Synthesis, characterization and DNA nuclease activity of oxo-peroxomolybdenum(VI) complexes

Journal of Coordination Chemistry, 2017

Vol. 70, no. 10, 1739–1760

ꢀꢁꢁpꢂ://ꢃꢄꢅ.ꢄꢆg/10.1080/00958972.2017.1310378

Synthesis, characterization and DNA nuclease activity of

oxo-peroxomolybdenum(VI) complexes

‡

Shiv Shankar Paul, Md. Selim and Kalyan K. Mukherjea

dꢇpꢈꢆꢁꢉꢇꢊꢁ ꢄꢋ Cꢀꢇꢉꢅꢂꢁꢆꢌ, Jꢈꢃꢈvpꢍꢆ uꢊꢅvꢇꢆꢂꢅꢁꢌ, Kꢄꢎkꢈꢁꢈ, iꢊꢃꢅꢈ

ABSTRACT

ARTICLE HISTORY

The synthesis and structural characterization of two oxo-peroxo

rꢇcꢇꢅvꢇꢃ 21 nꢄvꢇꢉbꢇꢆ 2016

accꢇpꢁꢇꢃ 2 mꢈꢆcꢀ 2017

−

molybdenum(VI) complexes, [Mo(O)(O) (PAA)] (1) and [Mo(O)

2

−

(

O) (PAH)] (2), with phenylacetic acid (PAA) and 2-phenylacetyl-

2

KEYWORDS

hydroxamic acid (PAHH) ligands have been accomplished. The

coordination geometry of the oxo-peroxo molybdenum(VI) complexes

is found to be pentagonal bipyramidal where, in both cases, the

ligands are coordinated in bidentate fashion through oxygen atoms.

The binding aﬃnities of 1 and 2 with calf-thymus DNA (CT DNA) are

determined using absorption spectroscopic measurements. The

spectroscopic as well as cyclic voltammetric (CV) studies and viscosity

measurements indicate that both complexes interact with CT DNA

oxꢄ-ꢃꢅpꢇꢆꢄxꢄ

ꢉꢄꢎꢌbꢃꢇꢊꢍꢉ(Vi) cꢄꢉpꢎꢇxꢇꢂ;

ꢂꢅꢊgꢎꢇ-cꢆꢌꢂꢁꢈꢎ X-ꢆꢈꢌ ꢂꢁꢆꢍcꢁꢍꢆꢇ;

dft; dna-bꢅꢊꢃꢅꢊg ꢂꢁꢍꢃꢌ;

dna ꢊꢍcꢎꢇꢈꢂꢇ ꢈcꢁꢅvꢅꢁꢌ

4

−1

in the groove. The intrinsic binding constants are 5.2 × 10 M and

4

−1

7

.3 × 10 M for 1 and 2, respectively, from UV–vis studies. Complexes

and 2 show nuclease activity with plasmid DNA in the presence

of H O . Concentration-dependent nuclease study suggests that 2

1

2

possesses higher ability to cleave plasmid DNA compared to 1. The

experimental results of the binding of 1 and 2 with DNA are further

supported by molecular docking studies.

CONTACT Kꢈꢎꢌꢈꢊ K. mꢍkꢀꢇꢆjꢇꢈ

Pꢆꢇꢂꢇꢊꢁ ꢈꢃꢃꢆꢇꢂꢂ: dꢇpꢈꢆꢁꢉꢇꢊꢁ ꢄꢋ Cꢀꢇꢉꢅꢂꢁꢆꢌ, Vꢅvꢇkꢈꢊꢈꢊꢃꢈ Cꢄꢎꢎꢇgꢇ, Kꢄꢎkꢈꢁꢈ 700063, iꢊꢃꢅꢈ.

k_ꢉꢍkꢀꢇꢆjꢇꢈ@ꢌꢈꢀꢄꢄ.cꢄꢉ

‡

©

2017 iꢊꢋꢄꢆꢉꢈ uK lꢅꢉꢅꢁꢇꢃ, ꢁꢆꢈꢃꢅꢊg ꢈꢂ tꢈꢌꢎꢄꢆ & fꢆꢈꢊcꢅꢂ Gꢆꢄꢍp

1740

S. S. PAUL ET AL.

1

. Introduction

Small molecules that interact with DNA through recognition, binding, modifying, cleaving,

or cross-linking have attracted wide attention in various ﬁelds of chemistry, biology, bio-

technology, and medicine [1]. Like natural enzymes, artiﬁcial nucleases can hydrolyze DNA,

and therefore these cleavage agents have found extensive applications in DNA manipula-

tions and as potential chemotherapeutics [2]. Oxidative cleavage of DNA requires co-

reactants to initiate and is mediated by reactive oxygen species (ROS) that cause other severe

cytotoxic eﬀects [3]. The phosphodiester bonds of DNA are exceptionally resistant to hydrol-

ysis [4], so to overcome hydrolysis, natural nucleases such as restriction endonucleases and

topoisomerases are very eﬃcient catalysts, wherein, their activity is attributed to the involve-

ment of active metal centers [5 ]. Artiﬁcial metallonucleases can be potentially used in gene

regulation, mapping of protein and DNA-interactions, probing of DNA speciﬁc structures,

and in cancer therapy [6]. Fe, Cu, Ni, Pt, Ru, Rh, V, Cr, Co, Mn, Os, and Pd complexes have been

reported to mediate DNA-cleavage [7] in the presence of oxidants or reductants or without

any assisting agents, whereas the role of molybdenum remained mostly unexplored as

nuclease. Molybdenum is a unique 4d transition element in the periodic table due to its

varied roles, and probably the most prominent use of this element is in the form of bio-

catalysts as found in the enzymatic reactions in several molybdoproteins in nature [8].

Investigation on the role of Mo as a biometal has become an area of research to understand

the fascinating coordination and bioinorganic modeling chemistry of mononuclear molyb-

denum-containing enzymes. Oxo-peroxo and dioxo Mo(VI) complexes with polydentate

nitrogen, sulfur, and oxygen ligands are considered valuable models for the active site of

several Mo enzymes [9 ].

DNA has been known to be one of the conventional targets of chemotherapeutics in the

management of human cancers [10]. Transition metal complexes are known to bind to DNA

via both covalent and/or non-covalent interactions. In the case of covalent binding, a labile

ligand of the complex can be replaced by a nitrogen base of DNA such as guanine N7, while

the non-covalent DNA interactions include intercalative, electrostatic, and groove (surface)

binding of a metal complex outside the DNA helix along the major or minor grooves [11].

The major and minor grooves of DNA act as a passage for molecular information required

for DNA-interaction with other molecules since hydrogen bonding centers in bases are

pointed into these grooves. Thus, small DNA-binders interact with DNA either by intercalation

in-between the base pairs or in the minor groove, or both [12]. Therefore, the development

of new small molecules capable of binding and nicking of DNA is considered to be a critical

aspect in the synthesis of new drugs. The present study is intended to examine the role of

molybdenum in form of complex as DNA-nuclease. Although the oxo-molybdenum com-

plexes are found to be good DNA-binders [13 ], only a very few peroxo-molybdenum-based

compounds have been found to exhibit nuclease activity [14]. Hence, the present work has

been directed toward the development of artiﬁcial DNA nucleases containing oxo-peroxo

molybdenum environment. Two oxo diperoxo molybdenum complexes, one with the phenyl

acetic acid and other with phenyl hydroxamic acid, have been synthesized. The ligands were

chosen so that they have planar moiety along with the oxygen and nitrogen atoms that can

establish hydrogen bonds with the DNA which will facilitate DNA cleavage through DNA

binding.

JOURNAL OF COORDINATION CHEMISTRY

1741

2

. Experimental

.1. Materials and physical methods

Molybdic acid (MoO ·2H O) and phenyl acetic acid were obtained from S.D. Fine Chemical

2

3

2

(

India). Hydroxylamine hydrochloride was of extra pure variety and was obtained from Merck

India). Potassium hydroxide pellets and methanol (G.R.) were products of Merck (India) and

were used directly. All other reagents used were of G.R. grade and were obtained from Merck

India). Analytical grade solvents used for physicochemical studies were further puriﬁed by

(

literature method before use, wherever necessary. Calf-thymus DNA (CT DNA) is a natural

DNA widely used in studies of DNA-binding anticancer agents while supercoiled (SC) DNA

refers to the over or under winding of a DNA strand (plasmid) marketed as pUC19 DNA,

obtained from Sigma Chemical Company, USA, and Genei Bangalore, India, respectively. All

DNA solutions were prepared inTris-HCl buﬀer at pH 7.4. Other stock solutions were prepared

in Tris-HCl buﬀer. Millipore water was used throughout the course of investigation.

2

.2. Preparation of the ligand and the molybdenum complexes

2

.2.1. Synthesis of N-(phenylacetyl)hydroxamic acid (PAHH)

The ligand was prepared by literature method [15 ]. Methyl phenylacetate was obtained by

reﬂuxing the mixture of phenylacetic acid (PAAH) (13.6 g, 0.1 mol) in 25 mL dry methanol

followed by addition of 1 mL conc. H SO . To the above mixture, solid NH OH∙HCl (14 g,

2

4

2

0.2 mol) was added followed by the addition of a 25% methanolic KOH (0.4 mol) solution

with constant stirring. The reaction mixture was neutralized with 1 N HCl solution, ﬁltered

oﬀ and the residue was washed with methanol. After evaporation of this methanolic solution

−1

a white solid crystalline phenylacetyl hydroxamic acid was obtained. IR (KBr disk, cm ):

1

634(s) ν(C=O), 1546(m) ν(C–N). H NMR (CD OD, 300 MHz) δ in ppm: 4.8 (s, 1H, –OH), 3.44

3

(

t, 2H, –CH –Ar), 7.226–7.312 (m, 5H, H-benzene ring), 5.46 (s, 1H, NH).

2

.2.2. Synthesis of (PPh )[MoO(O ) (PAA)] (1)

4 2 2

MoO (0.144 g, 1 mmol) was dissolved in 3 mL H O (30%, w/v) by stirring at room temper-

3

2

ature to get pale yellow solution. Addition of 10 mL methanolic solution of phenylacetic

acid (0.136 g, 1 mmol) to the above solution on stirring for 1 h produced a yellow solution.

This solution on treatment with PPh Br (0.375 g, 1 mmol) dissolved in 10 mL of methanol

4

yielded an orange-yellow solid, which was ﬁltered oﬀ. The solid obtained was then washed

with water under suction and ﬁnally with diethylether, and dried in vacuo. Yield: 90%. The

crude compound is soluble in acetonitrile, dichloromethane, chloroform, methanol, and

ethanol, but insoluble in water, diethyl ether, benzene, and toluene. The compound was

crystallized from slow evaporation of methanolic solution to get 1 as yellow crystals. ES m/z

3

12.92, Anal. Calc for C H O NPMo: C, 57.84; H, 4.10; N, 2.11; Mo, 14.44; P, 4.66. Found:

32 27 7

−

1

C, 57.14; H, 4.04; N, 2.10; Mo, 14.69; P, 4.73%. IR (KBr, cm ): 1622(s), 1587(m), 1443(s), 1117(s),

1

000(m), 955 (s), 915(s), 855(s), 754(m), 725(s), 692(m), and 526(s). UV-vis (λ_m_a_x/nm): 274, 267

1

and 220. H NMR (CD OD, 300 MHz) δ in ppm: 3.5 (–CH –Ar), 6.58–7.74 (m, 5H, H-benzene

3

2

ring).

1742

S. S. PAUL ET AL.

2

.2.3. Synthesis of (PPh )[MoO(O ) (PAH)] (2)

4 2 2

MoO (0.145 g, ~1 mmol) was dissolved in 3 mL H O (30%, w/v) by stirring at room temper-

3

2

ature to get pale yellow solution. Addition of 10 mL methanolic solution of phenyl acetyl

hydroxamic acid (0.151 g, 1 mmol) to the above solution on stirring for 1 h produced a yellow

solution. This solution on treatment with PPh Br (0.375 g, 1 mmol) dissolved in 10 mL of

4

methanol yielded an orange-yellow solid, which was ﬁltered oﬀ. The solid obtained was then

washed with water under suction and ﬁnally with diethyl ether, and dried in vacuo. Yield:

90%. The crude compound is soluble in acetonitrile, dichloromethane, chloroform, methanol

and ethanol, but insoluble in water, diethylether, benzene, and toluene. The compound was

crystallized by slow evaporation of methanolic solution to get 2 as yellow crystals. ES m/z

(

−) 327.94. Anal. Calc for C H O NPMo: C, 57.75; H, 4.24; N, 2.10; Mo, 14.42; P, 4.65. Found:

32 28 7

−1

C, 57.24; H, 4.06; N, 2.06; Mo, 14.29; P, 4.53%. IR (KBr, cm ): 1607(m), 1454(s), 1119(s), 998(m),

9

59 (s), 920(s), 860(s), 767(m), 734(s), 697(m), and 531(s). UV-vis (λ_m_a_x/ nm): 276, 268 and 224.

1

H NMR (CD OD, 300 MHz) δ in ppm: 3.4 (–CH –Ar), 7.21–7.84 (m, 5H, H-benzene ring).

3

2

.3. X-ray crystal structure determination

X-ray diﬀraction data for the crystal of 1 was collected at 273 K on a Bruker AXS SMART APEX

II diﬀractometer equipped with a CCD detector [16] with a ﬁne focus of 1.75 kW sealed tube

using Mo Kα radiation (λ = 0.71073 Å). Crystallographic data and details of structure deter-

mination are summarized in Table 1 . The data were processed using SAINT, and absorption

corrections were made using SADABS [17]. The structure was solved by direct methods and

2

reﬁned by full-matrix least-squares on the basis of F using the WINGX software, using the

Table 1. Cꢆꢌꢂꢁꢈꢎ ꢃꢈꢁꢈ ꢈꢊꢃ ꢂꢁꢆꢍcꢁꢍꢆꢇ ꢆꢇﬁꢊꢇꢉꢇꢊꢁ pꢈꢆꢈꢉꢇꢁꢇꢆꢂ ꢄꢋ 1.

Parameters

eꢉpꢅꢆꢅcꢈꢎ ꢋꢄꢆꢉꢍꢎꢈ

m_ꢆ

t/K

C h o Pmꢄ

32 27 7

650.45

273(2)

λ/Å

0.71073

mꢄꢊꢄcꢎꢅꢊꢅc

Cꢆꢌꢂꢁꢈꢎ ꢂꢌꢂꢁꢇꢉ

spꢈcꢇ gꢆꢄꢍp

P2 /c

1

Unit cell dimensions

ꢈ/Å

b/Å

c/Å

α/°

β/°

γ/°

10.0952(3)

22.4384(6)

12.7546(3)

90.00

93.980(2)

90.00

3

V/Å

Z, d /g cꢉ

2882.21(13)

4, 1.499

−3

c

f(000)

Cꢆꢌꢂꢁꢈꢎ ꢂꢅzꢇ/ꢉꢉ

θ rꢈꢊgꢇ ꢋꢄꢆ ꢃꢈꢁꢈ cꢄꢎꢎꢇcꢁꢅꢄꢊ (°)

rꢇﬂꢇcꢁꢅꢄꢊꢂ

1328

0.05 × 0.09 × 0.15

1.8, 24.8

2,1450

iꢊꢃꢇpꢇꢊꢃꢇꢊꢁ ꢆꢇﬂꢇcꢁꢅꢄꢊꢂ

Cꢄꢉpꢎꢇꢁꢇꢊꢇꢂꢂ ꢁꢄ θ = θ_ꢉ_ꢈ_x(%)

rꢇﬁꢊꢇꢉꢇꢊꢁ ꢉꢇꢁꢀꢄꢃ

(r ) 4954(0.035)

ꢅꢊꢁ

99.3

fꢍꢎꢎ-ꢉꢈꢁꢆꢅx ꢎꢇꢈꢂꢁ-ꢂqꢍꢈꢆꢇꢂ ꢄꢊ F²

dꢈꢁꢈ/ꢆꢇꢂꢁꢆꢈꢅꢊꢁꢂ/pꢈꢆꢈꢉꢇꢁꢇꢆꢂ

Gꢄꢄꢃꢊꢇꢂꢂ-ꢄꢋ-ﬁꢁ ꢄꢊ F²

r ꢅꢊꢃꢅcꢇꢂ (ꢈꢎꢎ ꢃꢈꢁꢈ) [i>2σ(i)]

lꢈꢆgꢇꢂꢁ ꢃꢅﬀ. pꢇꢈk, ꢀꢄꢎꢇ/Å⁻

4954/0/371

1.027

r =0.0315, wr =0.0680r =0.0438, wr =0.0733

1

2

1

2

3

−0.331, 0.274

JOURNAL OF COORDINATION CHEMISTRY

1743

SHELX suites [18 ]. The non hydrogen atoms were reﬁned anisotropically, while the hydrogens

were placed with ﬁxed thermal parameters at idealized positions. Perspective views of the

molecules were obtained by Mercury [18 ].

2

.4. Computational studies of 2

The DFT calculations were carried out using the Gaussian09 program [19 ] using the hybrid

density functional theory (B3LYP) method. The 6-311G* basis set was used to describe C, N,

O, P, and 6-31G* basis set for hydrogen atoms [20]. The Mo atom was described using the

LANL2DZ basis set [21]. The full geometry optimizations were carried out for 2. To compute

the UV–vis transitions of 2, the singlet-excited state geometries corresponding to the vertical

excitations were optimized using the time-dependent DFT (TD-DFT) scheme starting with

the ground state geometries. The percentages of the contributions for the vertical excitations

were calculated using Gauss sum 2.1.

2

.5. DNA binding studies

2

.5.1. UV-vis spectral study

The solutions of CT DNA in Tris–HCl/NaCl buﬀer medium (50 mM Tris-HCl and 50 mM NaCl,

pH 7.2) gave a ratio of A₂₆₀/A₂ ₈ ₀ , of ca. 1.8–1.85, indicating that the DNA was suﬃciently free

from protein contamination [22]. The DNA concentration per nucleotide was determined

−1

by absorption spectroscopy using the molar absorption coeﬃcient 6600 M cm at 260 nm

[

22]. Stock solutions were stored at 4 °C and used within four days.

UV-vis spectra were recorded in a Shimadzu UV-1700 spectrophotometer. The electronic

spectra of 1 and 2 were monitored in the presence and absence of DNA. In this absorption

titration experiment, a ﬁxed concentration of 1 or 2 was titrated with increasing amounts

of DNA over a range of 0–200 μM in appropriate cases. To eliminate the absorbance of DNA,

equal amounts of DNA were added to the r eference solution as well. The intrinsic binding

constant was determined by using eqn. (1 ) [23]:

[

DNA]∕(ꢀ − ꢀ ) = [DNA]∕(ꢀ − ꢀ ) + 1∕[K (ꢀ − ꢀ )]

a f b f b b f

(1)

Here, [DNA] is the concentration of DNA in base pairs, the apparent absorption coeﬃcients

ε , ε , and ε corresponds to A_o_b_s_d/[complex], the extinction coeﬃcient for the free complex,

a

f

b

and the extinction coeﬃcient for the complex in the fully bound form, respectively. Plots of

[

DNA]/(ε - ε ) versus [DNA] gave a slope 1/(ε − ε ) withY-intercept 1/[K (ε −ε )]. The intrinsic

a

f

b

f

b

f

binding constant K was obtained from the ratio of the slope to the intercept.

b

2

.5.2. Viscometric study

Viscosity of sonicated DNA [24] (average molecular weight of ~200 base pairs was made by

using a Labsonic 2000 sonicator) was measured by a fabricated micro viscometer, maintained

at 28 (±0.5) °C in thermostatic water bath. The viscosities of CT DNA, CT DNA-ligand,

1

/3

CT DNA-1, and CT DNA-2 were measured. Data were presented as (η/η_o) versus the ratio

of the concentration of the ligand or complexes 1 or 2 to that of the CT DNA, where η is the

o

viscosity of CT DNA solution alone and η is the viscosities of CT DNA solution in the presence

of the complexes or the ligand. Viscosity values were calculated from the observed ﬂow time

1744

S. S. PAUL ET AL.

of CT DNA by the relation η = t − t , where t and t are the values of ﬂow times for the solution

o

0

and the buﬀer, respectively.

2

.5.3. Cyclic voltammetry study

Electrochemical measurements were performed using a PAR Versa Stat-potentiostat/

Galvanostat II electrochemical analysis system by purging with puriﬁed nitrogen. The refer-

ence electrode used was saturated Ag/AgCl/KCl, which was isolated from the solution by

salt bridge to prevent contamination through leakage from the electrode. The auxiliary and

working electrodes were platinum foil and carbon paste electrode that were placed directly

to the solution. The cyclic voltammetric (CV) measurement was carried out at 25 °C in buﬀer

solution, and the concentration of the supporting electrolyte KCl was maintained at 0.1 M.

All potentials reported in this study were referenced against the Ag/AgCl electrode. Pure

CT DNA and blank solution are electrochemically inactive in the potential range of + 1.5 V

to -1.25 V under our experimental conditions.

2

.5.4. Gel electrophoresis study

The DNA cleavage activity of the complexes was monitored using agarose gel electropho-

resis. The super coiled (SC) pUC19 DNA (0.5 μg per reaction) in Tris–HCl buﬀer (50 mM) with

5

0 mM of NaCl (pH 7.2) was treated with H O , and the appropriate amount of the complex

2 2

followed by dilution with the Tris–HCl buﬀer to a total volume of 15 μL and then incubated

for 1 h at 37 °C. After incubation it was mixed with a loading buﬀer containing 25% bromo-

phenol blue, 30% glycerol (3 μL) and was loaded on a 0.9% agarose gel containing 1.0 μg mL⁻

ethidium bromide (EB). Electrophoresis was carried out at 60 V for 3 h in TAE buﬀer (40 mM

Tris, 20 mM acetic acid, 1 mM EDTA, pH 7.2). The bands were visualized by UV light and

photographed. The cleavage of SC pUC19 DNA induced by the complex was photographed

with the UVP BIO-DOC-IT Gel Documentation System, and the extent of nicking induced by

the complexes was determined by analyzing the intensities of the bands using UVP – BIO-

DOC-IT LS Software.

1

2

.6. Molecular docking

The rigid molecular docking studies were performed by using HEX 6.3 [25] software (http://

www.loria.fr/~ritchied/hex/). For the Docking study, the coordinates of 1 were taken from

its crystal structure as a CIF ﬁle and converted to the PDB format using Mercury software

(

http://www.ccdc.cam.ac.uk/) and for 2 coordinates were taken from the DFT optimized

structure and converted to the PDB format, and the geometries of 1 and 2 were optimized

by applying CHARMm force ﬁeld in Discovery studio 3.1. The crystal structure of the B-DNA

dodecamer d(CGCGAATTCGCG) (PDB ID: 1BNA) was downloaded from the protein data

2

bank (http://www.rcsb.org./pdb). All calculations were carried out on an Intel I5, 3.1 GHz

based machine with MS Windows 7 as the operating system. Visualization of the docked

pose has been done by using Discovery studio 3.1 and PyMol (http://pymol.sourceforget.

net/) molecular graphics program.

JOURNAL OF COORDINATION CHEMISTRY

1745

3

. Results and discussion

3

.1. Synthetic aspects of the complexes

Complexes 1 and 2 were synthesized by following Scheme 1 . The complexes are stable in

air. Diﬀractable yellow single-crystal of 1 was obtained by slow evaporation of a methanolic

solution.

3

.2. Spectral characterization of the complexes

−1

The IR spectra show strong v(Mo=O) vibration at 955 and 959 cm in 1 and 2, respectively.

−

1

The corresponding v(O–O) vibration appears as medium intensity bands at 855 and 915 cm

in 1 and at 860 and 920 cm⁻in 2. In free PAAH, the v(C=O) vibration occurs at 1622 cm

1

−1

which on coordination with Mo(VI) shifts to 1587 cm in 1, whereas the v(C=O) of free PAHH

at 1634 cm is shifted to 1607 cm after coordination in 2. The shifting of v(C=O) to lower

−

1

−1

energy region indicates the decrease in C = O bond order due to drainage of electron density

−

1

−1

from carbonyl oxygen to Mo-center. The vibrations at 646 cm and 584 cm in 1 and at

6

−

1

−1

42 cm and 578 cm in 2 appear as weak bands which are assignable to asymmetric and

symmetric vibrations, respectively, of the MO triangle formed by the engagement of the

2

−

−1

terminal O₂ligand. The bands at 1443, 1117, 995, 754, 725, 692, and 526 cm in 1 and

454, 1119, 998, 767, 734, 697, and 531 cm in 2 appear due to the Ph P moiety. Molar

conductivity values in acetonitrile solution of 1 and 2 are 148 ohm cm mol and 134

ohm cm mol , respectively. This indicates that both complexes are 1:1 electrolytes [26 ].

The electronic spectra of the free phenyl acetic acid and phenyl acetyl hydroxamic acid

ligands show a broad peak at 230 nm and 249 nm, respectively, which correspond to intra-

ligand π → π* transitions of the aromatic ring. The bands are shifted to 222 nm for 1 and

−1

+

1

4

−1

2

−1

−

1

2

−1

226 nm for 2, respectively. Two bands appear at 267 nm, 274 nm for 1 and 268 nm, 276 nm

for 2 due to the n → π* of C=O functional group of both coordinated ligands. This low energy

shift is due to the drainage of electron density of –C=O– bond through the coordination of

O atom to the metal center in the complexes [13].

Scheme 1. sꢌꢊꢁꢀꢇꢁꢅc ꢂcꢀꢇꢉꢇ ꢄꢋ 1 ꢈꢊꢃ 2.

1746

S. S. PAUL ET AL.

1

The H NMR spectroscopic study conﬁrmed that 1 and 2 as well as the ligands are stable

in solution phase. In 2 the hydroxamate –OH is deprotonated, which is characterized by the

disappearance of the –OH proton signal at δ 4.8 ppm, whereas in 1, –COOH proton of phe-

nylacetate ligand is deprotonated which is evidenced by the non-appearance of the –COOH

proton signal at δ 9.8 ppm. This suggests that both ligands behave as mono-anionic O,O-

donor centers. The methylene proton signal (–CH ) is observed around δ 3.5 ppm for 1 and

2

at δ 3.4 ppm for 2. The aromatic proton signals at 6.58–7.74 ppm and 7.21–7.84 ppm are

owed to intermixing of the signals of the aromatic protons of phenyl group of the phenyl

moiety and those for the PPh groups in both 1 and 2, respectively, and have appeared as

4

multiplets.

3

.3. Structural characterization of the complexes

3

.3.1. Crystal structure of 1

−

Crystal structure of 1 consists of discrete monomeric anions [MoO(O ) (PAA)] and tetrap-

henylphosphonium [PPh ] cations (see Figure 1 for the ORTEP view). The crystallographic

2

+

4

parameters of 1 are shown in Table 1. Complex 1 crystallizes in the monoclinic P2 /n space

1

group with the unit cell dimensions of a = 10.0952 Å, b = 22.4384 Å, c = 12.7546 Å, α = 90.0°,

β = 93.98°, γ = 90.0°. The coordination geometry around the metal atom is found to be pen-

tagonal bipyramidal with the axial sites being occupied by the carbonyl oxygen (O1) and

the oxo (O7) ligands. The carboxylate oxygen (O2) and the peroxo moieties (O3, O4 and O5,

O6) deﬁne the equatorial plane whereas the Mo atom is displaced by [-0.324(1) Å] from the

equatorial plane towards the oxo-oxygen (O7). This is consistent with the observations in

oxodiperoxo molybdenum(VI) complexes which generally feature the metal atom coordi-

nation to the oxo-group in the axial position and the two peroxo groups bound in the

equatorial positions. The chelated phenylacetyl moiety (C1–C7, O2, O1) is essentially planar

and is approximately orthogonal to the equatorial plane (O2,O3–O6); the dihedral angle

between the two planes is 78.3(1)°. Selected bond distances and angles for 1 (Table 2 ) cor-

respond to those of other seven-coordinate Mo-oxoperoxo complexes [27 ]. The lengthening

Figure 1. orteP ꢆꢇpꢆꢇꢂꢇꢊꢁꢈꢁꢅꢄꢊ ꢄꢋ ꢁꢀꢇ X-ꢆꢈꢌ cꢆꢌꢂꢁꢈꢎ ꢂꢁꢆꢍcꢁꢍꢆꢇ ꢄꢋ ꢈꢊꢅꢄꢊꢅc pꢈꢆꢁ ꢄꢋ 1 wꢅꢁꢀ ꢈꢎꢎ ꢊꢄꢊ-ꢀꢌꢃꢆꢄgꢇꢊ

ꢈꢁꢄꢉꢂ ꢂꢀꢄwꢊ ꢈꢂ 50% ꢁꢀꢇꢆꢉꢈꢎ ꢇꢎꢎꢅpꢂꢄꢅꢃꢂ.

JOURNAL OF COORDINATION CHEMISTRY

1747

Table 2. sꢇꢎꢇcꢁꢇꢃ bꢄꢊꢃ ꢎꢇꢊgꢁꢀꢂ (Å) ꢈꢊꢃ ꢈꢊgꢎꢇꢂ (°) ꢄꢋ 1.

Bꢄꢊꢃ ꢎꢇꢊgꢁꢀꢂ (Å)

mꢄꢏo1

mꢄꢏo2

mꢄꢏo3

mꢄꢏo4

mꢄꢏo5

2.428(17)

2.084(18)

1.909(19)

1.948(2)

1.913(2)

mꢄꢏo6

1.936(2)

1.662(19)

1.462(3)

1.469(3)

mꢄꢏo7

o3ꢏo4

o5ꢏo6

Bꢄꢊꢃ ꢈꢊgꢎꢇꢂ (°)

o2ꢏmꢄ1ꢏo1

o4ꢏmꢄ1ꢏo1

o6ꢏmꢄ1ꢏo1

o5ꢏmꢄ1ꢏo1

o3ꢏmꢄ1ꢏo1

o7ꢏmꢄ1ꢏo1

o4ꢏmꢄ1ꢏo2

o6ꢏmꢄ1ꢏo2

o5ꢏmꢄ1ꢏo2

o3ꢏmꢄ1ꢏo2

o7ꢏmꢄ1ꢏo2

57.06(6)

78.02(8)

77.95(8)

93.35(8)

93.30(8)

153.84(9)

85.79(8)

87.88(8)

130.69(8)

128.47(9)

96.78(9)

o7ꢏmꢄ1ꢏo4

o5ꢏmꢄ1ꢏo6

o3ꢏmꢄ1ꢏo6

o7ꢏmꢄ1ꢏo6

o3ꢏmꢄ1ꢏo5

o7ꢏmꢄ1ꢏo5

o7ꢏmꢄ1ꢏo3

o3ꢏmꢄ1ꢏo4

o5ꢏmꢄ1ꢏo4

o6ꢏmꢄ1ꢏo4

102.20(10)

44.87(9)

129.58(9)

102.90(11)

87.23(9)

105.69(11)

105.17(10)

44.53(9)

129.29(9)

154.66(9)

Table 3. rꢇꢎꢇvꢈꢊꢁ ꢅꢊꢁꢇꢆꢉꢄꢎꢇcꢍꢎꢈꢆ ꢀꢌꢃꢆꢄgꢇꢊ bꢄꢊꢃꢂ (Å) ꢅꢊ 1.

D-H⋯A

d(D-H)

d(H⋯A)

d(D⋯A)

∠(DHA)°

ꢈ

b

C24ꢏh23…o1

C24ꢏh24…o1

C19ꢏh19…o5

0.93

2.54

2.47

2.55

3.438(4)

3.145(3)

3.161(4)

161

130

124

ꢈ

1

−

/2 + x, 3/2−ꢌ.

1/2 + z, 1−x, 2−ꢌ, 2−z.

b

of the Mo–O1 [2.428(17) Å] distances in 1 compared to the Mo–O [2.194(3)–2.269(3) Å] bond

lengths in complexes where the ligand oxygen atoms coordinate the metal center equato-

rially reﬂects the strong trans inﬂuence of the oxo-ligand [27]. In addition to the strong

intramolecular O–H…O hydrogen bond [O6…O3, 2.764(2) Å in case of 1], some weak inter-

molecular C–H…O hydrogen bonds between the anions (Table 3 ) are also present, and these

interactions stabilize the structure in 1 (Figure 2 ).

3

.3.2. Structures of 1 and 2: density functional theory calculations

Geometry optimization for 1 and 2 has been carried out at the DFT level. The Mo atom was

described using the LANL2DZ basis set while the 6-311G* basis set was used to describe C,

N, O, P and 6-31G* basis set for hydrogen atoms [20] (Figure 3). The initial geometries were

taken from the single-crystal X-ray data of 1 and subjected to optimization. The geometrical

parameters viz. bond lengths and bond angles were calculated (Table 4 ) using the Gaussian

09 package [19]. Contour plots of molecular orbitals of the complexes were generated using

Gauss view 5.0 and the frontier molecular orbitals in 1 and 2 were calculated (Figure 3). The

DFT calculation conﬁrms the optimized structure of 2. It is seen that the highest occupied

molecular orbital (HOMO) is localized largely on the Mo atom and peroxo oxygen in 1 and

2

. However, the lowest unoccupied molecular orbital (LUMO) is localized largely on the

phenyl ring of both ligands. The calculated HOMO energies of the complexes vary as 1

(

−5.32 eV) < 2 (−5.91 eV) and those of LUMO exhibit a similar trend: 1 (−3.27 eV) < 2

−3.68 eV). Upon introducing a hydroxamic group in 1 to obtain 2, both HOMO and LUMO

energies increase, and interestingly, the increase in HOMO energy is more pronounced than

1748

S. S. PAUL ET AL.

Figure 2. Pꢈckꢅꢊg pꢈꢁꢁꢇꢆꢊ ꢂꢀꢄwꢅꢊg h-bꢄꢊꢃꢅꢊg ꢅꢊ 1.

that in LUMO energy. It is noteworthy that upon incorporating hydroxamic groups into the

phenylacetato ligand in 1 to obtain 2, the changes in both HOMO and LUMO energies are

not signiﬁcant revealing that the coordination of the ligand does not aﬀect the HOMO and

LUMO energy levels. This clearly supports that the HOMO orbitals in 1 and 2 are localized

on the peroxo moiety. The HOMO–LUMO energy gaps in 1 (2.45 eV) and 2 (2.23 eV) are

almost the same, which is consistent with other reported Mo-complexes [21 ].

The UV–vis spectrum of 2 in acetonitrile solution has also been explored by using aTD-DFT

approach. The calculated absorption energies, their associated oscillator strengths, the main

conﬁgurations and their assignments are given in Table 5 , while the combined experimental

and simulated UV–vis spectra of 2 are displayed in Figure 4 (A). The experimental wavelengths

do not exactly match with the theoretical one, but all the transitions are found in the theo-

retically generated spectra with very nominal shifts.

The structure of oxo-diperoxo complex 2 was further supported by IR frequency calcu-

−1

lations which were obtained by DFT. The v(O-O) vibrations at 946 and 871 cm and v(Mo=O)

−1

vibrations at 1102 cm and for v(–C = O) frequency at 1596 cm (Figure 4(B)) obtained from

the above calculations are within the tolerance limit with the value obtained experimentally

(

Table 6).

3

.4. DNA binding studies

The present study is directed toward the development of synthetic DNA nucleases, so, estab-

lishment of the ability to damage the double stranded DNA by a given molecule demands

a thorough study on the interaction of DNA with the potential nuclease molecule. Hence,

the binding of DNA by the synthetic molecules has been studied, results of which are being

presented herein.

JOURNAL OF COORDINATION CHEMISTRY

1749

Figure 3. (a) lanl2dZ ꢈꢊꢃ 6ꢏ31G* gꢆꢄꢍꢊꢃ ꢂꢁꢈꢁꢇ ꢄpꢁꢅꢉꢅzꢇꢃ gꢇꢄꢉꢇꢁꢆꢌ ꢄꢋ 2; (B) ꢂꢀꢄwꢅꢊg homo ꢈꢊꢃ lumo

ꢄꢋ ꢈꢊꢅꢄꢊꢅc pꢈꢆꢁ ꢄꢋ 2.

Table 4. tꢀꢇꢄꢆꢇꢁꢅcꢈꢎꢎꢌ cꢈꢎcꢍꢎꢈꢁꢇꢃ ꢂꢇꢎꢇcꢁꢇꢃ ꢅꢊꢁꢇꢆꢈꢁꢄꢉꢅc ꢃꢅꢂꢁꢈꢊcꢇꢂ (Å) ꢈꢊꢃ bꢄꢊꢃ ꢈꢊgꢎꢇꢂ (°) ꢋꢄꢆ 2.

Bꢄꢊꢃ ꢎꢇꢊgꢁꢀꢂ (Å)

mꢄꢏo5

mꢄꢏo3

mꢄꢏo4

mꢄꢏo2

n9ꢏh23

1.72205

2.01051

1.97534

2.00969

1.01781

mꢄꢏo5

mꢄꢏo7

mꢄꢏo8

n9ꢏo7

1.97588

2.18373

2.34743

1.35992

Bꢄꢊꢃ ꢈꢊgꢎꢇꢂ (°)

o5ꢏmꢄꢏo2

o5ꢏmꢄꢏo6

o5ꢏmꢄꢏo3

o5ꢏmꢄꢏo4

o5ꢏmꢄꢏo7

o5ꢏmꢄꢏo8

o7ꢏmꢄꢏo6

101.52442

104.76133

101.51411

104.79151

90.50030

162.14968

132.07420

o3ꢏmꢄꢏo2

o3ꢏmꢄꢏo5

o2ꢏmꢄꢏo4

o4ꢏmꢄꢏo7

o3ꢏmꢄꢏo7

o2ꢏmꢄꢏo7

156.68130

130.59589

130.58212

132.05222

88.11875

88.12613

1750

S. S. PAUL ET AL.

Table 5. sꢇꢎꢇcꢁꢇꢃ uVꢏvꢅꢂ ꢇꢊꢇꢆgꢌ ꢁꢆꢈꢊꢂꢅꢁꢅꢄꢊꢂ ꢈꢁ ꢁꢀꢇ td-dft/B3lyP ꢎꢇvꢇꢎ ꢋꢄꢆ 2 ꢅꢊ ꢈcꢇꢁꢄꢊꢅꢁꢆꢅꢎꢇ.

λ_c_a_l(nm)

Oscillator strength (f)

λ_e_x_p_t(nm) Key transitions

352

249

224

0.0089

315

264

232

h-3->lumo (64%), h-2->l+1 (14%), homo->lumo (11%),

h-2->l+2 (5%), h-1->lumo (2%)

h-7->lumo (31%), h-6->lumo (52%) h-11->l+1 (4%), h-5->l+1

0.0161

0.1444

(

5%), homo->l+3 (3%)

h-7->lumo (11%), h-7->l+1 (16%), h-5->l+2 (33%) h-11-

lumo (5%), h-6->lumo (6%), h-6->l+3 (5%), h-5->l+3

6%), h-4->l+3 (2%)

>

(

206

0.056

222

h-1->l+7 (15%), h-1->l+8 (17%), homo->l+7 (28%),

homo->l+8 (27%), h-6->l+3 (5%)

Figure 4. (a) Cꢈꢎcꢍꢎꢈꢁꢇꢃ (bꢎꢈck) ꢈꢊꢃ ꢇxpꢇꢆꢅꢉꢇꢊꢁꢈꢎ (ꢆꢇꢃ) ꢈbꢂꢄꢆpꢁꢅꢄꢊ ꢂpꢇcꢁꢆꢈ ꢄꢋ 2 ꢅꢊ ꢈcꢇꢁꢄꢊꢅꢁꢆꢅꢎꢇ ꢈꢁ ꢆꢄꢄꢉ

ꢇꢉpꢇꢆꢈꢁꢍꢆꢇ. (B) Cꢈꢎcꢍꢎꢈꢁꢇꢃ (bꢎꢈck) ꢈꢊꢃ ꢇxpꢇꢆꢅꢉꢇꢊꢁꢈꢎ (ꢆꢇꢃ) ꢅꢊꢋꢆꢈꢆꢇꢃ ꢂpꢇcꢁꢆꢈ ꢄꢋ 2.

ꢁ

JOURNAL OF COORDINATION CHEMISTRY

1751

−1

Table 6. Cꢄꢉpꢈꢆꢅꢂꢄꢊꢂ ꢄꢋ ꢇxpꢇꢆꢅꢉꢇꢊꢁꢈꢎ ꢈꢊꢃ ꢁꢀꢇꢄꢆꢇꢁꢅcꢈꢎ ꢂꢁꢆꢇꢁcꢀꢅꢊg ꢋꢆꢇqꢍꢇꢊcꢌ (ꢅꢊ cꢉ ) ꢄꢋ 2.

Frequency

Theoretical values

Experimental values

% of deviation

v(ꢏC=o)

v(ꢏnꢏh)

v(mꢄ=o)

v(oꢏo)

1596

1415

1102

946,871

662,529

1607

1454

959

920,860

642,578

0.7

2.7

13

3.0, 1.3

3.0, 8.0

v[mo (ꢁꢆꢅꢈꢊgꢎꢇ)]

2

3

.4.1. Electronic absorption spectral studies

Electronic absorption spectroscopy is utilized to examine the binding of metal complexes

with DNA. The electronic spectra of both 1 and 2 (Figures 5 and 6 ) were monitored in the

presence and absence of DNA. Upon addition of incremental amounts of DNA, the intensity

of the bands at 267 and 274 nm for 1 and 268 and 276 nm for 2 increased. This increase in

the absorptivity and red shift (4 nm) of both 1 and 2 support that the interaction occurred

of both complexes in the groove of CT DNA [13, 28]. Hoechst 33258 family groove binders

also exhibit red shifts of absorption bands when they bind to the grooves of a DNA helix

[

29]. A plot of [DNA]/(ε − ε ) versus [DNA] gives the binding constants which were calculated

a f

−1

4

−1

to be (5.2 ± 0.2)×10 M for DNA-complex 1 and (7.3 ± 0.2)×10 M for DNA-complex 2.

Complexes 1 and 2 show identical DNA-binding aﬃnities as both of them have identical

ligand environment with phenyl aromatic ring involved. Due to the absence of planarity of

the complexes, they compromise the weaker electrostatic interaction imparted by the neg-

atively charged phosphate groups of DNA.

3

.4.2. Viscometric studies

The measurement of DNA-viscosity is a sensitive technique to understand the mode of

DNA-binding [30]. The relative viscosity of CT DNA solution is known to increase on interca-

lative binding of substrates, because the insertion of intercalators causes the base pairs of

the DNA to get apart and thus causes lengthening of the DNA helix, while molecules bound

to DNA through groove do not alter the relative viscosity of DNA, and the partial or non-clas-

sical intercalation of ligand may bend or kink the DNA helix, thereby decreasing its eﬀective

length and subsequently viscosity [30]. The values of relative speciﬁc viscosities of DNA in

the absence and presence of 1 and 2 are plotted against [complex]/[DNA] (Figure 7). It is

observed that the addition of either 1 or 2 to the CT DNA solution does not show signiﬁcant

increase in the viscosity of CT DNA, thereby clearly demonstrating the groove-binding of

CT DNA by the present complexes 1 and 2.

3

.4.3. Electrochemical investigation of 1 and 2 with DNA

Electrochemical investigation of the metal complex-DNA interaction provides a useful com-

plement to the spectroscopic methods. It is known that the electrochemical potential of

metal complexes will shift positively when it intercalates into DNA, and if it is bound to DNA

by electrostatic interaction, the potential would shift in a negative direction [31]. Cyclic

voltammograms (CV) of 1 and 2 in the absence and presence of CT DNA in Tris-HCl buﬀer

solution are shown in Figures 8 and 9.

The quasi-reversible redox couples for 1 and 2 in acetonitrile:buﬀer (1:9) solution have

been studied upon addition of CT DNA and the shifts of the cathodic (E ) and anodic (E )

pc

pa

potentials are recorded. No new redox peaks appeared after the addition of CT DNA to 1

1752

S. S. PAUL ET AL.

Figure 5. abꢂꢄꢆpꢁꢅꢄꢊ ꢂpꢇcꢁꢆꢈ ꢄꢋ 1 (60 μm) ꢅꢊ ꢁꢀꢇ pꢆꢇꢂꢇꢊcꢇ ꢄꢋ ꢅꢊcꢆꢇꢈꢂꢅꢊg ꢈꢉꢄꢍꢊꢁꢂ ꢄꢋ Ct dna, [dna]/

9

−1

5

[

cꢄꢉpꢎꢇx] = (a − ꢎ): 0ꢏ200 μm. (iꢊꢂꢇꢁ: pꢎꢄꢁ ꢄꢋ {[dna]/(ε − ε )} × 10 m/m cꢉ vs. [dna] × 10 m).

ꢈ ꢋ

Figure 6. abꢂꢄꢆpꢁꢅꢄꢊ ꢂpꢇcꢁꢆꢈ ꢄꢋ 2 (60 μm) ꢅꢊ ꢁꢀꢇ pꢆꢇꢂꢇꢊcꢇ ꢄꢋ ꢅꢊcꢆꢇꢈꢂꢅꢊg ꢈꢉꢄꢍꢊꢁꢂ ꢄꢋ Ct dna, [dna]/

9

−1

5

[

cꢄꢉpꢎꢇx] = (ꢈ − ꢎ): 0ꢏ200 μm. (iꢊꢂꢇꢁ: pꢎꢄꢁ ꢄꢋ {[dna]/(ε − ε )} × 10 m/m cꢉ vs. [dna] × 10 m).

ꢈ ꢋ

and 2, but the current intensity of all the peaks increased signiﬁcantly, suggesting the exist-

ence of an interaction between 1 and 2 and CT DNA. The increase or decrease in current

intensity can be explained in terms of an equilibrium mixture of free and DNA-bound com-

plex to the electrode surface [32 ]. In both 1 and 2, with increasing concentration of CT DNA,

JOURNAL OF COORDINATION CHEMISTRY

1753

Figure 7. eﬀꢇcꢁ ꢄꢋ ꢅꢊcꢆꢇꢈꢂꢅꢊg ꢁꢀꢇ ꢈꢉꢄꢍꢊꢁ ꢄꢋ 1, 2 ꢈꢊꢃ eB ꢄꢊ ꢁꢀꢇ ꢂpꢇcꢅﬁc vꢅꢂcꢄꢂꢅꢁꢌ ꢄꢋ Ct dna.

Figure 8. Cꢌcꢎꢅc vꢄꢎꢁꢈꢉꢉꢄgꢆꢈꢉ ꢄꢋ ꢅꢊꢁꢇꢆꢈcꢁꢅꢄꢊ ꢄꢋ 1 ꢈꢊꢃ Ct dna. [Ct dna] = 0.0, 50, 100, 150, 200 μm.

−

1

scꢈꢊ ꢆꢈꢁꢇ: 80 ꢉV ꢂ .

the cathodic peak potentials of the complexes shifted toward lower values, indicating the

non-intercalative binding nature of the complexes with CT DNA. For 1 the shift of cathodic

peak potential is 0.947 to 0.929 V, whereas the shift observed for 2 is 0.942 to 0.9031 V after

addition of CT DNA. This shift in peak potentials supports the non-intercalative binding

nature of 1 and 2 with CT DNA.

1754

S. S. PAUL ET AL.

Figure 9. Cꢌcꢎꢅc vꢄꢎꢁꢈꢉꢉꢄgꢆꢈꢉ ꢄꢋ ꢅꢊꢁꢇꢆꢈcꢁꢅꢄꢊ ꢄꢋ 2 ꢈꢊꢃ Ct dna. [Ct dna] = 0.0, 50, 100, 150, 200 μm.

−

1

scꢈꢊ ꢆꢈꢁꢇ: 80 ꢉV ꢂ .

3

.4.4. Nuclease activity

The nuclease activity of the complexes has been studied using supercoiled (SC) pUC19 DNA.

The naturally occurring supercoiled form (Form I), nicked to circular (NC) plasmid with one

DNA-strand is cut by releasing the supercoiling and leaves a large ﬂoppy circle, may give

rise to linear and open circular relaxed forms, Forms II and III, respectively. Form I migrates

relatively faster in comparison to Forms II and III. The electrophoretic pattern of plasmid DNA

treated with 1 and 2 are shown in Figure 10. Firstly, the concentration-dependent DNA

cleavage experiments by 1 and 2 were monitored.

Complexes 1 and 2 (at concentration of 20 μM) converted the SC DNA into NC relaxed

form of DNA by 20% and 22%, respectively (Figure 10 ). The result indicated that 1 and 2 have

exhibited weak nuclease activity toward SC DNA (pUC19) (Table 7). The present experiment

suggests that untreated DNA and DNA incubated with peroxide alone did not show any

signiﬁcant DNA cleavage (lanes 1 and 2 in Figure 10 ). However, in the pr esence of peroxide,

1

and 2 were found to exhibit good nuclease activity (Figure 11, Table 8 ). The presence of

•

H O as an oxidizing agent leads to the formation of ROS (OH ) through the Fenton type

2

mechanism, which helps metal complex mediated DNA cleavage [33 ]. It is observed that 2

is more eﬀective in nicking pUC19 DNA either alone or in combination with H O than 1.

2

The control experiments suggest that untreated plasmid DNA (lane 1) contains 90% (SC)

and 10% (NC). The treatment of this DNA with incremental amounts (10 μM, 20 μM, and

3

0 μM) of either 1 or 2 induces a substantial cleavage of DNA in the presence of H O . It is

2 2

interesting to note that both complexes are capable of inducing both NC and linear form

under the present experimental setup.

Concentration-dependent DNA cleavage experiments were carried out in the presence

of ﬁxed concentration of H O (30 μM) by varying the concentration of 1 and 2 (10–30 μM).

2

At 20 μM concentration of 1 and 2, signiﬁcant DNA cleavage (NC DNA) 56% and 72% (Figure

JOURNAL OF COORDINATION CHEMISTRY

1755

Figure 10. agꢈꢆꢄꢂꢇ gꢇꢎ (9%) ꢇꢎꢇcꢁꢆꢄpꢀꢄꢆꢇgꢆꢈꢉ ꢄꢋ ꢂꢍpꢇꢆcꢄꢅꢎꢇꢃ puC19 dna (0.5 μg) ꢅꢊcꢍbꢈꢁꢇꢃ ꢋꢄꢆ 45 ꢉꢅꢊ ꢈꢁ

7 °C ꢅꢊ ꢈ bꢍﬀꢇꢆ cꢄꢊꢁꢈꢅꢊꢅꢊg 50 ꢉmtꢆꢅꢂꢏhCꢎ ꢈꢊꢃ 50 ꢉm nꢈCꢎ ꢈꢁ 37 °C ph 7.2 wꢅꢁꢀ ꢅꢊcꢆꢇꢈꢂꢅꢊg cꢄꢊcꢇꢊꢁꢆꢈꢁꢅꢄꢊꢂ

ꢄꢋ 1 ꢈꢊꢃ 2. lꢈꢊꢇ 1: dna cꢄꢊꢁꢆꢄꢎ; lꢈꢊꢇ 2, dna + h o (30 μm); lꢈꢊꢇ 3, dna + 1 (10 μm); lꢈꢊꢇ 4, dna + 1

3

2

(20 μm); lꢈꢊꢇ 5, dna + 2 (10 μm); lꢈꢊꢇ 6, dna + 2 (20 μm).

Table 7. puC19 pꢎꢈꢂꢉꢅꢃ dna cꢎꢇꢈvꢈgꢇ bꢌ 1 ꢈꢊꢃ 2.

Lane no.

Reaction condition

Form I (% SC)

Form II (% NC)

1

2

3

4

5

6

puC 19 dna Control

puC 19 + 30 μm h₂o₂

puC 19 + 10 μm cꢄꢉpꢎꢇx 1

puC 19 + 20 μm cꢄꢉpꢎꢇx 1

puC 19 + 10 μm cꢄꢉpꢎꢇx 2

puC 19 + 20 μm cꢄꢉpꢎꢇx 2

90

87

86

80

83

78

10

13

14

20

17

22

Figure 11. agꢈꢆꢄꢂꢇ gꢇꢎ (9%) ꢇꢎꢇcꢁꢆꢄpꢀꢄꢆꢇgꢆꢈꢉ ꢄꢋ ꢂꢍpꢇꢆcꢄꢅꢎꢇꢃ puC19 dna (0.5 μg) ꢅꢊcꢍbꢈꢁꢇꢃ ꢋꢄꢆ 45 ꢉꢅꢊ ꢈꢁ

7 °C ꢅꢊ ꢈ bꢍﬀꢇꢆ cꢄꢊꢁꢈꢅꢊꢅꢊg 50 ꢉmtꢆꢅꢂꢏhCꢎ ꢈꢊꢃ 50 ꢉm nꢈCꢎ ꢈꢁ 37 °C ph 7.2 wꢅꢁꢀ ꢅꢊcꢆꢇꢈꢂꢅꢊg cꢄꢊcꢇꢊꢁꢆꢈꢁꢅꢄꢊꢂ

ꢄꢋ 1 ꢈꢊꢃ 2. lꢈꢊꢇ 1: dna cꢄꢊꢁꢆꢄꢎ; lꢈꢊꢇ 2, dna + h o (30 μm) + 1 (10 μm); lꢈꢊꢇ 3, dna + h o (30 μm) + 2

3

2

2 2

(

10 μm); lꢈꢊꢇ 4, dna + h o (30 μm) + 1 (20 μm); lꢈꢊꢇ 5, dna + h o (30 μm) + 2 (20 μm); lꢈꢊꢇ 6,

2

dna + h o (30 μm) + 1 (30 μm); lꢈꢊꢇ 7, dna + h o (30 μm) + 2 (30 μm).

2

2 2

Table 8. puC19 pꢎꢈꢂꢉꢅꢃ dna cꢎꢇꢈvꢈgꢇ bꢌ cꢄꢉpꢎꢇxꢇꢂ 1 ꢈꢊꢃ 2 ꢅꢊ pꢆꢇꢂꢇꢊcꢇ ꢄꢋ h o .

2

Lane no.

Reaction condition

Form I (% SC)

Form III (%L)

Form II (% NC)

1

2

3

4

5

6

7

puC 19 dna Control

90

45

47

40

10

55

53

56

72

76

75

puC 19 + 30 μm h o + 10 μm cꢄꢉpꢎꢇx 1

2

puC 19 + 30 μm h o + 10 μm cꢄꢉpꢎꢇx 2

2

puC 19 + 30 μm h o + 20 μm cꢄꢉpꢎꢇx 1

4

2

puC 19 + 30 μm h o + 20 μm cꢄꢉpꢎꢇx 2

28

24

25

2

puC 19 + 30 μm h o + 30 μm cꢄꢉpꢎꢇx 1

2

puC 19 + 30 μm h o + 30 μm cꢄꢉpꢎꢇx 2

2

1756

S. S. PAUL ET AL.

11), respectively, was observed. As the concentration of 1 and 2 was increased, the amount

of NC (Form II) increased. At 20 μM concentration of 2, 72% NC (Form II) as well as 28% of

linear form of DNA (Form III) were obtained, whereas in the case of 1 (20 μM), 56% NC (Form

II) and 4% of linear form of DNA (Form III) obtained. When the concentrations of the com-

plexes were increased to 30 μM, the SC DNA was converted to 76% of NC, 24% of linear form

by 1 and 75% of NC, 25% of linear form by 2. At higher concentrations of 2 (20 and 30 μM),

SC plasmid DNA is fully converted to linear forms (L) and the NC forms.

Both complexes show eﬃcient nuclease activity in the presence of H O . The intense

2

nuclease activities of 1 and 2 are apparently due to enhanced stabilization of Mo-peroxo

species. This may be attributed to the fact that both complexes have diperoxo moiety which

shows higher stability in H O and induces nicking to SC plasmid DNA. Based on their ability

2

to convert the SC form (Form I) to the NC form (Form II) and linear form (Form III), it is observed

that 2 shows higher ability to cleave the SC plasmid DNA when compared to that of 1. This

may be due to the fact that 2 with phenyl acetyl hydroxamic acid as ligand shows better

interaction with DNA, as it can form better H-bond (vide docking study) compared to phenyl

acetic acid ligand of 1.

3

.5. Molecular docking investigation on the interaction of DNA with 1 and 2

The molecular docking technique is usually exploited to understand the drug–DNA inter-

actions, which is essential for rational drug design and discovery. This also helps to establish

the mechanism of action of the reactants by placing a small molecule into the binding site

of the target speciﬁc region of DNA [34]. Diﬀerent structural properties lead to diﬀerent

binding modes, whereby the molecular shape is a very important factor in determining the

binding mode. The forces responsible for maintaining the stability of the DNA–intercalator

complex include van der Waals forces, hydrogen bonding, hydrophobic charge transfer, and

electrostatic complementarity. In our experiment, 1 and 2 were successively docked with

the DNA duplex of the sequence d(CGCGAATTCGCG)2 dodecamer (PDB ID: 1BNA) in order

Figure 12. dꢄckꢇꢃ pꢄꢂꢇ ꢄꢋ 1 ꢂꢀꢄwꢅꢊg ꢅꢊꢁꢇꢆꢈcꢁꢅꢄꢊ wꢅꢁꢀ bꢈꢂꢇ pꢈꢅꢆꢂ.

JOURNAL OF COORDINATION CHEMISTRY

1757

Figure 13. dꢄckꢇꢃ pꢄꢂꢇ ꢄꢋ 2 ꢂꢀꢄwꢅꢊg ꢅꢊꢁꢇꢆꢈcꢁꢅꢄꢊ wꢅꢁꢀ bꢈꢂꢇ pꢈꢅꢆꢂ.

to predict the chosen binding site along with preferred orientation of the ligand inside the

DNA minor-groov e [35 ]. The energetically most favorable conformation of the docked pose

(

Figures 12 and 13) revealed that 1 and 2 bind to DNA-groove, thereby slightly adjusting

the DNA structure in such a way that part of the planar phenyl ring makes favorable stacking

interactions with DNA base pairs through van der Waals interactions with the DNA functional

groups which accounts for the stability of the groove. Moreover, two hydrogen bonding

interactions with 2 in the minor groove have been predicted. The resulting relative binding

−1

energies of the docked structures for 1 and 2 were found to be -306.8 kJ mol and

−

1

−

298.78 kJ mol , respectively. This indicates potent binding between the DNA and both 1

and 2 which correlates well with the experimental DNA binding studies. Thus, the spectro-

scopic experimental results are harmonized with the molecular docking studies as well.

4

. Conclusion

Two oxo-peroxo molybdenum complexes are synthesized and characterized. Complex 1 is

structurally characterized by single-crystal X-ray crystallography whereas 2 is optimized by

DFT calculations and the TDDFT study also supports the optimized structure of 2 having an

excellent agreement with the experimental ﬁndings. In the present study, the interaction of

1

and 2 with CT DNA is examined by absorbance and ﬂuorescence spectroscopy, cyclic

voltammetry and viscometric methods. The absorbance studies reveal that the intrinsic

4

−1

binding constant for 1 and 2 are 5.2 × 10 and 7.3 × 10 M , respectively. The results suggest

that 1 and 2 bind in the groove of CT DNA. This groove-binding nature of the complexes

was further supported by cyclic voltammetry and viscosity study. Both complexes exhibit

eﬀective nuclease activity in the presence of H O by cleaving the supercoiled plasmid

2

(pUC19) DNA to NC one. Complex 2 shows higher nuclease activity compared to 1. At higher

concentrations of 2, SC form of DNA is completely converted to L and NC forms. The present

1758

S. S. PAUL ET AL.

study reveals that the complexes may be used as a new class of rare non-platinum-based

molybdenum nucleases.

Electronic supplementary material

Crystallographic data for 1 (CCDC 1016513) are available as electronic supplementary infor-

mation. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/deposit

or from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ,

UK; Fax: (+44) 1223–336-033; or E-mail: deposit@ccdc.cam.ac.uk .

Disclosure statement

No potential conﬂict of interest was reported by the authors.

Funding

Authors are thankful to UGC, New Delhi for funding UVP Bio Doc-IT GEL Imaging system in the form of

a major research project to Kalyan K. Mukherjea [grant number 39-706/2010(SR)]. Shiv Shankar Paul

is thankful to UGC for fellowship. The single crystal X-ray diﬀractometer and NMR spectrometers used

in this work have been funded by the Department of Science and Technology (DST-FIST, Department

of Chemistry, J. U.), New Delhi, India.

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Synthesis, characterization and DNA nuclease activity of oxo-peroxomolybdenum(VI) complexes

DOI: 10.1080/00958972.2017.1310378

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