Synthesis, structural characterization, VHPO mimicking peroxidative bromination and DNA nuclease activity of oxovanadium(v) complexes

Article abstract of DOI:10.1039/c3dt51291f

The two novel oxovanadium(v) complexes [VO(PyDC)(BHA)] (1) [PyDC = pyridine-2,6-dicarboxylate, BHA = benzohydroxamate] and [VO(PyDC)(BPHA)] (2) [BPHA = benzophenyl hydroxamate] were synthesized by successive addition of a methanolic solution of H₂PyDC and the corresponding hydroxamic acid ligand to the aqueous solution of ammonium metavanadate (NH₄VO ₃). The hydroxamic acid ligands were characterized by elemental analysis, IR, UV-vis and NMR studies whereas the complexes were characterized by IR, UV-vis, CHN, molar conductance, magnetic moment, mass and NMR spectroscopic methods. The structures of the complexes were determined by single crystal X-ray crystallography. The structures of both complexes reveal that vanadium(v) has distorted octahedral geometry. The bromoperoxidase activities of these complexes have been demonstrated through the activation of C-H bonds of phenol, o-cresol and p-cresol. The catalytic products have been characterized by GC-MS analysis which shows that good conversions have been achieved. So far as the catalytic efficiency of the complexes are concerned complex 2 is found to be superior to complex 1. Both the complexes were tested for DNA nuclease activity with pUC19 plasmid DNA. The results show that both of them exhibited nuclease activity against pUC19 circular plasmid DNA. The complexes produced both nicked coils and linear forms. In this case also it is observed that complex 2 shows better nuclease activity than complex 1.

Full text of DOI:10.1039/c3dt51291f

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PAPER
Synthesis, structural characterization, VHPO mimicking
peroxidative bromination and DNA nuclease activity of
oxovanadium(V) complexes†
Cite this: Dalton Trans., 2013, 42, 13425
Swarup Patra, Suparna Chatterjee, Tapan Kr. Si and Kalyan K. Mukherjea*
The two novel oxovanadium(V) complexes [VO(PyDC)(BHA)] (1) [PyDC = pyridine-2,6-dicarboxylate,
BHA = benzohydroxamate] and [VO(PyDC)(BPHA)] (2) [BPHA = benzophenyl hydroxamate] were syn-
thesized by successive addition of a methanolic solution of H
2
PyDC and the corresponding hydroxamic
VO ). The hydroxamic acid ligands
acid ligand to the aqueous solution of ammonium metavanadate (NH
4
3
were characterized by elemental analysis, IR, UV-vis and NMR studies whereas the complexes were charac-
terized by IR, UV-vis, CHN, molar conductance, magnetic moment, mass and NMR spectroscopic methods.
The structures of the complexes were determined by single crystal X-ray crystallography. The structures of
both complexes reveal that vanadium(V) has distorted octahedral geometry. The bromoperoxidase activi-
ties of these complexes have been demonstrated through the activation of C–H bonds of phenol,
o-cresol and p-cresol. The catalytic products have been characterized by GC-MS analysis which shows that
good conversions have been achieved. So far as the catalytic efficiency of the complexes are concerned
complex 2 is found to be superior to complex 1. Both the complexes were tested for DNA nuclease
activity with pUC19 plasmid DNA. The results show that both of them exhibited nuclease activity against
pUC19 circular plasmid DNA. The complexes produced both nicked coils and linear forms. In this case
also it is observed that complex 2 shows better nuclease activity than complex 1.
Received 16th May 2013,
Accepted 9th July 2013
DOI: 10.1039/c3dt51291f
www.rsc.org/dalton
they exhibit a high degree of amino acid homology in their
active centres leading to almost identical active site structures.
Introduction
16
The coordination chemistry of vanadium with multidentate Reactions involving the oxidative bromination of organic sub-
ligands is receiving special attention because of the potential strates catalysed by vanadium complexes in the presence of
1
–6
7–10
therapeutic
plexes. Modelling the structure and monitoring the activity of model reactions for ‘VHPO’
various vanadium containing biomimetic and biomimicking route for the biosynthesis of many useful natural halogenated
and catalytic
application of vanadium com- halide under physiological conditions have been considered as
1
7–21
enzymes. This is an important
2
2
molecules have also influenced research on vanadium chemi- organic compounds. Moreover, the oxovanadium(V) com-
stry. Examples of interest in this context are the naturally plexes are also used in homogeneous catalysis of oxygen trans-
occurring vanadium dependent haloperoxidases (VHPO).
Vanadium dependent haloperoxidase enzymes isolated from compounds (hydrocarbons, alcohols,
different sources such as Ascophyllum nodosum (brown etc.). The synthesis of transition metal complexes capable of
1
1,12
fer in the field of oxidation reactions of various organic
2
3–29
30,31
organic sulfide
1
3
14
algae),
Corallina officinalis (red algae),
inaequalis (fungi) have been structurally characterized and current interest because it plays a major role in genomic
and Curvularia cleaving DNA at specific sites has been an area of considerable
1
5
3
2,33
research, photodynamic therapy of cancer,
lopment of new tools for nanotechnology.
and the deve-
Many oxovana-
3
4,35
dium(V) complexes have been shown to have the potentiality of
Department of Chemistry, Jadavpur University, Kolkata-700032, India.
3
6
37–40
41
nitrogen fixation, insulin mimetism
and antitumor
E-mail: k_mukherjea@yahoo.com; Fax: +91-33-2414-6584; Tel: +91-9831129321
†
4
2
Electronic supplementary information (ESI) available: The figures of gas chro- and antiamoebic activities, while many other such complexes
matograph (Fig. S1–S6), GC-Mass spectra (Fig. S7–S14), absorption spectra of the
complexes in presence and absence of increasing amounts of DNA (Fig. S15 and
S16), hydrogen bonding (Tables S1 and S2) and bond distances and bond angles
of the above two complexes (Table S3) are available as ESI. CCDC 870238 and
have been known to be the initiators in the photo-cleavage of
43,44
DNA.
Therefore, reactivity of oxovanadium(V) complexes is
receiving renewed attention in the fields of both bromination
of organic compounds via bromide oxidation and the develop-
ment of DNA cleavage reagents. However, reports in relation to
870239 for complexes 1 and 2 respectively. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c3dt51291f
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4
5–48
the interaction of vanadium complexes
with DNA are 7.7–7.4 ppm in BHAH and at 7.4 –7.2 ppm in BPHAH due to
rather scant. On the other hand, the hydroxamic acid deriva- the presence of the aromatic protons are shifted to
tives are good analytical reagents and have important biologi- 7.8–7.5 ppm in complex 1 and 7.6–7.2 ppm in complex 2. This
1
6
cal implications due to their siderophoric role. Hence, the clearly indicates that the ligands BHAH and BPHAH are
foregoing facts prompted us to make an attempt to design and involved in coordination with the metal in complexes 1 and 2
develop the vanadium based hydroxamate complexes in order respectively.
to employ them in mimicking enzymatic functions. As a result
Molecular structure of complexes 1 and 2. The coordination
of such an attempt, we could develop two new enzyme mimick- geometry around the metal center in complexes 1 (Fig. 2) and
ing oxovanadium complexes, viz. [VO(PyDC)(BHA)] (1) and 2 (Fig. 4) can be described as distorted octahedral with the oxo
[VO(PyDC)(BPHA)] (2).
oxygen (O1 in complexes 1 and 2) and carboxyl oxygen (O7 in
complexes 1 and 2) atoms occupying the apical sites. The
corresponding basal planes are defined by three donor atoms
(
2
O3, O4, N2 in complexes 1 and 2) of the tridentate pyridine-
,6-dicarboxylate ligand (PyDC ) and one oxygen atom (O6 in
Results and discussion
Characterisation of the complexes
2
−
complexes 1 and 2) from the hydroxamate ligand (BHA in 1
IR and UV-vis spectroscopic characterization of the complex. and BPHA in 2). The axial VvO bond distances V1–O1 in
5
3
56
The IR spectra of pyridine-2,6-dicarboxylic acid [H PyDC] show complex 1 and complex 2 are 1.5804(16) Å and 1.5770(17) Å
2
−
1
a strong absorption band in the region 3067–2535 cm due to respectively. The vanadium atom is displaced from the basal
4
9,50
the O–H stretching mode
of the COOH group. The other plane towards the oxo ligand by 0.241(1) Å and 0.237 Å in com-
5
0
two stretching vibrations of the H PyDC ligand at 1705 and plexes 1 and 2 respectively. As a result, the V–O bond distance
2
1
1
573 cm− assignable to νasym(COO–) and νsym(COO–), respectively, [V1–O7 in 1 and 2] trans to the oxo ligand is elongated to
−
1
are shifted to 1674 and 1557 cm in complex 1 and 1700 and 2.1594(13) Å and 2.1471(15) Å in complexes 1 and 2 respect-
1
1
537 cm− in complex 2. This downward shift in ν(COO–) ively as compared to the corresponding equatorial bond
vibrations is suggestive of the involvement of carboxylate lengths (Table 1). The equatorial V1–N2 bond distance in 1 is
O-atom in chelating with the metal ion in both the complexes. 2.0422(14) Å which is nearly the same as in 2 [2.0548(17) Å].
The νv–o vibrations in complexes 1 and 2 appear at 989 and The unit cells of the crystals of complexes 1 and 2 contain
1
24,51
9
87 cm− respectively.
In uncoordinated benzohydroxamic eight and six asymmetric [VO(PyDC)(BHA)] and [VO(PyDC)-
acid [BHAH] and benzophenylhydroxamic acid [BPHAH] the (BPHA)] units respectively. The packing pattern in complex 1
ν(CvO), ν(N–O) and ν stretching frequencies appear at 1608, (Fig. 3) shows that a zigzag one dimensional infinite molecular
(C–N)
20, 1487 cm− and 1623, 925, 1491 cm
1
−1 52
respectively. The
9
shifting of the ν(CO) vibration to lower energy indicates the
coordination of the carbonyl oxygen to the vanadium(V) center
in both the cases. The minimal shifting of ν(C–N) vibrations of
−
1
BHAH and BPHAH ligands to 1485 cm in complex 1 and
488 cm− in complex 2 indicates a marginal change in C–N
1
1
bond order after coordination. The stretching frequencies of
the ν(N–O) after complexation appear at 914 and 918 cm− in
complexes 1 and 2 respectively.
1
Fig. 1 Structural representation of benzohydroxamic acid (BHAH) and N-ben-
zophenylhydroxamic acid (BPHAH).
No d–d transition bands are expected for either of the com-
plexes as there are no d electrons. Complexes 1 and 2 exhibit
−
2
ligand [PΠ (O )] to metal [V(d )] charge transfer (LMCT) tran-
xy
sition at 268 and 269 nm respectively. The other bands that
appeared at 222 and 225 nm in complexes 1 and 2 respectively
5
3–55
are due to intraligand transitions.
1
1
H NMR spectra of the complex. H NMR spectrometry
lends strong support in the elucidation of the structure of the
compound. The signals recorded at 8.3–8.2 ppm in the ligand
spectrum are due to the presence of three aromatic protons in
2
H PyDC. The presence of multiple proton signals in the range
8
7
.7–8.3 ppm in complex 1 and one triplet at 8.5 ppm (J =
.7 Hz) as well as one doublet at 8.3 ppm (J = 7.6 Hz) in
complex 2 indicates the coordination of the H
metal centre in both the complexes. The signal observed at
.1 ppm in the BPHAH ligand has disappeared in complex 2,
as a result of the deprotonation of the –OH group during
2
PyDC to the
9
Fig. 2 Ortep view of complex 1, [VO(PyDC)(BHA)], with the 25% ellipsoid
coordination. The multiple proton signals appearing at probability.
1
3426 | Dalton Trans., 2013, 42, 13425–13435
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Table 1 Selected bond lengths (Å) and bond angles (°) for the complexes
[
VO(PyDC)(BHA)] (1)
[VO(PyDC)(BPHA)] (2)
Bond distances:
V(1)–O(1)
V(1)–N(2)
1.5804(16)
2.0422(14)
2.1594(13)
V(1)–O(1)
V(1)–N(2)
V(1)–O(7)
1.5770(17)
2.0548(17)
2.1471(15)
V(1)–O(7)
Bond angles:
O(1)–V(1)–O(6)
O(1)–V(1)–O(4)
O(1)–V(1)–O(7)
O(1)–V(1)–N(2)
94.31(7)
96.60(7)
169.92(7)
102.84(7)
O(1)–V(1)–O(6)
O(1)–V(1)–O(4)
O(1)–V(1)–O(7)
O(1)–V(1)–N(2)
93.52(7)
94.31(8)
165.50(8)
108.03(8)
Fig. 4 Ortep view of complex 2, [VO(PyDC)(BPHA)], with the 25% ellipsoid
probability.
chain is formed due to strong hydrogen bonding (N1–H1⋯O2,
.840 Å) between the hydrogen atom (H1) attached with the N group, the formation of the extended H-bonding is hindered.
2
2
−
atom of the coordinated BHA ligand with the carboxylate The co-ligand PyDC plays an important role in stabilizing
oxygen (O2) of the coordinated PyDC ligand of another unit. the supramolecular packing in complex 2. Precisely, the car-
Two anti-parallel zigzag chains are closely spaced through the boxylate oxygen of the PyDC
2
−
2
−
ligand (O5 and H18–C18)
cross-linked hydrogen bonding (C3–H3⋯O7, 2.830 Å) between formed an intermolecular H-bonding enclosing a ten-mem-
aromatic hydrogen (H3) and carbonyl oxygen (O7) of hydroxa- bered ring motif which can be designated through Etter’s
2
mate ligands (BHA) of two different chains. Similarly, in graph set notation as R (10) (Fig. 5). All other important bond
2
complex 2 the packing structure (Fig. 5) shows that the two lengths and bond angles are given in Table 1 which are com-
dimensional molecular layer is formed due to weak hydrogen parable to the corresponding values reported earlier for mono-
5
7
bonding [(C18–H18⋯O5, 3.316(3) Å and (C11–H11–O2, 3.329(3) meric oxovanadium(V) complexes. The tables of hydrogen
Å] between aromatic hydrogen atoms (H18) and (H11) and bonding of both the complexes are provided as ESI.†
carboxylate oxygen (O5) and carbonyl oxygen (O2) atoms of
Peroxidative bromination of functionalized organic com-
2
−
PyDC and BPHA ligands respectively. In complex 2, the two pounds. As the vanadium based active site structure of VHPO
essentially planar 2,6-pyridine dicarboxylate and benzophenyl- enzyme plays a key role in the biosynthesis of halogenated
hydroxamate ligands are nearly orthogonal to each other, the organic compounds via the oxidation of halides, the ability to
dihedral angle between the least-square planes through the mimic such a type of reaction by the newly synthesized oxo-
ligand atoms is 84.96° (1). In complex 1 the infinite 1D vanadium(V) complexes has been examined for the bromina-
H-bonding is formed due to the presence of a N–H hydrogen tion of phenol, o-cresol and p-cresol in the presence of H O
2
2
of the primary hydroxamic acid ligand, which forms the supra- and KBr. Both complexes 1 and 2 have been found to catalyse
molecular crystal packing network, whereas in complex 2, the the bromination reaction effectively in the presence of H O2
2
N–H hydrogen of the BHA ligand is replaced by a phenyl group though their efficiencies are different (Table 2). The mechan-
in the BPHA ligand and because of the presence of this phenyl ism of bromide oxidation may take place in a similar fashion
Fig. 3 Extended H-bonding and packing arrangement of the complex [VO(PyDC)(BHA)] (1).
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Fig. 5 H-bonding enclosing a ten-membered ring motif present in the unit cell of the crystal lattice of the complex [VO(PyDC)(BPHA)] (2).
thereafter this in situ generated bromonium ion was trapped
Table 2 Details of the catalytic bromination of functionalized organic com-
4
3
a
b,c
by suitable organic substrates as per the earlier proposition.
To get the optimum result, the pH of the reaction medium was
pounds in stirring acetonitrile using 1 and 2 as a catalyst in the presence of
as a terminal oxidant and KBr in acidic medium at room temperature
2 2
H O
5
3
adjusted to ∼3.0. Control experiments of the bromination
reactions performed by maintaining all other additives and
parameters fixed without the catalyst show that the yield of the
%
Yields of
brominated products
Entry Substrate Brominated products
1
Catalyst 1 Catalyst 2 brominated products is negligibly small after a long period of
reaction, while in the presence of the catalysts, the percentage
69
72
yield of the brominated products is appreciably high (Table 2).
The results of the catalytic bromination reaction show that the
efficiency of the bromination reaction is dependent on the
nature of the catalyst which is governed by the ligand environ-
ment of the vanadium centre. The yield percentage of the bro-
minated product in the case of the phenol substrate is
maximum (69% for catalyst 1 and 72% for catalyst 2) compared
to o-cresol (50% for catalyst 1 and 61% for catalyst 2) and
p-cresol (45% for catalyst 1 and 69% for catalyst 2). During the
course of the catalytic bromination reaction, although other
possible brominated products are obtained depending on the
substrates, the mono brominated products are the major ones
in the case of ortho-cresol and para-cresol, while in the case of
phenol, the dibrominated one is the major product. So, it is
observed that catalyst 1 is relatively less potent than catalyst 2.
It can be realised that the metal centre of catalyst 1 is co-
A(1)
B(17)
C(51)
A(11)
B(12)
C(41)
2
50
61
D(4)
E(14)
F(32)
D(4)
E(22)
F(35)
3
45
G(20)
H(25)
69
G(30)
H(39)
a
b
2
4 h (entry 1), 20 h (entries 2 and 3). Blank experiments were ordinated with the hydroxamate moiety whereas catalyst 2 is
performed, i.e. dropping the catalyst alone while other additives and
parameters remain the same. For entries and substrate
bromination was found to be negligible. For entry 1 ca. 7% and 5%
coordinated with a secondary hydroxamate in which the hydro-
gen of the hydroxamate nitrogen is replaced by the phenyl
conversion took place for catalysts 1 and 2 respectively. The mole group. Hence, the presence of the phenyl group in catalyst 2
2
3
c
ratio of catalyst/substrate = 1 : 200 (entry 1 using catalyst 2), 1 : 100
might have induced higher reactivity of the hydroperoxovana-
dium(V) intermediate coordinated with the secondary hydroxa-
mate ligand. The results of the GC-Mass analysis are included
(entry 1 using catalyst 1 and entries 2 and 3).
4
3
as has been reported earlier, and hence, in the present case, in the ESI.†
the oxovanadium(V) moiety of the complex is proposed to be
DNA binding study by absorption spectrophotometry. Elec-
converted to the hydroperoxovanadium(V) intermediate by tronic absorption spectroscopy is one of the useful techniques
5
8,59
reacting with H
2
O
2
and subsequently this peroxide co- for monitoring the binding
of metal complexes with DNA.
ordinated vanadium(V) intermediate oxidized the bromide The significant modification of the UV absorption band of
−
+ 43
(
Br ) under mild acidic condition to a bromonium ion (Br );
both complexes 1 and 2 on the addition of increasing amounts
1
3428 | Dalton Trans., 2013, 42, 13425–13435
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of DNA indicates the binding of both complexes 1 and 2 with
DNA. Upon the addition of increasing amounts of CT DNA
−
4
−4
(
0–10 M) to complex 1 (10 M), the ligand based charge
transfer band at 268 nm exhibited hyperchromism with a sig-
nificant blue shift (5 nm). Such hyperchromism along with the
concomitant blue shift in the spectra rules out groove binding
and suggests an intimate association of complex 1 with CT
DNA and it is likely that this complex 1 binds to CT DNA elec-
trostatically via external contact (surface binding) with the
6
0,61
DNA duplex.
On the other hand, upon the addition of
−4
−4
increasing amounts of CT DNA (0–10 M) to complex 2 (10 M),
the ligand based charge transfer band at 269 nm exhibited
hypochromism with a significant red shift (5 nm). This indi-
cates that there is an involvement of a strong stacking inter-
action between the aromatic chromophore of complex 2 and
the DNA base pairs.
ported by quantitative studies. Hypochromism results from
the contraction of DNA helix as well as the conformational
Fig. 6 Fluorescence spectra of (a) 1.25 × 10−4 M EB only, (b) EB + 10−4 M DNA
5
9,62
−4
This observation has further been sup- control, and (c)–( j) EB + DNA + (0.1–1.0) × 10 M complex 1. The arrow shows
that the intensity increased with the concentration of complex 1.
1
6,63
changes to DNA,
change in the secondary structure of the DNA double helix.
while hyperchromism results from a
6
4
The substantial difference in binding nature of the complexes
could arise due to the presence of more planar rings in
complex 2 in comparison to complex 1. In order to quantitat-
ively compare the binding strength of complexes 1 and 2 with
CT DNA, the intrinsic binding constant (K
b
) values were calcu-
4
lated following eqn (2) and were found to be (1.34 ± 0.2) × 10
5
−1
and (1.37 ± 0.3) × 10 M , for complexes 1 and 2 respectively.
The higher K value of complex 2 is due to the benzophenyl-
b
hydroxamic acid ligand which possesses a greater planar area,
thereby leading to stronger binding within the DNA base pairs
6
5
by the intercalative mode. The K
support the binding nature as suggested qualitatively from
the change in intensity and position of UV bands. The K
b
values of complexes 1 and
2
b
values revealed that complex 2 possesses a higher affinity for
DNA binding in comparison to complex 1. The corresponding
results of absorbance spectral studies are provided as ESI.†
Fluorescence emission study for DNA interaction. The
Fig. 7 Fluorescence spectra of (a) 1.25 × 10− M EB only, (b) EB + 10−4 M DNA
4
−
4
control, and (c)–( j) EB + DNA + (0.1–1.0) × 10 M complex 2. The arrow shows
that the intensity decreased with the concentration of complex 2. Inset: Stern–
Volmer plot for the quenching of fluorescence of the ethidium bromide (EB)
results obtained from spectrofluorometric titrations indicated DNA complex caused by complex 2.
that both complexes 1 and 2 could effectively bind to DNA. In
order to confirm the binding mode and compare the binding
the amount of EB intercalated into DNA, or there exists com-
petitive intercalation between the metal complex and EB with
DNA, thereby releasing some EB from the DNA–EB system.
To get more straightforward information on the quenching of
fluorescence intensity, the Stern–Volmer quenching constant
KSV was determined. The KSV value was calculated from the
affinities of the metal complexes to DNA, an ethidium
bromide (EB) displacement experiment was carried out. Ethi-
dium bromide is a weakly fluorescent compound, but its fluo-
rescence is greatly increased when EB is specifically
6
7,68
6
6
intercalated into the base pairs of double stranded DNA.
Further enhancement of the emission intensity of the CT–
DNA–EB system with increasing concentrations (0–10−4 M) of
complex 1 is observed (Fig. 6). It is to be noted that complex 1
alone does not show any fluorescence in PBS buffer, but it
induces an increase in the fluorescence of the DNA–EB
plot of I /I versus [Q]. According to the linear Stern–Volmer
0
6
9
equation,
I0=I ¼ 1 þ KSV ½Qꢀ
ð1Þ
complex. This effect could not be explained at this point. On where I
0
and I are the fluorescence intensities in the absence
the other hand, under the same experimental conditions, it is and presence of a quencher [Q (Complex)] respectively. KSV is
observed that there is a decrease in emission intensity of the the Stern–Volmer quenching constant, which is obtained from
CT–DNA–EB system with increasing concentration of complex the slope of the plot of I
0
/I vs. [Q]. KSV was given by the ratio of
(0–10− M) (Fig. 7). This may happen because either EB the slope to the intercept. The KSV value for complex 2 is found
4
2
5
−1
binds the metal complex strongly, resulting in a decrease in to be (1.72 ± 0.3) × 10 M at 37 °C. These data suggest that
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complex 2 binds strongly with CT-DNA. The high Ksv value
indicates a strong binding of complex 2 with DNA by displa-
cing the EB from DNA base pairs. This observation also sup-
ports the proposition from spectrophotometric studies [vide
5
−1
the K value of DNA–complex 2 which is (1.37 ± 0.3) × 10 M
]
b
that complex
intercalation.
2 binds the double stranded DNA by
Gel electrophoresis study for nuclease activity. The
efficiency of DNA cleavage activity of complexes 1 and 2 has
been assessed by gel electrophoresis using super coil (SC) pUC
Fig. 9 Cleavage of super coil pUC19 DNA (150 ng) by complex 2 in Tris-HCl
−
2
−1
1
9 DNA in Tris-HCl–NaCl buffer (5 × 10 mL , pH 7.2). The
−2
−1
−2
−1
buffer (5 × 10 mL , pH 7.2) containing 5 × 10 mL NaCl at 37 °C for an
−
6
double-stranded plasmid pUC19 DNA exists in a compact hour. Lane 1: DNA control, lane 2–6: DNA + (1–5) × 10 M of complex 2. SC:
super coil form. Upon induction of strand breaks, the super super coil, NC: nicked coil and LC: linear coil.
coil form of DNA is disrupted into the nicked coil (NC) form
and the linear coil (LC) form. If one strand is cleaved, the
6
0% nicking in plasmid DNA, whereas under the same experi-
mental conditions, complex 2 produces 20–41% of form II
NC) and 18–30% of form III (LC), i.e. thereby induces up to
1% nicking (Table 3). It may be noted that the metal ion or
super coil form will relax to produce a nicked coil form. If
both the strands are cleaved, a linear coil form will be pro-
duced. A relatively fast migration is observed for the super coil
form when the plasmid DNA is subjected to electrophoresis.
The nicked coil form migrates slowly and the linear coil form
(
7
the ligand alone are not capable of inducing any cleavage in
the plasmid DNA. It is evident from the above experiments
that complex 2 has greater efficiency of cleaving SC DNA
7
0
migrates between SC and NC. Hence, DNA strand breaks
induced by complexes 1 and 2 were quantified by gel electro-
phoresis experiment by measuring the transformation of the
super coil form into nicked coil and linear coil forms and the
results are presented in Fig. 8 and 9 respectively. The control
experiment suggests that untreated DNA (lane 1) has 86%
(
form I) into NC (form II) and LC (form III) than complex 1.
This may be a result of the involvement of the extended aro-
matic ring of the BPHA ligand
DNA, which in turn facilitates nicking.
71,72
in partial intercalation with
form I (SC) and 14% form II (NC). The treatment of DNA with
1–5) × 10− mol of complex 1 produces 17–36% of form II
6
(
(
NC) and 17–24% of form III (LC), i.e. complex 1 induces up to
Conclusions
In the present communication, the design, synthesis and bio-
mimicking activity of two oxovanadium complexes have been
presented, where complex 1 has the hydroxamate group and
complex 2 is having a secondary hydroxamate group. The com-
plexes were tested for bromoperoxidation activity. It is found
that both the complexes are capable to oxidatively brominate
the phenol, o-cresol and p-cresol, thereby mimicking the role
of the vanadium based bromoperoxidase enzyme. The nucle-
ase activity of both the complexes has been demonstrated with
pUC19 DNA. The gel electrophoregram and subsequent ana-
lysis show that the complexes induce substantial nicking in
the DNA strand, thereby producing both nicked coil (NC II)
and linear coil (LC III) forms of DNA. So, the two structurally
Fig. 8 Cleavage of super coil pUC19 DNA (150 ng) by complex 1 in Tris-HCl
−2
−1
−2
−1
buffer (5 × 10 mL , pH 7.2) containing 5 × 10 mL NaCl at 37 °C for an
−
6
hour. Lane 1: DNA control, lanes 2–6: DNA + (1–5) × 10 M of complex 1. SC: characterized oxovanadium(V) complexes can catalyse the per-
super coil, NC: nicked coil and LC: linear coil.
oxidative bromination of organic substrates in general, and
Table 3 Extent of DNA SC pUC19 (150 ng) cleavage by complexes 1 and 2
Complex 1
Complex 2
Lane no.
Reaction conditions
Form I (% SC)
Form II (% NC)
Form III (% LC)
Form I (% SC)
Form II (% NC)
Form III (% LC)
1
2
3
4
5
6
DNA control
86
66
56
54
52
40
14
17
21
23
24
36
0
17
23
23
24
24
86
62
55
45
35
29
14
20
23
31
36
41
0
18
22
24
29
30
DNA + 1 μM complex
DNA + 2 μM complex
DNA + 3 μM complex
DNA + 4 μM complex
DNA + 5 μM complex
1
3430 | Dalton Trans., 2013, 42, 13425–13435
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phenol and phenol derivatives in particular, and also exhibit (300 MHz, CD
3
OD, δ ppm): 7.7–7.4 (5H, m, aromatic protons).
nuclease activity by inducing nicking in the super coil (SC) UV-vis: λmax, nm (ε, M− cm ): 223 (7790). The structural rep-
1
−1
DNA.
resentation of the ligand benzohydroxamic acid (BHAH) is
shown in Fig. 1.
Synthesis of the ligand, N-benzophenylhydroxamic acid
Experimental
Materials
(
BPHAH)
The ligand was prepared as described previously. Yield: 1.5 g
70%). Anal. Calc. for C13 N: C – 73.2, H – 5.2, N – 6.6.
Found: C – 73.2, H – 5.1, N – 6.6%. IR (KBr, cm ): 1623(s):
7
5
Ammonium metavanadate and sodium bicarbonate were of
extrapure variety and purchased from SRL, India and were
used directly. Pyridine-2,6-dicarboxylic acid was obtained from
Avra, India. Extrapure zinc dust, o-cresol and p-cresol were
obtained from Loba Chemie (India). Nitrobenzene and
benzoyl chloride were obtained from B.D.H. (India). Liquid
ammonia was obtained from Ranbaxy (India). All the other
chemicals needed were obtained from Merck (India). Aceto-
nitrile, dichloromethane and acetone were further purified by
a literature method for physicochemical studies. Ultra high
pure grade dioxygen, dihydrogen, zero air and dinitrogen gas
used for chromatographic analysis were obtained from Indian
Refrigeration Stores, Calcutta. The ligands benzohydroxamic
acid and N-benzophenylhydroxamic acid were prepared as
(
11 2
H O
−1
1
ν(CvO), 1491(w): ν(C–N), 925(w): ν(N–O)
.
H NMR (300 MHz,
CD OD, δ ppm): 7.4–7.2 (10H, m, aromatic protons): 9.1(1H, s,
3
−1
−1
from N(ph)–OH). UV-vis: λmax, nm (ε, M cm ): 267 (15 128).
The structural representation of the ligand benzophenyl hydr-
oxamic acid (BPHAH) is shown in Fig. 1.
Synthesis of the complex [VO(PyDC)(BHA)] (1)
7
3
−
4
NH VO (58 mg i.e. 5 × 10 mol) was dissolved in warm water
4
3
with constant stirring and acidified with dilute HCl, then
4
8
4 mg, i.e. 5 × 10− mol aqueous solution of H PyDC was
2
added followed by the addition of a 15 mL methanolic solu-
tion of BHAH (69 mg i.e. 5 × 10− mol). Immediately, a deep
purple precipitate of complex 1 was obtained (Scheme 1). The
precipitate was filtered off and washed with water. The com-
pound is soluble in dichloromethane, chloroform, acetone,
acetonitrile and methanol and is a nonelectrolyte. Single crys-
tals suitable for X-ray diffraction were obtained by the slow
diffusion of complex 1 in an acetone–petroleum ether mixture.
It is air stable and diamagnetic at 298 K. Yield: 135 mg (64%).
4
7
4,75
described previously
and characterized by elemental ana-
1
lysis, UV-vis spectroscopy, IR, mass and H NMR spectral
studies. All the solvents used for chromatographic analysis
were either of HPLC, spectroscopic or GR grade and in all
cases their purity was confirmed by GC analysis before use. CT
DNA was obtained from the Sigma Chemical Company, USA
and super coil plasmid pUC19 DNA was procured from Genei
(Bangalore, India).
9 2 7
Anal. Calc. for C14H N O V: C – 45.7, H – 2.5, N – 7.6. Found:
−1
C – 45.6, H – 2.4, N – 7.6%. IR (KBr disc, cm ): 1674(s): νasym
Physical measurements
COO–), 1603(m): ν(C–O), 1557(m): νsym(COO–), 1485(m): ν(C–N), 989
(
Infrared spectra were recorded as KBr pellets using a Perkin-
Elmer RFX-I spectrophotometer and electronic spectra were
taken using an Agilent 8453E UV-vis spectrophotometer using
a 1 cm quartz cell against an appropriate reagent blank.
Elemental analyses were performed using a Perkin Elmer 2400
series II CHNS analyzer. The conductances of 10 (M) solu-
tions were measured using a Systronics 304 Conductivity
Meter. Magnetic susceptibility measurements were made
using a Magway MSB MKI Magnetic Susceptibility Balance
s): ν(VvO), 914(m): ν(N–O). UV-vis: λmax, nm (ε, M cm−1): 268
−1
(
(
1
6428), 222 (11 930). MS: m/z 368. H NMR (300 MHz, CDCI
3
,
δ ppm): 8.7–8.3 (3H, m, H PyDC), 7.8–7.5 (5H, m, aromatic
2
protons of BHAH).
−3
Synthesis of the complex [VO(PyDC)(BPHA)] (2)
4
NH
4
VO
3
(58 mg i.e. 5 × 10− mol) was dissolved in warm dis-
tilled water with constant stirring and acidified with dilute
HCl, then 84 mg, i.e. 5 × 10− mol aqueous solution of H
4
PyDC
2
(
Sherwood Scientific Ltd, Cambridge, England) at 298 K. NMR
spectra were recorded at room temperature using a Bruker
00 MHz NMR spectrometer. Mass spectra were obtained
was added followed by the addition of a 15 mL methanolic
solution of BPHAH (106 mg i.e. 5 × 10− mol), while a reddish
brown precipitate of complex 2 was obtained (Scheme 1). The
4
3
using a Qtof Micro YA263 mass spectrometer. GC measure-
ments were made either on an Agilent 6890N gas chromato-
graph using HP-1 and INNOWAX capillary column in the FID
mode with dinitrogen as the carrier gas or a SHIMADZU-
QP-5050A spectrometer whereas GC-MS measurements were
made using a SHIMADZU-QP-5050A spectrometer.
Synthesis of the ligand, benzohydroxamic acid (BHAH)
7
4
The ligand was prepared as described previously. Yield: 1.1 g
80%). Anal. Calc. for C N: C – 61.3, H – 5.1, N – 10.2.
Found: C – 61.4, H – 5.1, N – 10.2%. IR (KBr, cm ): 3254(m):
(
7 7 2
H O
−
1
Scheme 1 The synthetic pathway of the oxovanadium(V) complexes [VO(PyDC)-
1
ν(N–H), 1608(s): ν(CvO), 1487(w): ν(C–N), 920(w): ν(N–O). H NMR (BHA)] (1) and [VO(PyDC)(BPHA)] (2).
This journal is © The Royal Society of Chemistry 2013
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7
6
product was filtered off, washed several times with water and done using SHELXS-97 and SHELXL-97 programs. The struc-
finally dried in vacuum. The compound is soluble in dichloro- tures were solved by a direct method.
methane, chloroform, acetone, acetonitrile and methanol and
behaves as a nonelectrolyte. Single crystals suitable for X-ray Experimental set-up for catalytic bromination
diffraction studies were obtained by the slow diffusion of a
A mixture of complex 1 (the catalyst) (8.8 mg, i.e. 2.4 × 10−
dichloromethane solution of complex 2 in hexane. Complex 2
5
mol), and
a
representative substrate, namely phenol
is air stable and diamagnetic at 298 K. Yield: 150 mg (60%).
−3
(
226.2 mg, i.e. 2.4 × 10 mol; for the other cases see Table 2),
Anal. Calc. for C H N O V: C – 54.1, H – 3.0, N – 6.3. Found:
2
0
13 2 7
was dissolved in a 5.0 mL CH CN solvent and the solution was
taken in a 100 mL stoppered conical flask. To the above solu-
tion, 1.0 mL aqueous solution of KBr (589.2 mg, i.e. 4.8 × 10
mol) and 1.0 mL (9.8 × 10 mol) of 30% H O were added
under stirring conditions. The pH of the resulting solution
was adjusted to 3 by adding 2 M nitric acid. The resulting
yellow solution was stirred continuously at room temperature
for 24 h followed by quantitative extraction of the organic part
with 2.0 mL of diethyl ether so that practically the entire reac-
tion product was transferred to the ether layer. Thereafter, the
ether extract was concentrated to ∼1.0 mL by slow evaporation.
From the extract, 1.0 μL of the solution was taken in a gas
−1
3
C – 54.0, H – 2.9, and N – 6.3%. IR (KBr disc, cm ): 1700(s):
ν
9
2
asym(COO–), 1598(m): ν(C–O), 1537(w): νasym(COO–), 1488(w): ν(C–N)
,
−3
87(s): ν(vvO), 918(m): ν(N–O). UV-vis: λmax, nm (ε, M cm−1):
−1
−3
1
2 2
69 (10 754), 225 (20 700). MS: m/z 444. H NMR (300 MHz,
CDCI
.6–7.2 (10H, m, aromatic protons). C NMR (75 MHz, CDCI3,
δ ppm): 166.7, 150.9, 146.3, 139.8, 133.0, 130.6, 129.7, 129.5,
28.7, 128.5, 127.5, 127.4, 126.1. The synthetic pathway of
3
, δ ppm): 8.5 (1H, t, J = 7.7 Hz), 8.3 (2H, d, J = 7.5 Hz),
1
3
7
1
complex 2 is shown in Scheme 1.
X-ray structure analysis for complexes 1 and 2
Single crystals of [VO(PyDC)(BHA)] (1) and [VO(PyDC)(BPHA)] (2) syringe and injected through a GC port. The same method was
were obtained by slow diffusion of an acetone solution of adopted in the case of the reaction with catalyst 2 except that
complex 1 in petroleum ether and a dichloromethane solution complex 2 was added in place of complex 1. The products were
of complex 2 in hexane respectively. Selected crystal data and characterized by GC-MS spectrometry.
data collection parameters are given in Table 4. Data were col-
lected on a Bruker SMART Apex CCD area detector using DNA binding measurements
graphite monochromated Mo Kα radiation (λ = 0.71073 Å).
UV-vis spectral study. Absorption spectral titration experi-
X-ray data reduction, structure solution and refinement were
ments were performed by monitoring a 268 nm band for
complex 1 and 269 nm for complex 2 in the respective cases.
In each case the concentration of the complex was maintained
Table 4 Crystal data and structure refinement parameters for the complexes at 10− M, while the concentration of the CT DNA was varied
4
−
4
[
VO(PyDC)(BHA)] (1) and [VO(PyDC)(BPHA)] (2)
between the range of (0.2–1.0) × 10 M. An appropriate quan-
tity of CT DNA was added to both the complex solution and
the reference solution to eliminate the absorbance of DNA
itself. From the absorption data, the intrinsic binding constant
Parameters
[VO(PyDC)(BHA)]
[VO(PyDC)(BPHA)]
Molecular formula
Formula weight
Crystal system
Space group
a, b, c [Å] α, β, γ [°]
14 9 2 7
C H N O V
20 13 2 7
C H N O V
444.26
Monoclinic
P21/n
12.3056(3), 6.0449(2),
26.4794(6), 90,
102.664(2), 90
368.17
Kb was determined from a plot of [DNA]/(εa − ε ) vs. [DNA]
f
Orthorhombic
Pbcn (no. 60)
16.9290(13),
using the equation:
½
DNAꢀ=ðεa ꢁ εf Þ ¼ ½DNAꢀ=ðεb ꢁ εfÞ þ 1=Kb ðεb ꢁ εf Þ
ð2Þ
1
1
9
1.0728(9),
5.1442(12),
0, 90, 90
where [DNA] is the concentration of DNA in base pairs. The
3
V [A ], Z
D
μ [mm
F(000)
2838.8(4), 8
1.723
0.742
1921.78(9), 4
1.535
0.563
apparent absorption coefficients ε , ε and ε correspond to
a
f
b
−
3
calc. [g cm ]
−1
A
obsd./[complex], the extinction coefficient for the free
V-complex and the extinction coefficient for the V-complex in
the fully bound form, respectively. Plots of [DNA]/(εa − εf)
) with intercept 1/K
where K is obtained from the slope to the intercept ratio.
Fluorescence emission study. Emission intensity measure-
ments were carried out using an RF-5301PC Shimadzu spectro-
flourimeter. In this binding experiment, 50 μL of a CT DNA
]
1488
904
Crystal size [mm]
0.05 × 0.05 × 0.30
Data collection
273
0.20 × 0.05 × 0.04
versus [DNA] gave a slope 1/(ε
b
− ε
f
b
(ε
b
f
− ε ),
Temperature (K)
Radiation [Å] MoKα
Φ Range [°]
293
0.71073
1.58, 27.55
−16: 15, −7: 7,
−34: 34
0.71073
b
2.41, 27.45
−21: 21, −13: 14,
Dataset
−19: 19
Tot., uniq. data,
R(int)
Observed data
21460, 3236, 0.0949 16721, 4414, 0.039
−
4
−2
(10 M) solution in Tris-HCl–NaCl buffer (5 × 10 mol Tris-
2679
3193
−2
HCl and 5 × 10 mol NaCl, pH 7.2) was added to 2.0 mL of
[
I > 2.0σ(I)]
ethidium bromide (1.25 × 10− M) in the same buffer medium
4
Refinement
3236, 217
−
3
Nref, Npar
R, wR , S
w = 1/[s (F
where P = (F
Max. and av. shift/error
4414, 271
to get the maximum fluorescence intensity. Aliquots of 10
M
2
0.0359, 0.1180, 0.818 0.039, 0.1019, 1.034
stock solution of the complex in DMF were added to the ethi-
dium bromide bound CT DNA solution and the fluorescence
was measured for each test solution after 2 hours of incubation
2
2
2
o
) + (0.0710P) ]
2 2
o
c
+ 2F )/3
0.001, 0.000
0.00, 0.00
1
3432 | Dalton Trans., 2013, 42, 13425–13435
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at 37 °C. The solutions were excited at 515 nm (with excitation
and emission slit 3 nm) and emission spectra were recorded
from 520 to 800 nm. The solutions containing an equivalent
amount of a CT DNA solution and either complex 1 or complex
5 V. L. Pecoraro, C. Slebodnick and B. Hamstra, 1998
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2
and buffer when excited at 515 nm did not exhibit any fluo-
rescence emission.
Gel electrophoresis study. The stock solution of supercoiled
−
2
−1
pUC19 DNA (5 μL, 150 ng) in Tris-HCl buffer (5 × 10 mL
,
8 V. Conte, F. D. Furia and G. Licini, Appl. Catal., A, 1997,
157, 335–361.
−
2
−1
pH 7.2) containing 5 × 10 mL NaCl (20 μL) was prepared.
From the stock solution, a 2 μL aliquot was treated with the
appropriate metal complex (stock solution 2 mL, 4 × 10
mL ) followed by dilution with Tris-HCl buffer to a total
volume of 20 μL. The samples were then incubated for an hour
at 37 °C, loading buffer containing 25% bromophenol blue
and 30% glycerol (3 μL) was added and loaded on 0.9%
9 (a) P. Adao, J. C. Pessoa, R. T. Henriques, M. L. Kuznetsov,
F. Avecilla, M. R. Maurya, U. Kumar and I. Correia, Inorg.
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−
2
−
1
−
3
−1
agarose gel containing 10 mL EB. Electrophoresis was
carried out at 40 V for 2 h in TAE buffer (4 × 10 mL Tris,
−
2
−1
−
2
−1
−3
−1
2
× 10 mL acetic acid, and 10 mL EDTA, pH 7.2). The 10 A. Butler, M. J. Clague and G. E. Meister, Chem. Rev., 1994,
gel electrophoregrams were photographed using a UVP-Bio- 94, 625–638.
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The extent of super coil (SC) pUC19 DNA cleavage induced by Bouwman, Marcel Dekker, New York, 2nd edn, 1999, ch. 5.
either complex 1 or complex 2 was determined by analysing 12 D. C. Crans, J. J. Smee, E. Gaidamauskas and L. Yang,
the intensities of the bands using UVP Doc It LS 2.0 Gel Docu-
mentation Software.
Chem. Rev., 2004, 104, 849–902.
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1
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Acknowledgements
1
1
1
5 A. Messershmidt and R. Wever, Proc. Natl. Acad.
Sci. U. S. A., 1996, 93, 392.
The authors wish to extend their thanks to UGC for funding in
the form of a Major Research Project to KKM [Sanction no.
F.NO. 39-706/2010(SR)]. The authors are thankful to Jadavpur
University for facilities. The NMR and X-ray diffractometer
used in this work were funded by DST, India in the form of
DST-FIST to the Department of Chemistry, Jadavpur
University. T. K. S. is thankful to CSIR, India for a Research
Associateship (Award No. 9/96(0624)2K10-EMRI). The authors
are thankful to Md Selim and Shiv Shankar Paul for
assistance.
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