Oxovanadium(IV) Schiff base complex derived from phenylalanine analogue containing 2,3-diaminopropionic acid (DAP): Synthesis, computational study, and biological evaluation

Article abstract of DOI:10.1080/15533174.2013.841205

Reduced Schiff base ligand by condensation of phenylalanine analogue containing 2,3-diaminopropionic acid (DAP) with salicylaldehyde and its oxovanadium(IV) complex have been prepared. Chemical and structural properties were fully characterized. Density f

Full text of DOI:10.1080/15533174.2013.841205

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Synthesis and Reactivity in Inorganic, Metal-Organic,
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Oxovanadium(IV) Schiff Base Complex Derived
From Phenylalanine Analogue Containing 2,3-
Diaminopropionic Acid (DAP): Synthesis, Computational
Study, and Biological Evaluation
Le Weiab, Xia Yanga, Zeng-Qiang Gaoc, Dong-Qi Wanga, Jing-Quan Xuead, Wen-Jiang Yangad,
Jian-Jun Wangad, Yan-Hua Zhangad, Guo-Liang Fangb & Yu Liuad
a Key Laboratory of Nuclear Radiation and Nuclear Energy Technology, Beijing, P. R. China
b University of Chinese Academy of Sciences, Beijing, P. R. China
c Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy
of Sciences, Beijing, P. R. China
d Beijing Engineering Research Center of Radiographic Techniques and Equipment, Beijing, P.
R. China
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Accepted author version posted online: 16 Sep 2014.Published online: 15 Oct 2014.
To cite this article: Le Wei, Xia Yang, Zeng-Qiang Gao, Dong-Qi Wang, Jing-Quan Xue, Wen-Jiang Yang, Jian-Jun Wang, Yan-
Hua Zhang, Guo-Liang Fang & Yu Liu (2015) Oxovanadium(IV) Schiff Base Complex Derived From Phenylalanine Analogue
Containing 2,3-Diaminopropionic Acid (DAP): Synthesis, Computational Study, and Biological Evaluation, Synthesis and
Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 45:3, 455-467, DOI: 10.1080/15533174.2013.841205
To link to this article: http://dx.doi.org/10.1080/15533174.2013.841205
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry (2015) 45, 455–467
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2013.841205
Oxovanadium(IV) Schiff Base Complex Derived
From Phenylalanine Analogue Containing
2,3-Diaminopropionic Acid (DAP): Synthesis,
Computational Study, and Biological Evaluation
LE WEI1,2, XIA YANG1, ZENG-QIANG GAO3, DONG-QI WANG1, JING-QUAN XUE1,4, WEN-JIANG YANG1,4
JIAN-JUN WANG1,4, YAN-HUA ZHANG1,4, GUO-LIANG FANG2, and YU LIU1,4
,
1Key Laboratory of Nuclear Radiation and Nuclear Energy Technology, Beijing, P. R. China
2University of Chinese Academy of Sciences, Beijing, P. R. China
3Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, P. R. China
4Beijing Engineering Research Center of Radiographic Techniques and Equipment, Beijing, P. R. China
Received 6 June 2013; accepted 1 September 2013
Reduced Schiff base ligand by condensation of phenylalanine analogue containing 2,3-diaminopropionic acid (DAP) with
salicylaldehyde and its oxovanadium(IV) complex have been prepared. Chemical and structural properties were fully characterized.
Density functional theory was used to pin down the structure combined with IR. The natural bond orbital analysis and energy
calculations indicate that tetracoordinated complex of R-type is the most probable structure where vanadium atom is coordinated to
2 £ Ophenolate and 2 £ Nimine of the ligand. By biological evaluation, the metal complex exhibits antibacterial activity against four
bacterial strains and antitumor activity against two tumor cell lines.
Keywords: reduced Schiff base, oxovanadium(IV) complex, density functional theory (DFT), biological evaluation
Introduction
systems. Besides the use of vanadyl Schiff bases as catalysts
with good enantioselectivity,[7,8] they also have important
Schiff bases are a class of important multidentate structures applications in the biological field, such as DNA cleavage
which are considered to be privileged ligands and exhibit agent,[9] insulin mimic for the treatment of diabetes,[10] and
great versatility of coordination patterns to various metals.[1] antitumor agent.[11]
Transition metal Schiff base complexes are well known as
Amino acids are environmentally benign and especially
efficient catalysts in both homogeneous and heterogeneous appropriate for synthesis of Schiff base catalysts through
reactions, such as polymerization of olefins,[2] asymmetric condensation of salicylaldehyde and aldehyde derivatives.[12]
chemical transformations,[3] epoxide ring opening,[4] and 2,3-Diaminopropionic acid (DAP), which was discovered in
Diels–Alder reactions.[5] In addition, many Schiff base com- Bombyx[13] and Murchison meteorite,[14] exists widely in
plexes exhibit biological activities including antibacterial and nature. Since this kind of amino acid derivatives possess
antitumor activities, and have been studied to understand important biological structure, much more attention
their biochemical significance and structure–activity relation- has been paid by both chemists and biologists for many
ships.[6] The complexation of biologically active Schiff base years.[15–17]
ligands with transition metal ions can potentially produce a
Nevertheless, very limited researches on metal Schiff base
large number of drug candidates in therapeutical and bio- complexes derived from DAP or its derivatives are carried
medical fields. Vanadium is an essential element in biological out.[18–20] Costa Pessoa et al.[21] explored the chemical prop-
erties of vanadyl Schiff base complexes by condensation of
DAP with salicylaldehyde using potentiometric and spectro-
scopic techniques; however, so far theoretical computations
Address correspondence to Yu Liu, Key Laboratory of Nuclear
have not yet been reported. As is known to all, density func-
Radiation and Nuclear Energy Technology, Beijing Engineering
tional theory (DFT) computations are quite successful in the
Research Center of Radiographic Techniques and Equipment,
description and explanation of transition-metal complexes
Institute of High Energy Physics, Chinese Academy of Sciences,
for their formation, structures, energies, and barriers.[22]
Beijing 100049, P. R. China. E-mail: yuliu@ihep.ac.cn.
Color versions of one or more of the figures in the article can be
found online at www.tandfonline.com/lsrt.
Herein, we synthesize a novel oxovanadium(IV) Schiff base
complex (abbr. VIVO complex) derived from phenylalanine

456
Wei et al.
analogue containing DAP, and study the possible coordination cases. Elemental analysis (C, H, and N) were performed
structure by DFT computations as well as the biological activi- using a Flash EA 1112 model analyzer, and consistent with
ties. The antibacterial and antitumor activities are evaluated the composition proposed for the VIVO complex. Melting
for potential applications in discovery of new pharmaceuticals points (m.p.) were determined on Electrothermal X-4
in medical field.
apparatus.
Synthesis
Experimental
Products were prepared using modified methods described
previously,[15,17,20,21] as shown in Scheme 1.
Materials and Methods
All chemicals and solvents were of reagent grade and used as
received from commercial sources without further purification.
Ethyl 2-acetamido-2-cyano-3-phenylpropanoate (4)
Ethyl-N-acetyl-3-nitriloalaninate 2 was produced according to To a flask containing absolute ethanol (50 mL) was added
the literature.[23]
sodium (0.1495 g, 6.5 mmol) with stirring under Ar. After
NMR spectra were recorded on Bruker 400 MHz spec- complete dissolution, 2 (1.0539 g, 6.2 mmol) was added and
trometer. Chemical shifts were referenced to DMSO-d6 or the solution was stirred at 60ꢀC for 30 min. After cooling
1
D2O as solvent and TMS as internal standard. H and 13C down to room temperature, benzyl bromide 3 (1.0589 g,
NMR spectra were obtained and reduced Schiff base ligand 9 6.2 mmol) was added. The reaction solution was refluxed
was fully assigned with the aids of 2-D NMR Spectroscopy overnight and the solvent was removed under vacuum. The
(1H-1H COSY, HSQC, and HMBC). Fourier transform resulting residue was treated with H2O (100 mL) and
infrared (FT-IR) spectroscopy was taken on a Bruker Tensor extracted with EtOAc (3 £ 50 mL). The combined organic
27 instrument with KBr disks. Electrospray ionization mass phase was washed with brine (2 £ 50 mL) and dried over
spectra were obtained by using Bruker ESI-Q-TOF-Mass MgSO4. The filtrate was concentrated and the obtained solid
spectrometry. The spectra were measured fully in the positive was crystallized from EtOAc/Hexane (v/v, 1:3) to give white
ion mode and showed the expected molecular ion peaks in all crystals. Yield: 1.5089 g (94%) and m.p. 128.6–130.0ꢀC.
Sch. 1. The reaction conditions are: (a) EtOH, NaOEt, benzyl bromide 3; reflux (b) (1) MeOH, NaBH4, NiCl2, Boc2O, (2) diethylene-
triamine; (c) (1) NaOH, (2) NaHSO4; (d) (1) HCl, (2) Et2O, (3) NaHCO3; (e) (1) MeOH, Et3N, salicylaldehyde 8 (2) MeOH, NaBH4,
0ꢀC; (f) EtOH, NaOH, VOSO4, NaOAc.

Oxovanadium(IV) Schiff Base Complex
457
ESI-MS: m/z 283.1022 [MCNa]. IR (KBr, cm¡1): 3,310 (m), overnight. After cooling down to room temperature, the mix-
3,067 (w), 3,050 (w), 2,989 (w), 2,933 (w), 1,749 (vs), 1,666 ture was neutralized by NaHCO3 and washed with diethyl
(s), 1,514 (s), 1,501 (sh), 1,456 (m), 1,443 (sh), 1,373 (m), ether. The residual solution was concentrated under vacuum
1
1,324 (w), 1,303 (w), 1,280 (s), 1,088 (s), 1,043 (s). H NMR and afforded corresponding product, which could not be sep-
1
(400 MHz, DMSO-d6) dH 9.27 (1H, s, NH), 7.40–7.21 (5H, arated from NaCl. H NMR (400 MHz, D2O) dH 7.30–7.12
m, ÀÀC6H5), 4.10–3.93 (2H, q, J D 7.1 Hz, ÀÀCH2CH3), 3.37 (5H, m, Ar-H), 3.16 (1H, d, J D 13.3 Hz), 3.06 (1H, d, J D
(1H, d, J D 13.4 Hz, ÀÀCHHÀÀC6H5), 3.17 (1H, d, J D 13.5 Hz), 2.89 (1H, d, J D 13.3 Hz), 2.74 (1H, d, J D
13.4 Hz, ÀÀCHH-C6H5), 1.95 (3H, s, ÀÀCOCH3), 1.01 (3H, 13.5 Hz) ppm. 13C NMR (101 MHz, D2O) dC 170.71,
t, J D 7.1 Hz, -CH2CH3) ppm. 13C NMR (101 MHz, 131.52, 130.16, 129.36, 128.66, 61.25, 42.65, 39.37 ppm.
DMSO-d6) dC 169.96, 165.86, 132.24, 130.15, 128.27, 127.93,
117.05, 62.20, 58.62, 40.96, 21.63, 13.54 ppm.
2-Benzyl-2,3-bis[(2-hydroxybenzyl)amino]propanoic
acid (9)
Ethyl 2-acetamido-2-benzyl-3-[(tert-butoxycarbonyl)amino]
Triethylamine (0.5 mL) was added to a suspension of 7
(6.0 mmol) in anhydrous methanol (20 mL). Small portions of
salicylaldehyde (1.7549 g, 14.4 mmol) in MeOH (10 mL) were
slowly added to this solution. The color changed to yellow and
became darker with the addition. MgSO4 was added and the
solution was stirred overnight. After filtration, the filtrate was
cooled in ice and the following addition of NaBH4 (1.3255 g,
35.0 mmol) in portions produced white precipitates. Acetic
acid was used to adjusted pH to weak acidic. Then the solution
was filtered and the obtained white solid was washed with water
(2 £ 50 mL) and MeOH (2 £ 50 mL) and dried under vacuum.
Yield: 0.9749 g (40%) and m.p. 229.2–230.4ꢀC. For
C24H26N2O4: Anal. Calcd. C, 70.92; H, 6.45; N, 6.89; Found
C, 71.06; H, 6.60; N, 7.04 %. ESI-MS: m/z 407.1944 [M C H].
IR (KBr, cm¡1): 3,401 (br), 3,219 (w), 3,057 (w), 3,031 (w),
1,613 (vs), 1,595 (vs), 1,548 (sh), 1,490 (s), 1,462 (vs), 1,443 (w),
propanoate (5)
To the solution of 4 (0.5209 g, 2.0 mmol) in anhydrous
MeOH (50 mL) cooled to 0ꢀC were added Boc2O (0.4583 g,
2.1 mmol) and NiCl2¢6H2O (0.0476 g, 0.2 mmol) to give a
pale green solution. NaBH4 (0.6063 g, 16.0 mmol) was added
in portions with stirring. The purple mixture was stirred over-
night and then diethylenetriamine (0.2 mL) was added. After
1 h, the volatile part of the mixture was removed under vac-
uum. The residue was partitioned between EtOAc (3£50 mL)
and saturated NaHCO3 solution (50 mL). The organic phase
was washed with brine (50 mL) and dried over MgSO4. The
filtrate was evaporated and the residue was recrystallized from
EtOAc/Hexane (v/v, 1:4) to give white crystals. Yield:
0.5597 g (77%) and m.p. 74.0–74.5ꢀC. ESI-MS: m/z 387.1896
[M C Na]. IR (KBr, cm¡1): 3,400 (s), 3,305 (m), 1,741 (vs),
1714 (vs), 1,650 (s), 1,530 (vs), 1,391 (w), 1,375 (sh), 1,368 (s),
1,339 (w), 1,322 (w), 1,280 (w), 1,252 (s), 1,167 (s), 1,109 (m).
1H NMR (400 MHz, DMSO-d6) dH 7.69 (1H, s,
ÀÀNHCOCH3), 7.32–7.11 (5H, m, ÀÀC6H5), 6.79 (1H, s,
ÀÀNHBoc), 4.02–3.86 (2H, q, J D 7.1 Hz, ÀÀCH2CH3), 3.38
(1H, dd, J D 13.8 Hz, 6.1 Hz, -CHH-), 3.27 (1H, dd, J D
13.9 Hz, 6.7 Hz, ÀÀCHH-), 3.22–3.13 (1H, m, ÀÀCHHÀÀ),
3.01 (1H, d, J D 13.4 Hz, ÀÀCHHÀÀ), 1.81 (3H, s, ÀÀCOCH3),
1.39 (9H, s, ÀÀCOOC(CH3)3), 1.10 (3H, t, J D 7.1 Hz,
ÀÀCH2CH3) ppm. 13C NMR (101 MHz, DMSO-d6) dC
170.83, 169.12, 155.69, 135.86, 130.30, 127.83, 126.49, 77.91,
62.43, 60.30, 42.26, 36.96, 28.11, 22.71, 13.77 ppm.
1
1,389 (m), 843 (w), 761 (s), 745 (sh). H NMR (400 MHz,
DMSO-d6) dH 8.17 (4H, br s, ArÀÀOH and NH), 7.27–6.66
(13H, m, ArÀÀH), 3.91 (2H, s, ÀÀCH2NHCH2ÀÀ), 3.74 (1H, d,
J D 12.6 Hz, ÀÀCNHCHHÀÀ), 3.61 (1H, d, J D 12.6 Hz,
ÀÀCNHCHHÀÀ), 2.98 (2H, q, J D 13.5 Hz, C6H5ÀÀ
CH2ÀÀCÀÀ), 2.86 (2H, s, J D 13.0 Hz, ÀÀCCH2NHÀÀ) ppm.
13C NMR (101 MHz, DMSO-d6) dC 174.08, 156.30, 156.27,
136.52, 130.45, 130.21, 129.52, 129.30, 128.28, 127.87, 126.30,
124.78, 121.39, 118.71, 118.44, 115.38, 115.28, 63.90, 49.95,
47.84, 43.48, 40.05 ppm.
Sodium 2-benzyl-2,3-bis[(2-hydroxybenzyl)amino
oxovanadium(IV)] propionate, the VIVO complex
2-Acetamido-2-benzyl-3-[(tert-butoxycarbonyl)amino]
Under Ar atmosphere, reduced Schiff base 9 (0.2029 g,
0.5 mmol) was dissolved in 10 mL ethanol/water (v/v, 1:3)
with the aid of a few drops of NaOH aqueous solution (4 M).
Then an aqueous solution of sodium acetate (2.5 M, 1 mL)
was added. With the addition of VOSO4¢5H2O (0.5 M,
1 mL), the solution gradually turned brown and a grey solid
precipitated. After filtered, the precipitate was washed with
cold water (5 mL, ca. 4ꢀC), ethanol (5 mL) and diethylether
(10 mL) in order. After drying under vacuum, product was
obtained as grey solid. Yield: 0.1084 g (44%) and m.p. >
300ꢀC. For C24H23N2O5NaV: Anal. Calcd. C, 58.42; H,
4.70; N, 5.68; Found C, 58.80; H, 4.97; N, 5.92 %. ESI-MS:
m/z 493.0865 [M]. IR (KBr, cm¡1): 3,421 (br), 3,274 (m),
3,126 (mw), 2,928 (m), 2,865 (w), 1,639 (vs), 1,596 (vs), 1,391
propionic acid (6)
To the aqueous solution of NaOH (30 mL, 0.5 M) was added
5 (1.8222 g, 5.0 mmol). The mixture was stirred at 65ꢀC for
3 h. After complete dissolution of solids, NaHSO4 was added
to adjust the pH value to 2–3 and white solid 6 precipitated.
After filtration, the solid was washed with water (50 mL) and
diethyl ether (50 mL). Yield: 1.3900 g (83%) and m.p. 210.0–
211.5ꢀC. ESI-MS: m/z 359.1598 [M C Na]. IR (KBr, cm¡1):
3,415 (m), 3,255 (m), 3,061 (m), 1,743 (s), 1,688 (vs), 1,667
(vs), 1,559 (m), 1,512 (s), 1,337 (w), 1,317 (w), 1,293 (s), 1,255
(m), 1,110–1,032 (mw), 931 (w).
2-Benzyl-2,3-diaminopropionic acid (BDAP) (7)
To the aqueous hydrochloric acid solution (4 M, 10 mL) was (m), 1,338 (w), 1,308 (w), 1,142 (s), 1,080 (m), 1,037 (m), 962
1
added 6 (0.8409 g, 2.5 mmol) and the mixture was refluxed (s), 760 (s), 468 (w), 440 (m). H NMR (400 MHz, DMSO-

458
Wei et al.
d6) dH 7.25 (13H, d, J D 118.3 Hz), 3.60 (7H, br s), 1.67 (3H, coordinates at the same levels. The B3LYP/6-31G* vibra-
br s) ppm.
tional frequencies were scaled by a factor of 0.9804.[36]
Antibacterial Assays
Crystallographic Study
The bacteria were cultured in sterile liquid Luria-Bertani
(LB) medium (pH 7.2), which was made up of NaCl (1 g),
tryptone (1 g), and yeast extract (0.5 g) in 100 mL distilled
water at 37ꢀC. The following common infectious agents were
used including Staphylococcus aureus, Lactobacillus acidophi-
lus, Enterococcus faecalis, and Escherichia coli, which were
cultured in 5 mL LB medium at 37ꢀC, 200 rpm for 16 h, and
subsequently were applied to biological study.
In the inhibition zone test, the antibacterial activities were
evaluated by measuring the diameter of inhibition zone
according to the disc-agar diffusion method.[37] The tested
compounds were dissolved in DMSO (conc. 1 mg mL¡1) and
soaked in sterile discs (diam. 5 mm) that were later placed on
the seeded plates. After incubation at 37ꢀC for 24 h, the
diameter of inhibition zone surrounding each disk was mea-
sured. The data presented in Table 2 are the average value
from quadruplicate measurements.
Above cultured microbes were also used to study the
inhibitory effect on the bacterial growth according to
reported methods.[38,39] 16 h later, the synthesized com-
pounds (dissolved in DMSO) were added with increasing
concentrations ranging from 0 to 1500 mg mL¡1 to 1 mL LB
containing 0.1 mL inoculum. After incubation for 4 h at
37ꢀC and 200 rpm, the absorbance was measured at 600 nm
(OD600) with a microplate reader (SpectraMax M2, Molecu-
lar Devices Corp., USA).
Single crystals were obtained by slow evaporation of n-hex-
ane–CHCl3 (4) and n-hexane–EtOAc (6) solutions at room
temperature. Crystallographic data were collected at Beijing
Synchrotron Radiation Facility (BSRF) beamline 1W2B,
which mounted with a MARCCD-165 detector with storage
ring working at 1.89 GeV. In the process, the crystals were
protected by liquid nitrogen at 100 K. Data were collected by
the program marccd and processed using HKL 2000.[24] The
structures were solved by direct methods and refined by full-
matrix least-squares on F2 using SHELXL97 program pack-
age.[25] Molecular graphics were provided with ORTEP3.[26]
Significant crystal data and structure refinements can be
found in Table S1.
Computational Methods
Gaussian09 package[27] was used to perform calculations,
based on the basic laws of quantum mechanics, in order to
identify the possible structure of ligand 9 and VIVO complex.
Gaussian 09 contains a series of electronic structure programs
to predict the energies, molecular structures, vibration fre-
quencies, and molecular properties and reactions of mole-
cules in chemical environments.
As shown in Table 1, computations were carried out using
DFT[28] at the B3LYP level,[29,30] a hybrid functional combin-
ing Becke’s 1988 nonlocal exchange[31] with Hartree-Fock
exchange along with the Lee-Yang-Parr[32] correlation func-
tional. All possible configurations were fully optimized with a
Cytotoxicity Assays
description of V atom by a pseudopotential ECP10MDF[33,34] Cytotoxicity assays were tested on human lung carcinoma
and all the other elements by 6-31G* basis set.[35] The spin epithelial cell (A549) and human cervical carcinoma cell
state was set to be doublet for complexes and singlet for (Hela) respectively. The cell viability was evaluated by using
ligands.
a standard Cell Counting Kit-8 (CCK-8) colorimetric assay,
The nature of the optimized structure was checked using performed as follows: Cells were seeded into 96-well sterile
normal-mode frequency analysis (i.e., the real minimum plates in 0.1 mL of supplemented Dulbecco’s Modified
structure must have no negative frequencies). The vibrational Eagle’s Medium (DMEM) at a density of 5£103 cells per
frequencies were determined by evaluating analytically the well and incubated for 24 h at 37ꢀC under 5% CO2 atmo-
second derivatives of the energy with respect to the nuclear sphere at constant humidity.
Table 1. Mayer bond order analysis of four complexes and relative electronic energiesa of complexes, Gibbs free energiesb of
complexing reactions, and deformation energiesc of ligands for four complexes at B3LYP/6-31G* level with ZPE correction.
Bond
R_VIVO Complex_a
R_VIVO Complex_b
S_VIVO Complex_c
S_VIVO Complex_d
Mayer bond order
V(32)¡O(27)
V(32)¡O(30)
V(32)¡N(25)
V(32)¡N(26)
V(32)¡O(28)
V(32)¡O(29)
DErelative
0.86
0.83
0.52
0.46
—
—
0.00
—
0.86
0.53
—
0.79
0.06
0.85
0.82
0.06
0.57
—
—
0.06
0.86
0.26
0.60
0.71
0.05
Energies
45.81
–765.99
54.95
26.79
–783.31
70.15
13.74
–802.26
74.29
DGreaction
DEdeformation
–814.87
58.97
a,b,cCalculated in kcal mol¡1. bThe Gibbs free energy is defined as DGreaction D Gcomplex – (Gligand3- C GVO2C).

Oxovanadium(IV) Schiff Base Complex
459
Table 2. Inhibition zone (mm) of Schiff base ligand 9 and its VIVO complex.
Diameter
Sample
S. aureus Mean § RSD L. acidophilus Mean § RSD E. faecalis Mean § RSD E. coli Mean § RSD
Schiff base ligand
VIVO complex
Standard: Kanamycin
0
0
0
0
8.52 § 0.388
9.70 § 0.381
16.51 § 0.127
9.51 § 0.338
13.58 § 0.378
16.32 § 0.309
21.40 § 0.168
13.17 § 0.270
After washing each well with phosphate buffered saline NMR Spectra
(PBS, 0.01 M, pH D 7.4), compounds dissolved in DMEM
1
The structure of ligand 9 was fully analyzed by H and 13C
were added with increasing concentrations ranging from 0 to
1200 mg mL¡1 to a volume of 0.1 mL per well. Subsequent
incubation for another 24 h, culture medium solution of
CCK-8 was added to each well and the plate was incubated
further for 1 h at 37ꢀC in cell culture incubator in a humidi-
fied 5% CO2 atmosphere. The cell viability was determined
by acquiring the absorbance, which was the average value
from triplicate measurements at 450 nm (OD450) with the
microplate spectrophotometer.
NMR along with 2-D H–1H COSY, H–13C HSQC, and
1
1
1H–13C HMBC, as illustrated in Figures 1–3.
1H–1H COSY Spectrum has established the correlations
between equivalent protons and adjacent protons. In the
Figure 1, two doublets 3.69–3.78 ppm and 3.56–3.65 ppm
can be ascribed to equivalent proton pairs at C18. The active
hydrogen atoms give rise to the resonance at 7.91–8.43 ppm.
From the 13C NMR spectroscopy we can see that the signals
observed at 156.27 and 156.30 ppm can be attributed to the
C23 and C22, which are the aromatic carbons attached to
Ophenolate atoms. The resonances due to aromatic carbons
can be located in the 115.28–156.30 ppm range. The resonan-
ces recorded in high field at 49.95, 47.84, 43.48, and
40.05 ppm can be assigned to C15, C14, C18, and C16,
respectively while signal at 63.90 ppm can be attributed to
Results and Discussion
Synthesis and Crystal Structure
Scheme 1 provided a general procedure for the synthesis
of VIVO complex from reduced Schiff base ligand 9 with
DAP aryl-substituted at its a-carbon position. Compound
2 was deprotonated by NaOEt and alkylated by benzyl
bromide 3 to give compound 4 in high yield with 94%.
The nitrile group was reduced by NaBH4 and then pro-
tected by Boc2O with the catalyst NiCl2 to give compound
5. This is a novel but key step for designing the protected
DAP derivatives in our study.[15] In situ hydrolysis of the
ethyl ester group resulted in compound 6. Subsequent
deprotection afforded BDAP 7 in D- and L-type forms.
This routine synthesis of the phenylalanine analogue
avoids using rather expensive reagents/catalyst[16] and
exhibits a straightforward and convenient method for
BDAP. The formation of Schiff base is usually favored by
the presence of dehydrating agents,[40] and therefore
MgSO4 was added to remove the water produced in con-
densation reaction. In order to avoid the imine hydrolysis,
the product was further reduced by NaBH4 in methanol
after the Schiff base was synthesized. Subsequent reaction
of ligand 9 and vanadyl gave the corresponding product
VIVO complex.
the quaternary carbon C17. 1HÀÀ C HSQC spectrum
13
(Figure 2) shows the respective correlation between H18,
H18’ with C18. Aromatic carbons are confirmed throughout
the correlations between the carbon and its neighboring pro-
ton by using HMBC spectrum. Figure 3 has shown that the
H5 (H6) is correlated with the carbons C20 and C7 (C8) with
2J, and correlated with carbon C9 with 3J long-range con-
nectivity. HMBC spectrum also shows that H14 (H18) is cor-
related with C19 (C21) with 2J long-range conductivities,
and the correlation between H14 with C1 and C23 (H18 with
C10 and C22) with the 3J long range connectivities. The
appearances of cross peaks show the correlations of C24 with
respective H15 and H16 with 3J long-range connectivities.
The VIVO complex was characterized by H NMR using
1
DMSO-d6 solvent. However, a resolvable 1H NMR spectrum
could not be exactly measured and display only broad signals
owing to paramagnetism of tetravalent vanadium.
IR Spectra
ORTEP presentations of the molecular structures for com- IR spectra (Figures S2–S6) were taken to validate the struc-
pounds 4 and 6 are given in Figure S1. Both 4 and 6 were tures and exhibited characteristic bands corresponding to
crystallized in racemic forms in the space groups P21/n and various functional groups in the 400–4000 cm¡1 region. The
ꢀ
P21/c, respectively. The bond length 1.147(2) A of C(9)ÀÀN imines NÀÀH stretching frequencies of the free ligand 9 and
(1) in compound 4 is typical for a triple bond. Although com- VIVO complex are expected in the 3100–3500 cm¡1 region.
pound 6 has a little bulky benzyl group, the bond angle of C N-H stretching frequencies are shifted to a lower wavenum-
(6)ÀÀC(7)ÀÀC(8) almost stays the same with only slight differ- ber, indicating the ligation of imines nitrogen to the metal
ence of 2ꢀ compared to reported DAP with alkyl chain vanadium, which is supported by the literature.[21] The
group.[17]
bands ranged at 2800–3000 cm¡1 are associated with the

460
Wei et al.
Fig. 1. 1H–1H connectivities in the COSY spectrum for ligand 9.
asymmetric (gas) and symmetric (gs) stretching vibrations of DFT Computations
aliphatic methylene (ÀÀCH2ÀÀ) and aromatic CH. Their fre-
Geometries of the neutral and deprotonated ligands
At the experimental condition, the possible complexation
processes of Schiff base ligand (L) and VOSO4 are as follows:
quencies and intensities nearly stay the same in changing
from Schiff base ligand 9 to VIVO complex. The CHO
stretching vibration ascribes at the band 1613 cm¡1 in the
Schiff base ligand and at the band 1639 cm¡1 in the VIVO
complex, respectively.[41] The carboxylate ion group -COO¡
absorbs strongly at 1595 cm¡1 in ligand and at 1596 cm¡1
in complex as asymmetrical C(HO)2 stretching, and more
weakly at 1389 cm¡1 in ligand and at 1391 cm¡1 in complex
as symmetrical C(HO)2 stretching. CÀÀN stretching absorp-
tion frequencies of the imines distribute in a wide range at
1020–1250 cm¡1 and 1266–1342 cm¡1 region.[42]
LH3 C 3NaOH ! L3 ¡ C 3NaC C 3H2O
VOSO4 C 2NaOAc ! VO.OAc/2 C Na2SO4
L3 ¡ C VO.OAc/2 ! [VOL]¡ C 2[OAc]¡
(1)
(2)
(3)
In order to predict preference on a specific configuration of
the ligand 9, R- and S- enantiomer, each of which covers four
conformers differing in the relative position of two phenol
hydroxyl groups, were considered to construct the neutral
ligands in the calculations. These fully optimized stereoisom-
ers of the neutral ligands are shown in Figure 4. R-conform-
The strong and sharp VHO stretching band in the complex
shows at 962 cm¡1 similar to that of relevant referen-
ces.[21,40,43] The assignments of vanadium-oxygen and vana-
dium-nitrogen are sometimes very difficult. As reported by
Zamian,[43] VÀÀO and VÀÀN is tentatively assigned at 468 ers are more stable than S-type. Among the explored isomers
(w) cm¡1 and 440 (m) cm¡1 respectively, where the bands are
observed as new absorption peaks and not exist in the spec-
trum of the free ligand 9.
of neutral ligand, LR_d is the most stable with energy differ-
ences of more than 5 kcal mol¡1 compared to other ligands.
These optimized geometries were then used to prepare the

Oxovanadium(IV) Schiff Base Complex
461
Fig. 2. One bond CH correlations in the HSQC spectrum for ligand 9.
is coordinated to Ophenolate, Ocarboxylate, or Nimine. Their struc-
tures and natural bond orbital diagram are illustrated in
Figure 5. Mayer bond order analysis of four complexes and
the relative electronic energies of complexes, Gibbs free ener-
gies of the complexing reactions, and deformation energies of
ligands for four complexes are listed in Table 1.
starting structures of corresponding deprotonated ligands,
which were also fully optimized followed by vibrational fre-
quency analysis. Results reveal that deprotonated LS_d and
LR_b anions are thermodynamically minima. The electronic
energy of LS_d anion is slightly higher 1.05 kcal mol¡1 than
that of LR_b anion, while others are more than 6.40 kcal
mol¡1 relative to LR_b anion. Figure S7 illustrates the pre-
dicted IR spectra of deprotonated LS_d and LR_b anions. It
seems that the predicted spectrum of LR_b anion agrees well
with that determined in experiment.
Figure 5 discloses that R_VIVO Complex_a has the coor-
dination sites of V atom with 2 £ Ophenolate and 2 £ Nimine
donors, forming a tetradentate complex. HOMO-11 and
HOMO-13 of R_VIVO Complex_a show the interaction of V
with O and N, respectively. The NBO analysis indicates that
O27 coordinated with V has major contribution to orbital
HOMO-11. The contribution consists of d-shells of V
(22.9%) and p-shells of O27 (36.0%), O30 (18.6%), and N26
(8.5%). Orbital HOMO-13 mainly consists of d-shells of V
(16.2%) and p-shells of N25 (7.2%) and N26 (7.4%). The
composition of these orbitals indicates that V atom coordi-
nated to Ophenolate takes precedence over other sites in
R_VIVO Complex_a, which is in accord with the Mayer
bond order analysis shown in Table 1, where the bond orders
of V with O27 and O30 are 0.86 and 0.83, respectively. These
Structure of the VIVO Complex
We consider all possible coordination sites of deprotonated
ligand anions to VIVO (i.e., in the initial guess V atom was
coordinated to imine N or to O atoms of ligand 9). In total
there are 20 possible coordination situations for all deproto-
nated ligands. The computational results reveal four preferred
complexes (R_VIVO Complex_a, R_VIVO Complex_b,
S_VIVO Complex_c, and S_VIVO Complex_d), where V atom

462
Wei et al.
Fig. 3. Long range CH correlations in the HMBC spectrum for ligand 9.
two bonds are stronger than that between V and N25 or N26 free energies of complexing reactions, and deformation ener-
(0.46 and 0.52, respectively).
gies of ligands are calculated at B3LYP/6-31G* level. It can
Similarly, it can be concluded that R_VIVO Complex_b be shown from Table 1 that R_VIVO Complex_a is located
forms tridentate complex with V¡O30, V¡O28, and V¡N25 as the most thermodynamically stable minimum among all
coordination bonds, in which V binds to Ocarboxylate instead complexes due to the lowest relative electronic energy. The
of 2 £ Ophenolate. S_VIVO Complex_c has three-coordination Gibbs free energy of R_VIVO Complex_a is the lowest (i.e.,
bonds of V¡O30, V¡O27, and V¡N26, while S_VIVO Com- –814.87 kcal mol¡1), which reveals that forming of R_VIVO
plex_d is tetra-coordinated ones.
Complex_a is relatively dominant. In addition, the deforma-
From Mayer bond order analysis, it can be shown that V tion energies of ligands in R-type complexes are lower than
coordinated to O is of priority relative to N atom in four those in S-type ones, in which the deformation energy is
complexes. This can be explained according to Pearson’s defined as the energy difference between the ligand in com-
hard soft acid base (HSAB) principle,[44] which states that the plex and free ligand ion. The larger deformation energy indi-
hard and soft cations prefer to complex to hard and soft elec- cates the larger strain in complex. Obviously, from the
tron donors, respectively. The stability of complexes formed relative electronic energy, reaction free energy and deforma-
largely depends on the nature of the electron donor atoms tion energy of ligand in complex, it can be suggested that
2C
present in the ligand. In term of HSAB theory, [VIVO]
classified as hard acids, while the charged Ophenolate and Ocar- est-lying stationary point.
are harder bases than Nimine. Hence, V atom binds to Theoretical IR spectra of four complexes are shown in
Figure S8. It can be found that the spectra of R-type com-
is R_VIVO Complex_a is easy to form and identified as the low-
boxylate
O stronger than to N during complexation.
In order to further understand the stability of four com- plexes are much closer agreement with the experimental
plexes, the relative electronic energies of complexes, Gibbs observations relative to S-type ones. Accordingly, R_VIVO

Oxovanadium(IV) Schiff Base Complex
463
Fig. 4. The stereoisomers of the neutral ligand and their relative energies with zero-point energy correction at B3LYP/6-31G* level.
Fig. 5. The predicted structures of VIVO complex and natural bond orbital diagram at B3LYP/6-31G* level (V atom is labeled as
No.32).

464
Wei et al.
Complex_a is predicted as the most possible structure in the from this molecular gives a fragment ion peak at m/z
present study from the viewpoint of the thermochemistry.
471.1055 corresponding to the [MÀÀNa C H] species. The
molecular ion continuously undergoes demetallation to give
a fragment ion peak at m/z 407.1902, which belongs to
[MÀÀNa-VOC4H] species equivalent to the ligand 9. The
molecular ion peaks are shown at 963.1832 and 1433.2801,
corresponding to [2M-Na] and [3M-2Na], respectively.
ESI-MS Spectra
ESI-MS spectra of the ligand 9 and its VIVO complex are
depicted in Figure 6. Overall, the suggested structural formu-
lae are further confirmed by analysis data, and the results are
in agreement with a metal/ligand ratio of 1:1 in the VIVO
complex.
In Vitro Biological Evaluation
The molecular ion peak for 9 is observed at m/z 407.1944 Antibacterial activities were qualitatively screened by using
corresponding to [M C H]. This species by the loss of Gram-positive bacteria, namely S. aureus, L. acidophilus, and
ÀÀCH2ÀÀC6H4ÀÀOÀÀ section produces a fragment ion E. faecalis, and a Gram-negative bacterium E. coli. Pure
[MÀÀC7H6O C H] at m/z 301.1537. The molecular ion peaks DMSO as a reference did not show any inhibition against the
observed at 813.3821 and 1219.5643 corresponds to [2M C H] tested bacteria. Table 2 shows the comparative data by mea-
and [3M C H], respectively. A molecular ion peak of the suring the diameter of inhibition zone. Schiff base ligand 9
VIVO complex shown at m/z 493.0867 is equivalent to the showed no antibacterial activity against all the four strains. A
molecular weight of its parent ion. Removing a sodium ion clear zone around each disk indicates that the growth of
Fig. 6. ESI-mass spectra of ligand 9 (a) and VIVO complex (b) in the positive mode (the data shown are on the top traces).

Oxovanadium(IV) Schiff Base Complex
465
Fig. 7. Inhibition growth curves of VIVO complex against S. aureus, L. acidophilus, E. faecalis, and E. coli.
microbes is evidently inhibited in the presence of VIVO com-
Schiff base ligand 9 and VIVO complex were chosen to
plex. The inhibitory ratios against above microbes are all evaluate in the cytotoxicity assays due to the lower toxicity
above 50% compared with standard kanamycin as positive than that of vanadate.[45] CCK-8 assay was used to determine
control. The inhibitory effect of VIVO complex on the bacte- cellular survival rates at a particular time when exposed to
rial growth was recorded spectrophotometrically after incu- cytotoxic complex. As shown in Figure 8, ligand 9 is not
bation. From the growth-inhibitory curves in Figure 7 we remarkable towards the tumor cells. The VIVO complex
can see clearly that antibacterial activity is concentration presents greater antitumor activity in vitro against both A549
dependent: with the increasing concentration ranging from 0 and Hela cell lines compared with free ligand as negative con-
to 1500 mg mL¡1, the absorbance at 600 nm decreases. trol. The inhibitory action is strengthened with the concentra-
Hence, it demonstrates that VIVO complex can perform as an tion increases. In above biological assays, both Schiff base
inhibitor on the bacterial growth.
ligand 9 and VIVO complex were distributed homogeneously
Fig. 8. Cell viability of Schiff base ligand 9 and VIVO complex on growth inhibition on A549 (a) and Hela (b).

466
Wei et al.
in the form of emulsion, and showed excellent stability in the
culture medium without precipitation phenomenon. A brief
summary drawn from the previous in vitro biological evalua-
tion is that the VIVO complex has shown inhibitory activities
toward either the bacteria or the tumor cells and exhibits the
potential as antibacterial and antitumor pharmaceuticals.
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Conclusions
We have described the synthesis of VIVO complex of reduced
Schiff base derived from phenylalanine analogue containing
DAP. The composition and chemical properties are charac-
terized and analyzed. Theoretical study has been conducted
and presents the most probable binding mode. In vitro biolog-
ical evaluation, the VIVO complex shows enhanced activity as
antibacterial agents against both Gram-negative and Gram-
positive bacteria as well as antitumor activity against two
tumor cell lines. DFT computations in this paper may pro-
vide theoretical base for the description and explanation of
13. Corrigan, J. J.; Srinivasan, N. G. Biochemistry 1966, 5, 1185.
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€
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21. Costa Pessoa, J.; Marcao, S.; Correia, I.; Goncalves, G.;
This research is supported by One Hundred Person Project of
the Chinese Academy of Sciences (Grant No.
292011312D1117110). The Supercomputing Center of Chinese
Academy of Sciences is gratefully acknowledged for providing
the computational resources.
€
Dornyei, A.; Kiss, T.; Jakusch, T.; Tomaz, I.; Castro, M. M.
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