, J = 7.9 Hz, 2H; H5), 7.12 (dd, J = 8.1, 1.4 Hz, 2H; H4), 7.25
(dd, J = 7.9, 1.5 Hz, 2H; H6), 7.38–7.42 (m, 2H; H10), 7.44–7.47 (m,
2H; H9), 8.92 (s, 2H; H7), 13.00 (s, 2H; OH). 13C: 55.65 (OCH3), 115.42
(C4), 118.53 (C5), 119.32 (C1), 119.78 (C9), 123.76 (C6), 127.78 (C10),
142.08 (C8), 147.86 (C3), 150.60 (C2), 164.29 (C7).
soluble
1 in 75 parts of DMSO at 25 °C. Anal. Calcd. for VO
(C20H14N2O4) (M = 413.3 gmol−1): C, 58.12; H, 3.41; N, 6.79%.
Found: C, 57.82; H, 3.03; N, 6.99%. IR (ATR, υ cm−1): 3393 (O–H),
3038 (CeH)arom, 1598 (C]N), 1548, 1491, 1442, 1404 (C]C)arom
1197 (CeO), 972 (V]O). µeff 0.86 BM. TOF+ m/z calcd. for (M+H)+
414.3. Found: 414.0. UV/Vis (DMSO) λ (nm): 334, 351, 430.
,
:
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L.J. Hernández-Benítez et al.
InorganicaChimicaActa480(2018)197–206
2.5.2.5. N,N′-bis(3-methoxysalicylidene)-o-phenylenediamine vanadium
(IV) oxide complex (10). Reagents: VO(acac)2 (0.712 g, 2.7 mmol)
and 5 (1.131 g, 3.0 mmol). Product: 1.080 g (2.45 mmol) of a khaki
powder was obtained after purification. Yield: 91%. Mp > 300 °C.
Solubility: soluble 1 in 75 parts of DMSO at 25 °C. Anal. Calcd. for VO
(C22H18N2O4) (M = 441.3 gmol−1): C, 59.87; H, 4.11; N, 6.34%.
Found: C, 59.81; H, 3.82; N, 6.68%. IR (ATR, υ cm−1): 3049
(CeH)arom, 1603 (C ] N), 1580, 1544, 1434 (C]C)arom, 1204 (C-O),
977 (V]O). µeff 0.89 BM. TOF+ m/z calcd. for (M+H)+: 442.3. Found:
442.1. UV/Vis (DMSO) λ (nm): 329, 352, 425.
derivative acted as a tetradentate ligand through its o-phenylenedia-
mine N atoms and its deprotonated phenol O atoms. The metal co-
ordination implied the formation of a system of six fused cycles; five of
them were six-membered rings and one was a five-membered ring.
Displacement ellipsoids plot of 6, 7 and 8 are shown in Figs. 2, 5 and 8,
respectively.
In relation to oxidovanadium(IV) complexes, a new monoclinic (C
2/c; Z = 16) polymorph of compound 6 was obtained. Previously, a
monoclinic polymorph (P2(1)/c; Z = 8) of 6 was reported by Tshentu
[25]. There are two crystallographically independent molecules in the
asymmetric unit of compound 6, Fig. 2. The structure analysis of 6
showed a square-pyramidal geometry with the vanadium atom lying at
0.585 Å above the mean plane defined by atoms N1/N2/O1/O2 (mo-
lecule B) and 0.597 Å for molecule A (N3/N4/O4/O5 plane). The N(1)N
(2)O(1)O(2) and N(3)N(4)O(4)O(5) planes from the two molecules bi-
sect each other at an angle of 81.01°. The geometric parameter (τ) of
0.0067 (B) and 0.0083 (A) confirmed a perfectly square-pyramidal
geometry [30] for both molecules in complex 6.
3. Results and discussion
3.1. General
Ligands 1–5 were obtained with high yield and purity. Additionally,
ligands characterization results were highly consistent and in good
agreement with previously reported data [16–21]. For vanadium co-
ordination compounds (6–10) the Schiff bases acted as tetradentate
ligands and coordinated to vanadium(IV) to give a stoichiometric ratio
of 1:1 [M:L]. Complexes 7–10, as well as, their characterization, are
reported for their first time; 6 had been previously reported [10,22–25]
and the characterization results obtained for this complex were also
consistent with the report, except for the effective magnetic moment
[22]. Complexes 6–10 were poorly soluble in common organic and
inorganic solvents except in DMSO but was possible to solubilize them
in water by using the cosolvency technique with propylene glycol as
cosolvent. In addition, coordination compounds were stable in air,
DMSO and DMSO-Propylene glycol–water solution.
Chemical stability of coordination compounds 6–10 was in-
vestigated by UV/Vis spectroscopy. First, stability studies of the com-
plexes in DMSO (c.a. 2.5 × 10−2 M) at 37 °C for 72 h were carried out
to determine possible structural changes, such as ligand substitution
processes leading to the well-known [VO(DMSO)5] (absorption bands at
830 and 690 nm) [26]. Such bands were not observed during the study.
Subsequently, stability in DMSO-propylene glycol–water (1:9:90) was
investigated to verify that coordination compounds were stable under
incubation conditions for the in vitro studies. The electronic absorption
spectra of compounds 6–10 remained unchanged for 72 h at 37 °C.
These results allowed to continue with the biological tests.
Fig. 2. A perspective view of two molecules, A (left) and B (right), of complex 6
with the atomic labelling scheme. Displacement ellipsoids are shown at the 70%
probability level.
3.2. Infrared spectroscopy
In complex 6, molecules A formed centrosymmetric dimers stabi-
lized by π⋯π stacking interactions (3.549 Å). The bilayers formed by
these centrosymmetric dimers were also stabilized by π contacts
(3.636 Å), Fig. 3.
On the other hand, molecules B of complex 6 were found stacked in
monolayers with short π contacts of 3.636 Å, Fig. 4.
Complex 7 consisted of one unit of neutral N,N'-bis(4-hydro-
xysalicylidene)-o-phenylenediamine oxidovanadium(IV) compound
and two ethanol solvent molecules, Fig. 5. The vanadium atom in 7 is
pentacoordinate and is located at 0.580 Å above the mean plane defined
by atoms N1/N2/O1/O2. The structural index parameter (τ) of 0.093
evidenced a slightly distorted square-pyramidal geometry [30].
In complex 7, the molecules formed centrosymmetric dimers by a
wide π interaction (3.418 Å) between two cycles of each molecule
which also involved the vanadium atom with short distances to the
C16 = C17 double bond of the second molecule (C16⋯V 3.677 and
C17⋯V 3.680 Å; ΣrVdW = 3.7 Å). This C16 = C17 bond occupied the
sixth coordinative position of vanadium, Fig. 6.
The infrared spectra of ligands 1–5 exhibited bands at
1607–1617 cm−1 corresponding to υ(C]N) stretching mode [27].
These bands shifted toward lower wavenumbers (1596–1603 cm−1) in
the complexes spectra indicating vanadium imine coordination [28].
[VIVO]2+ complexes exhibit the IR band associated to the stretching
of the (V]O) group in the region of 995–940 cm−1 [29]. According to
the literature, this band for the square-pyramidal oxidovanadium(IV)
complexes appears at higher wave numbers (995–960 cm−1), while for
octahedral [VIVO]2+ complexes emerges at 960–940 cm−1 [29]. In the
IR spectra of complexes 6–10, the IR band assigned to the stretching
vibration of the (V]O) group was observed at 985–970 cm−1. These
observations indicated the square-pyramidal molecular geometry of the
complexes.
3.3. Crystal structures
Single crystal X-ray analysis of complexes 6–8 as dark brown (7)
and dark green (6, 8) blocks, showed similar neutral complexes of the
form [VO(L)], exhibiting a metal oxidation state of +4. The basal
square plane was constituted by the N,N′-bis(salicylidene)-o-phenyle-
nediamine molecule for 6, N,N'-bis(4-hydroxysalicylidene)-o-phenyle-
nediamine molecule for 7 and N,N'-bis(4-methoxysalicylidene)-o-phe-
nylenediamine molecule for 8. In all solid-state structures, the salphen
In addition, centrosymmetric dimers formed bilayers which in turn
were bound together by hydrogen bonds of the phenol protons with the
V = O oxygen atom (O5-H5D⋯O3V 1.947 Å), Fig. 7.
The asymmetric unit of 8 consisted of a monomeric vanadium(IV)
complex, co-crystallized with one equivalent of water solvent molecule
in the triclinic P-1 space group, Fig. 8. The metal center atom is
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InorganicaChimicaActa480(2018)197–206
Fig. 3. Centrosymmetric dimers and bilayers formed by molecules A in the crystal of compound 6.
Fig. 4. π-Stacking interactions of molecules B in complex 6.
Fig. 5. A perspective view of complex 7 with the atomic labelling scheme. Displacement ellipsoids are shown at the 70% probability level. The ethanol solvent
molecules were omitted for clarity.
1.922, and 1.595 Å, respectively. Vanadium atom is located at 0.616 Å
above the mean plane defined by atoms N1/N2/O1/O2. The τ para-
meter of 0.0085 for this compound indicated a purely square-pyramidal
geometry [30] for complex 8.
pentacoordinate and the metrics of the molecule V–N bonds of 2.055(4)
Å, V–O bonds of 1.928(2) Å, and a V = O bond of 1.617(1) Å were
similar to the current 127 oxidovanadium(2+)-salen complexes found
in the Cambridge Structural Database (CDS: ConQuest Version 1.19,
[31]). Average literature values for these types of bonds are 2.058,
Compound
8 also formed centrosymmetric dimers and were
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InorganicaChimicaActa480(2018)197–206
Fig. 6. Centrosymmetric dimer found at the crystal of compound 7.
Fig. 7. Hydrogen bonds of the phenol protons with the V = O oxygen atom observed in the bilayers formed by centrosymmetric dimers of compound 7.
Fig. 8. A perspective view of complex 8 with the atomic labelling scheme. Displacement ellipsoids are shown at the 60% probability level. The water solvent
molecule was omitted for clarity.
arranged in two different layers formed by π contacts (3.737 Å) and
water hydrogen bonds as is shown in Figs. 9 and 10, respectively.
In the crystal array, intermolecular interactions of O–H⋯O
hydrogen bonds between the coordinated oxygen atoms and the water
molecule were evident: O1W-H1D⋯O1 (2.177 Å), O1W-H1E⋯O5
(2.141 Å) and O1W-H1D⋯O2 (2.501 Å).
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InorganicaChimicaActa480(2018)197–206
Fig. 9. Centrosymmetric dimer found at the crystal of compound 8.
Fig. 10. Centrosymmetric dimers of compound 8 formed bilayers which in turn were also stabilized by water hydrogen bonds.
3.4. Magnetic studies
formed by molecules A, as well as, the monolayer found at molecules B
also stabilized by π interactions. For complexes 7 and 8 the subnormal
µeff maybe due to the existing intermolecular interactions; in both cases
to the presence of centrosymmetric dimers stabilized by wide π inter-
actions and by hydrogen bonds (in the case of compounds 9 and 10 we
propose a similar behavior). In addition, all samples were magnetically
concentrated because the solid state EPR spectra (X-band) at room
temperature consisted of only one wide isotropic signal with g-values
close to 1.990 (Table 3).
The EPR spectrum of [VO(salphen)]·MeCN in acetonitrile solution at
room temperature has been previously reported by Wang [24,38].
However, they reported a g-value larger than that observed in most
[VIVO]2+ complexes. Herein, the EPR spectra of oxidovanadium(IV)
compounds 6–10 in DMSO solution at room temperature (295 K) dis-
played a quasi-isotropic signal with g-values around 1.97 which was
split into eight hyperfine lines due to the spin of 51V nucleus (I = 7/2)
but an unequal separation of the hyperfine component was observed,
Fig. 11. This occurrence could be due to the second-order effect like
rotational incipient slow-tumbling of the V(IV) ion in DMSO solution
generating asymmetric absorption line shapes and a wide linewidth
[39]. The g-values were very similar in all coordination compounds
studied. However, the quasi-isotropic A-values showed greater changes,
indicating to be more sensitive to the coordination environment of the
[VIVO]2+ ion as was early reported by Pecoraro [40] and Liboiron [41].
EPR parameters for complexes 6–10 in fluid DMSO solution at RT are
collected in Table 3.
Effective magnetic moments (µeff) for vanadium coordination com-
pounds 6–10 were in the range 0.85–0.89 BM. According to the lit-
erature, the µeff for [VIVO]2+ complexes range from 1.7 to 1.8 BM
which correspond to a single electron of the 3d1 system of square-
pyramidal oxidovanadium(IV) [32]. Since the spin–orbit coupling for
[VIVO]2+ complexes is positive [33,34], magnetically dilute oxidova-
nadium(IV) complexes should display µeff close to the spin-only mag-
netic moment of 1.73 BM [35]. Considering that magnetic susceptibility
measurements of the complexes 6–10 were obtained at room tem-
perature using the Gouy method without a previous magnetic dilution,
the low µeff may arise from antiferromagnetic spin–spin interaction
between the neighboring VIV centers [36] or through a polymeric ar-
rangement [37]. The X-ray crystal structures allowed to discard the two
previous explanations.
It is important to emphasize that although the µeff reported by
Kolawole [22] for complex 6 agrees with the expected value, the in-situ
synthesis strategy, the reagents employed, as well as, the purification
techniques carried out by Kolawole, differ considerably from those used
by us. Additionally, they did not obtain an X-ray crystal structure. On
the other hand, in the paper by Tshentu [25], the µeff was not de-
termined and the X-ray crystal structure crystallized in a different space
group from the one reported herein. For these reasons, we suggest that
the low µeff value obtained for compound 6 maybe due to the short π
contacts observed in the centrosymmetric dimers and the bilayers
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InorganicaChimicaActa480(2018)197–206
Table 3
Table 4
Best fit EPR parameters of complexes 6–10. Hyperfine coupling constants (A)
are given in units of 10−4 cm−1 and the pick-to-pick first-derivative linewidth
(ΔBpp) in units of Gauss.
IC50 values of complexes 6–10 toward the selected cell lines. ND = Not
Determined.
Compound
IC50 (μM)
Compound RT (298 K)
LN (77 K)
HeLa
HCT-15
Solid state
DMSO solution
Frozen DMSO solution
6
7
8
9
1.502
1.075
0.483
0.443
0.042
1.200
0.023
0.003
0.003
0.005
0.004
0.004
1.415
ND
0.373
0.875
2.122
2.135
0.009
g
ΔBpp
g
A
g∥
g⊥
gaver
A∥
A⊥
0.004
0.005
0.008
0.010
6
7
8
9
1.987 98
1.994 138
1.996 85
1.980 53
1.992 184
1.976
1.978
1.976
1.977
1.975
87
81
85
85
85
1.956 1.975 1.969 160 54
1.956 1.975 1.969 160 56
1.956 1.976 1.970 160 54
1.959 1.986 1.977 160 56
1.959 1.976 1.971 160 54
10
Cisplatin
10
the 96-well microplates.
Cytotoxic activity in HeLa indicated that complexes 7–10 were more
active than the control, complex 6 was not effective enough compared
with cisplatin. Statistical analysis revealed that IC50 value corre-
sponding to each compound was significantly different from that ob-
tained for the control. By contrast, in vitro cytotoxic effect in HCT-15
indicated that all compounds were more active than cisplatin, except
complex 7, for which the IC50 was not determined because the per-
centage of cell survival at 1000 μg/mL exceeded the 50%. Statistical
analysis indicated that IC50 values corresponding to the complexes
prepared were significantly different from the control except for com-
pound 10, whose IC50 value was statistically equal to that observed for
cisplatin. The difference previously described is entirely associated with
the experiment per se (i.e. the effect of treatment on cells) and not by
issues related to the experimenter since the assays were performed
under the same conditions.
RT
77 K
Simulated
A
2
2600
2800
3000
3200
3400
3600
3800
4000
4200
*
1.5
Gauss
Fig. 11. X-band EPR spectra of 9 in DMSO solution recorded at room tem-
perature (top), in frozen DMSO solution at 77 K (middle) and simulated (bottom).
*
1
The X-band EPR spectra of frozen DMSO solutions for complexes
6–10 showed typical axial spectra with two sets of eight lines each
(Fig. 11), indicating an equatorial binding mode. The best fit EPR
parameters are compiled in Table 3. In all cases, g∥-values were very
similar among them and gaverage-values were around 1.97. A-values
were 160 × 10−4 cm−1 for the parallel component (A∥) and around
56 × 10−4 cm−1 for the perpendicular component (A⊥). The latter
were slightly higher than the reported values for other oxidovanadium
(IV) salen-type complexes [25,42–43]. Vanadium complexes 6–10 ex-
hibited a similar coordination sphere by the N2O2 donor group of the
salphen ligand in the equatorial plane, for this reason the A∥ did not
show great changes and resulted in 160 × 10−4 cm−1. Likewise, A⊥-
values showed small changes in line position, mainly for compounds 6,
8 and 10 which displayed the lowest A⊥-value while complexes 7 and 9
the highest. This suggested a higher electron density over the V(IV)
atom in compounds 7 and 9 due to the contribution of the salphen-type
ligand employed in each case. The effect of the contribution of donor
group to the hyperfine coupling in V(IV) complexes has been already
reported [36,37].
*
*
0.5
*
0
6
7
8
9
10
Cisplatin
B
2.5
2
*
1.5
1
*
0.5
0
*
6
8
9
10
Cisplatin
3.5. Cytotoxicity
Fig. 12. Cytotoxic effect of complexes 6–10 and cisplatin (control) against HeLa
(A) and HCT-15 (B). * = significantly difference with p < 0.05. IC50 for
compound 7 was not possible to determine on HCT-15.
Cytotoxic activity results of complexes 6–10 on human cancer
(HeLa and HCT-15) cell lines after 24 h of exposition are summarized in
Table 4 and Fig. 12. Cisplatin is included for comparison. The IC50 value
indicates the concentration required to inhibit 50% of the cancer cell
growth. In the present study, propylene glycol was used as cosolvent in
Regardless of the cancer cell line type, compounds 6 and 8 displayed
similar IC50 values. On the other hand, compound 10 showed larger
sensitivity for colorectal cancer. Although this assay cannot give further
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InorganicaChimicaActa480(2018)197–206
insights into the structure-activity relationship, it could be thought that
the effect observed by complexes 6 and 8 is due to the complex per se
and is not influenced by the cancer cell type. Since the antiproliferative
and anticancer effects of vanadium compounds have been ascribed to
protein tyrosine phosphatases inhibition (e.g., due to phosphate-an-
tagonizing vanadates or peroxovanadium species, formed as possible
biotransformation products from [VIVO]2+ ions, dependent on pH and
redox environment) and the generation of reactive oxygen species
(elicited by the complex redox chemistry of vanadium) as the foremost
[44–47], the underlying mechanisms continue not to be well under-
stood [3,48].
Complexes whose IC50 value is lower than that obtained for cisplatin
are promising candidates for further investigations, however, in this
study it would be interesting to learn about the effect of the complexes
upon a longer exposure time to establish the time of maximum effect
and then expand the research to other tumor and healthy cell lines to
understand the cytotoxic potential of these oxidovanadium(IV) com-
plexes.
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In summary, five vanadium coordination compounds (6–10) have
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Acknowledgments
This research was supported by grants from PAIP 50009036 and
CONACyT 178851. Authors thank BSc. M. Gutiérrez-Franco, MSc. N.
López-Balbiaux and MSc. V. Lemus-Neri for data processing, BSc. P.
Fierro-Ramírez for technical support and PhD. Karla P. Salas-Martin for
her invaluable help and assistance in the preparation of this manu-
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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.ica.2018.05.013.
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