Spectral characterization, CT-DNA binding, DFT/B3LYP, molecular docking and antitumor studies for new nano-sized VO(II)-hydrazonoyl complexes

Article abstract of DOI:10.1016/j.molliq.2017.06.113

New hydrazonoyl chloride derivatives were prepared and characterized. Their VO(II) complexes were isolated after adjusting reaction medium to slightly basic by 0.5?g acetate. Neutral tridentate mode is a general coordination feature of ligands towards bin

Full text of DOI:10.1016/j.molliq.2017.06.113

Accepted Manuscript
Spectral characterization, CT-DNA binding, DFT/B3LYP,
molecular docking and antitumor studies for new nano-sized
VO(II)-hydrazonoyl complexes
Ismail Althagafi, Marwa G. Elghalban, Fawaz Saad, Jabir H.
Al-Fahemi, Nashwa M. El-Metwaly, Samir Bondock, Layla
Almazroai, Kamel A. Saleh, Gamil A. Al-Hazmi
PII:
DOI:
Reference:
S0167-7322(17)31730-0
doi: 10.1016/j.molliq.2017.06.113
MOLLIQ 7559
To appear in:
Journal of Molecular Liquids
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Revised date:
Accepted date:
22 April 2017
23 June 2017
24 June 2017
Please cite this article as: Ismail Althagafi, Marwa G. Elghalban, Fawaz Saad, Jabir H.
Al-Fahemi, Nashwa M. El-Metwaly, Samir Bondock, Layla Almazroai, Kamel A. Saleh,
Gamil A. Al-Hazmi , Spectral characterization, CT-DNA binding, DFT/B3LYP, molecular
docking and antitumor studies for new nano-sized VO(II)-hydrazonoyl complexes,
Journal of Molecular Liquids (2017), doi: 10.1016/j.molliq.2017.06.113
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ACCEPTED MANUSCRIPT
Spectral characterization, CT-DNA binding, DFT/ B3LYP, molecular docking
and antitumor studies for new nano-sized VO(II)-hydrazonoyl complexes
Ismail Althagafi1, Marwa G. Elghalban1,2, Fawaz Saad1, Jabir H. Al-Fahemi1, Nashwa M. El-Metwaly*1,2, Samir
Bondock2,3, Layla Almazroai1, Kamel A. saleh4 and Gamil A. Al-Hazmi 3,4
1Chemistry Department, College of Applied Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
2Chemistry Department Faculty of Science, Mansoura University, Mansoura, Egypt
3Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha, Saudi Arabia
4Biology Department, Faculty of Science, King Khalid University, P.O. Box 9004, Abha, Saudi Arabia
5Chemistry Department, Faculty of Applied Sciences, Taiz University, P.O. Box 82, Taiz, Yemen
Abstract
New hydazonoyl chloride derivatives were prepared and characterized. Their VO(II) complexes
were isolated after adjusting reaction medium to slightly basic by 0.5 g acetate. Neutral tridentate
mode is a general coordination feature of ligands towards binuclear VO(II) atoms. Square
pyramidal is a proposed configuration for all complexes. XRD and SEM analysis offer an assertion
about the presence of all compounds excellently in nano-scale for well crystals. TGA and DTA
analysis reflect low thermal stability for crystals occluded with water molecules as well as kinetic
parameters clarify rigidity of coordination spheres. Molecular modeling using Gaussian09 software
was implemented through DFT/B3LYP method by definite base sets. The best configurations were
extracted and essential parameters were calculated over visualized structures. Log P was calculated
for all hydazonoyl derivatives and offering distinguish biological feature of HL3. Docking process
was executed using AutoDock tools 4.2 over 1sm3, 4uy9 and 5j6a protein receptors (breast, colon
and liver cancers, respectively) beside 2ki2 for DNA. This study was concerned to make matching
with biological investigation intended in the study. The best interaction was recorded with 1sm3 and
2ki2 receptors. Antitumor activity was screened for all compounds by a comparative view over
breast, colon and liver carcinoma cell lines. IC50 values represent promising efficiency of most
tested compounds against breast, colon and liver carcinoma cell lines. The binding efficiency of
ligands towards CT-DNA was tested. Binding constant (Kb)values are in agreement with electron
drawing character for p-substituent which offer high Kb values. Also variable Hammett's relations
were drawn.
Keywords: VO(II) complexes, Docking, DFT, Antitumor and DNA binding
*Corresponding author: Prof. Nashwa M. El-Metwaly
E- mail address: n_elmetwaly00@yahoo.com , Telephone No.: +966538553123
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1. Introduction
Hydazone compounds and their derivatives represent a wide class of chelating ligands. These
compounds are biologically interesting, they have anti-inflammatory, analgesic, anticonvulsant,
anti-tuberculosis, antitumor, anti-HIV and antimicrobial efficiency [1-3]. They are important
compounds for constructing drugs, effective ligands towards complexation, organo-catalysis and
also for syntheses of heterocyclic compounds [4-8]. Hydrazone ligands have been studied
extensively for years, due to synthetic flexibilities, selectivity as well as sensitivity toward transition
metal ions [9]. Metallo- hydrazone compounds are perfect area of study in coordination field due to
their high ability to form complexes with all metals in periodic table. Moreover, exhibit variety of
molecular architectures as well as, electrochemical, spectroscopic, magnetic and biological
properties [10].Vanadium has a growing influence on coordination chemistry, due to its biological
and potential catalytic ability [11-13]. This work is interested in preparing a series of hydrazonoyl
chloride derivatives by variable substituent's to clarify the effect of substituent's on the chemical
behavior. New vanadyl complexes will be prepared and characterized using different experimental
and theoretical tools. CT-DNA binding will be tested along the organic series only to discuss the
effect of substituent's . Theoretical implementation will be accomplished over all prepared
compounds by different standard programs and essential parameters will be extracted and discussed.
Antitumor activity will be scanned utilizing all prepared compounds for comparative study.
2. Methodology
2.1. Chemicals utilized
Chemicals essential for preparation of hydrazonoyl halides derivatives as; 3-chloro-2,4-
pentanedione, sodium acetate trihydrate, aromatic amines HCl and NaNO2 were purchased from
Fluka and used without previous treatments. Also, VOSO4.xH2O salt used for complexation process
was commercially available from Sigma-Aldrich. All handled solvents were Merck and used
without previous purification.
2.2. Synthesis
2.2.1. Synthesis of hydrazonoyls chloride
To a stirred solution of 3-chloro-2,4-pentanedione 3 (1.34 g, 0.01 mol), ethanolic solution (50 mL)
from sodium acetate trihydrate (1.3g, 0.01 mol) was added. After stirring for 20 min, the mixture
was cooled in ice bath at 0°C and treated with cold solution from appropriate diazotized aromatic
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amines 2, prepared by diazotizing the respective amines 1 (0.01 mol) dissolved in hydrochloric acid
(6 M, 6 mL) with solution of aqueous sodium nitrite (0.71 g, 0.01 mol in10 mL H2O). The addition
of diazonium salt solution was carried out with rapid stirring over a period of 30 min, after which
the reaction mixture was stirred for further 45 min and left for 6 h in a refrigerator. The precipitate
obtained was filtered and washed with water, re-crystallized from ethanol and dried to give intended
hydrazonoyls chloride (4a-e, Scheme 1). 2-Oxo-N-phenylpropane hydrazonoyl chloride
(4a,HOPH,HL1), N-(4-Methylphenyl)-2-oxopropanehydrazonoyl chloride (4b,HMPH,HL2), N-(4-
Methoxylphenyl)-2-oxopropanehydrazonoyl chloride (4c,HMoPH, HL3), N-(4-Chlorophenyl)-2-
oxopropanehydrazonoyl
chloride
(4d,HCPH,HL4)
and
N-(4-Bromophenyl)-2-
oxopropanehydrazonoyl chloride (4e, HBPH, HL5) are the scientific names of isolated ligands (Fig.
1A, B).
NaNO2 / HCl
R
NH2
R
O
N2Cl
0-5 0C
1a-e
2
R
4
O
a
b
c
d
e
H
Me
OMe
Cl
Me
Me
H O
N
N
3
Cl
R
Me
Br
EtOH / AcONa
0-5 0C
Cl
4a-e
Scheme 1. Synthesis of hydrazonoyls halide 4a-e.
2.2.2. Synthesis of VO(II) complexes
New solid VO(II) complexes were prepared by mixing appropriate amounts from each hydrazonoyl
ligand and VOSO4.xH2O in absolute ethanol by molar ratio of 1:2(L:M). Weighted molar ratio from
vanadyl salt was calculated attributing to anhydrous form. 0.5 g from sodium acetate will be added
after dissolving in a little amount of bi-distilled water for precipitation. Resulting mixtures were
then heated under reflux for 2-3 h; till solid complexes appeared. Each precipitate was separated out
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on hot, filtered off, washed several times with ethanol, diethyl ether and finally dried in vacuum
desiccators.
2.3. DNA binding experiments
The binding properties of hydazonoyl ligands towards calf thymus-DNA (CT-DNA) have been
studied using Uv-Vis spectroscopy. CT-DNA (50 mg) was dissolved by stirring overnight in double
de-ionized water (pH = 7.0) and kept at 4°C. Bi-distilled water was used to prepare buffer (5.0 mM
tris(hydroxymethyl)-aminomethane and 50 mM NaCl, pH=7.2). Tris–HCl buffer was prepared
using de-ionized water. A buffering solution of CT-DNA gave ratio of UV absorbance at 260 and
280 nm (A260/A280) of 1.8-1.9, indicating that the DNA was sufficiently free from protein[14].
Using UV absorbance spectroscopy, DNA concentration was determined by knowing molar
absorptivity coefficient of 6600 M−1 cm−1 at 260 nm for CT-DNA (5.25 × 10−4 M). The wave
lengths applicable for electronic transitions, 200-900 nm range, by using 1cm quartz cuvette at 25°C
with fixed ligands (HL1-5) concentration ( 2.5 ×10-5M). While, gradual increase in CT-DNA
concentration from 0.00 till 1.58 × 0-4 mol L-1, was utilized. The same amount of CT-DNA was
added to each compound solution and reference buffer solutions to remove the absorbance of free
DNA. Significant binding constant (Kb) for interaction between ligands towards CT-DNA was
determined by using the following Eq.; [DNA] / (єa − єf) = [DNA] / (єb − єf) + 1 / Kb (єa − єf)[15].
Where [DNA] is the concentration of CT-DNA in base pairs, єa is the extinction coefficient
observed for Aobs/[compound] at used DNA concentration, єf is the extinction coefficient for each
free compound (HL1-5) in solution. Moreover, єb is the extinction coefficient of the compound when
fully bond to DNA. In plots of [DNA] / (єa − єf) vs. [DNA], Kb is given by the following ratio ;
slope / intercept.
2.4. Antitumor efficiency
The domination advantage versus three sever carcinoma cell lines (MCF-7, HEPG-2 and HCT-116)
will be tested over organic compounds and their VO(II) complexes to confirm their antitumor
influence by sulfo-rhodamine B (SRB). Cells were protected in RPMI medium enhanced with 100
µg/mL streptomycin, 100 units/ml penicillin and 10% from bovine heat-inactivated genetic serum
moisture with 5% (v/v) atmospheric CO2 at 37ºC. Then cells were sub-cultured two times over a
week. The growing cells were gathered by using tryps in–EDTA(0.25% ) and plated in 96-
wellplates at 1000 cells/well. Cells were isolated along 72h and therefore fixed with TCA(10%) for
1h at 4°C. After washing several times, cells were treated with SRB solution(0.4%) for 10 min away
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from light and then washed with glacial acetic acid (1%). Keeping cells over night, Tris–HCl was
used to dissolve SRB-stained cells and the depth of color was measured at 540 nm. Cell viability
was measured by Trypan blue (0.4) stain, permit us to differentiate live (non-stained) from dead
(stained) cells. Live and dead cells were counted with Nikon microscope implementing
hemocytometer. Surviving cells percentage = [1.00–(Number of blue cells÷Number of total cells)]×
100. Statistical analysis was executed by using Sigma Plot version 12.0. Fluorescent stain Acridine
Orange after treated with the IC50 of impacted complexes .(c) control; HL3(1), HL5(2) and HL4(3)
complexes (Fig. 2A, B).
2.5. Physical measurements
Elemental analysis
Content of main elements (carbon, hydrogen and nitrogen) was recorded at Micro analytical unit of
Cairo University. Vanadium and sulfate contents were evaluated by standard methods [16].
X-Ray diffraction and SEM
Rikagu Diffractometer using Cu / Kα radiation was used to record X- ray diffraction patterns
(XRD). Scanning Electron Microscopy (SEM) images were obtained by using Joel JSM-6390
equipment.
IR , 1HNMR and 13CNMR Spectra
JASCO FT-IR-4100 spectrophotometer (400–4000 cm-1) was used to record KBr - IR spectra
while, NMR spectra were recorded in Burker 500MHz.
UV/Vis spectra and magnetic moments
UV2 Unicam UV/Vis spectrophotometer was used to conduct electronic transitions in DMSO
solvent. Magnetic moment values of VO(II) complexes were calculated through magnetic
susceptibility recorded by Johnson Matthey Magnetic Susceptibility Balance at room temperature.
Thermal analysis
o
o
Thermal analysis was scanned on Shimadzu Thermogravimetric Analyzer (20- 900 C) by 10 C
min-1 heating rate under nitrogen. Theoretical treatments (kinetic, modeling and docking) were
accomplished by known standard programs.
Antitumor activity
Antitumor activity was conducted at Regional Center for Mycology and Biotechnology.
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2.6. Theoretical Treatment
2.6.1. Kinetic investigation
Significant thermodynamic parameters were executed over definite stages along TG curves. Over
suitable effective degradation stages, order (n) and energy of activation (E) were computed.
Previously, different researchers[17-25] were executed equations and discussing their advantages
for calculating thermal parameters. Applying Coat-Redfern [19] and Horowitz-Metzger methods
[24], intended kinetic parameters were computed.
2.6.2. DFT/B3LYP study
Hydrazonoyl ligands and their VO(II) complexes were geometrically optimized in gas phase
utilizing Gaussian09 software [26]. Applying DFT/B3LYP method by different base sets, the best
structural configurations were obtained. All output files were visualized by Gauss-View program
[27]. According to numbering scheme, DFT parameters were extracted using frontier energy gaps
(EHOMO & ELUMO) for all investigated compounds. Moreover, other significant computations were
taken from log files as; oscillator strength, excitation energy, charges assigned for coordinating
atoms and some bond lengths.
2.6.3. QSAR computation
The organic compounds were structurally optimized to establish well distribution for elements
applying HyperChem software program (8.1). Pre-optimization process was achieved for all ligands
by molecular mechanics force field (MM+) accompanied by semi-empirical AM1 as soft adjustment
procedure. The computation process was executed without fixing any parameters till geometric
structures reach to equilibrium state. System for minimizing energy was employed Polake-Ribiere
conjugated gradient algorithm. QSAR process leads to compute essential parameters in between,
Partition coefficient (log P) was obtained. Log P is considered an essential indicator to predict the
biological activity feature for optimized compounds[28].
2.6.4. Docking methodology
Applying Autodock tools 4.2 using Gasteiger partial charges added over hydrazonoyl ligands
elements, simulation procedure was accomplished to reflect a shadow on biological behavior of
compounds. Rotatable bonds were cleared and non-polar hydrogen atoms were conjoined.
Interaction complexes obtained between inhibitor ligands and protein receptors (1sm3, 4uy9 and
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5j6a) or CT-DNA (2ki2) are referring to energy parameters computed. Docking process was
accomplished after addition of; fundamental hydrogen atoms, Kollman united atom type charges
and salvation parameters [29]. Affinity (grid) maps of ×× Å grid points and 0.375Å spacing were
generated applying Autogrid program [30]. Vander Waal forces and electrostatic terms were
obtained. This by applying auto dock parameter set- and distance-dependent dielectric functions,
respectively. Docking process were executed using Solis & Wets local search method and
Lamarckian Genetic algorithm (LGA)[31]. Initial position, orientation, and torsions of inhibitor
molecule were set indiscriminately. All rotatable torsions were expelled during docking process.
Each experiment is the mean value for 10 different runs that are set to close after maximum of
250000 energy assessments. 150 is the used population size. During process, translational step of
0.2 Å, quaternion and torsion steps of 5 were applied.
3. Results and discussion
3.1. Physical properties
Some significant analytical and physical features for ligands and their VO(II) complexes were
aggregated in Table 1. All investigated complexes are stable, non-hygroscopic in nature, having
o
high yield and m.p ( ˃ 300 C). Analysis of elements suggests 1:2 (HL:M) molar ration as the
general formula observed. All complexes are sparingly soluble in DMSO and DMF solvents. Such
solubility feature prevents conductivity measurements for complexes and asserts on nonionic nature
of coordination spheres[32]. This coincides with sulfate anion which favors covalent attachment
inside complex sphere or expelled as acidic form after ionization process.
3.2. IR and NMR studies
The assignments for all characteristic bands attributing to HL(1-5) and their VO(II) complexes were
summarized in Table 2. (NH) , δ(NH), (C=N) and (C=O) are significant bands for coordinating
donors which appear nearby with all free hydazonoyl derivatives. This may refer to far effect of
aromatic substituent on bond movement inside such groups. Comparative study between ligands
and their VO(II) complexes reveals the following observations; i) lower shifted appearance of
former bands is considered a strong evidence for contribution of C=O, NH and C=N groups in
coordination towards two central atoms. II) New bands appeared at ≈ 1160 and ≈ 1120 cm-1 assign
for as(SO4) and s(SO4), respectively through bi-dentate attachment[33]. III) Other bands appeared
at ≈750 and ≈630 cm-1 are attributing to δr(H2O) and δw(H2O), respectively. IV) (M-L) bands
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appeared at low wave number region belong to M-O and M-N bonds. These spectral observations
suggest a tridentate mode of coordination towards two vanadyl atoms. As well as, band observed at
944- 996 cm-1 range, assigns for (V=O), significantly point to square-pyramidal configuration[34].
1HNMR spectra of four hydazonoyl ligands (Fig. 3,1S) represent peaks by shifts (Table 3) coincide
13
with proposed structures. Moreover, CNMR spectra were recorded (Fig.2S) to give further well
support for the formulae suggested and the assignments were also tabulated (Table 3).
3.2. Electronic spectra
Electronic transition features and magnetic moment values were summarized in Table 4. Uv-Vis
spectra were recorded qualitatively in DMSO solvent, to gain smoothly absorption curves. Intra-
ligand transition bands appeared at 290-320, 320-350 and 350-420 nm are attributing to n→ σ*, π
→ π* and n→ π* transitions, respectively inside variable groups [35]. Also, incomplete conjugation
for chromophors in structures, leads to faint colors observed. This is accompanied with the
appearance of n→ π* band at the border of visible region(350-420nm). VO(II) complexes spectra
display intra-ligand transitions suffer shift due to coordination. The appearance of charge transfer
bands attributes to O→ V and N→V transitions. Also, new significant d-d transition band was
observed at 620 assigned for 2B2→ 2B1 transition in square-pyramidal configuration(Fig. 4) around
vanadium. Reduced magnetic moment values (μeff = 1.65 -1.67BM) recorded for all complexes
support the proposal of binuclear complexes[36].
3.3. X-ray diffraction and SEM analysis
X-ray diffraction patterns were executed over 10˚ < 2θ < 90˚ rang (Fig. 5,3S). This analysis gives a
well view about crystal lattice dynamics for solid compounds. Using known standard methods, a
comparative study for patterns with reactants reflects the purity of isolated compounds [37]. Also,
significant parameters related to crystalline compounds can be calculated using high intense peak
(full width at half maximum, FWHM). All scanned compounds are crystalline in nature which
reflects steady of process for crystal aggregation with different compounds. Such may refer to
fixing central atom (vanadyl) beside the similarity inside coordination spheres. 2θ, d spacing,
FWHM, relative intensity (%) and particle sizes were represented in Table 5. The crystallite sizes
were computed by utilizing Deby–Scherrer equation:  = 0.94 λ/(S Cos θ), where S is the crystallite
size, θ is the diffraction angle,  is FWHM, Cu/Kα (λ)= 1.5406 Ao. The d-spacing between inner
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crystal planes, were extracted from Bragg equation: nλ = 2dsin(θ) at n = 1. The sizes calculated for
all investigated compounds fall by excellent way in nanometer range (≈21- 62 nm) which may
suggest broad application area especially with biological field. Also, crystal strain (ε) was

calculated by;  =
, equation, while dislocation density (δ) was computed by; δ =
 tan
Scos
1/S2 [38]. The dislocation density and strain are the aspects for network dislocation in compounds.
The lower values of them indicate high quality of compounds. SEM is a further tool gives clear
view about topographic surface of solid compounds which may coincide with XRD data.
Hydazonoly images (Fig. 4S) display road shapes by regular way observed in all derivatives, this
reflects the absence of substituent effect on crystal shapes. Also, an observable difference in surface
appearance of complexes than original ligands confirms purity from starting materials. A spherical
shape is a general feature for all complexes which may refer to fixed metal atom (vanadyl). Also,
the round shape suggests an excellent property from compounds[39] toward application.
3.4. Thermal study
A plausible degradation aspects for all VO(II) complexes beside HL1 and HL4 ligands were
tabulated (Table 6). The applied temperature range (20- 900oC) appears sufficient for complete
degradation of investigated compounds. HL1 and HL4 ligands are completely degraded at 619.8 and
o
791.6 C with residual carbons with HL4 process. While, their attributed complexes are displaying
different attitude in decomposition process which clarify the effect of metal atom on thermal
behavior of organic compounds. All VO(II)- HL(1-5) complexes degradation process are starting at
lower temperature (˂ 60 oC) and attributing to expel of water molecules in coordination or crystal
feature. The first degradation stage for HL1 and HL4 complexes are broad enough for decomposing
o
one covalent sulfate also. The second degradation stage in complexes were ended at ≈ 300- 450 C
range suitable for complete degradation of covalent sulfate molecules around two central atoms.
The third degradation stage was appeared attributing to removal of coordinating ligand molecule
o
o
moiety. Such stage was ended reaching to ≈ 800 C except for HL1 complex (≈ 700 C). The
residual part includes two metal atoms which is considered further support for proposing bi-nuclear
complexes. A considerable conformity between calculated and found weight loss percentage may
reflect the exact determination for each stage border which serve in deliberate kinetic calculations.
3.5. DNA binding studies
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The efficiency of binding mode for ligands towards CT-DNA was clarified using absorption
titration method. A fixed ligand concentration was used with regular increase for DNA amount at
25°C. Electronic absorption measurements was recorded for freshly prepared solutions by using
reference solution for each concentration. Such includes the same amount used from DNA to
remove its absorbance from binding medium. We have determined effective binding constants
towards CT-DNA by observing absorption intensity of charge transfer bands at ; 344, 350, 359, 246
and 247 nm for HL1-5 ligands, respectively. Recorded spectra for ligands bind with CT-DNA at 300
-700 nm range were exhibited in Fig. 5S. A gradual increase of DNA amount, leads to
bathochromic effect for significant band of ligand which minimized gradually this is appeared
clearly with HL4 and HL5 ligands. This minimization is followed by appearance of slightly shifted
peak (1-2 nm) assign for binding complex and suffer gradual increase in absorbance. This is
indicative for the stabilization of coupled DNA helix, after interaction process. Such investigation
suggests the coupling for binding sites through electrostatic binding or occluded in major and minor
grooves inside DNA. Moreover, the bathochromic feature can be discussed referring to two basis;
broad surface area of ligands as well as the presence of planar aromatic chromophore which
facilitate well binding towards CT-DNA. This groove binding leads to structural reorganization of
CT-DNA which required partial disassemble or deterioration for double helix at the exterior
phosphate leading to formation of cavity suitable for entering compounds[40]. Bathochromic
feature observed with HL4 and HL5 ligands, is attributing to electron withdrawing character of Cl
and Br atoms. Their binding constants (Kb) were calculated by known spectral relationships [15] as;
5
5
4.76 × 10 and 1.397 × 10 M−1, respectively with priority for chloride effect. While, another
reverse feature is clearly observed with HL(1-3) ligands, the significant new band suffer
minimization in absorbance with gradual increase of DNA amount. This feature was reported with
different articles [41,42] as a legal feature may be observed. Their binding constants (Kb) values
are; 1.01 × 105, 2.53 × 105 and 2.02 × 105 for HL(1-3), respectively according to Hammett's
constants(σR).
3.6. Theoretical treatment
3.6.1. Kinetic investigation
To investigate the influence of metal atoms on decomposition behavior and kinetic attitude for
organic compounds, thermodynamic parameters must be calculated (Table 7). Also, are used to
emphasis on degree of bond strength inside complex sphere. The first degradation stage is chosen
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for kinetic calculations except for HL4 (second stage). This is referring to its wide range and
moderate sharpness feature which leads to exact determination for fraction decompose (α) at
variable temperatures inside the step. Two standard methods were used separately on the same step
for comparison and assertion. E, ∆H, ∆S and ∆G are the parameters calculated by Coats–Redfern
[19] and Horowitz–Metzger equations[24]. The correlation diagrams were displayed in Figure 6S.
Enthalpy of activation (∆H) and Gibbs free energy were estimated using ∆H = E -RT and ∆G= ∆H-
Ah


T∆S, equations. While, entropy of activation (∆S) was extracted from
equation,
S* R ln




K
B
T
s
where h is the Plank’s constant, kB is the Boltzmann constant and Ts is the DTG peak midpoint
temperature. The data obtained were displayed the following aspects; i) the reduction for activation
energy values in complexes as appeared with HL1 and HL4complexes, which is considered a
measurable feature for weak intra-ligand bonds after complexation. ii) An expected increase in
activation energy from step to another due to low decomposition rate sequentially from ligand
moiety, which raises ∆G values over following stages. This may predict the reduction in
decomposition rate along the process as a logical behavior. iii) Negative signs for activation
entropies (∆S) indicate more ordered activated complex than the reactants and/or slow rate of
reaction. iv) Also, positive signs for ∆H values mean that the degradation stags are endothermic in
nature.
3.6.2. DFT/B3LYP study
Optimization process for geometric structures were executed using reference methods through
Gaussian09 program. This process leads to redistribution of elements along molecule space. Some
important computational parameters were estimated using frontier energy gaps between EHOMO
&
ELUMO. These parameters offer a well insight about the chemistry of treated compounds and point to
their expected biological behavior. Frontier molecular orbital's images for free hydrazonoyl and
their complexes were displayed in Figure 6A and B. Free Ligands images display the concentration
of HOMO and LUMO levels along all function groups which predict a strong interaction with metal
atoms. Also, the images for two boarders in VO(II) complexes display their concentration
surrounding over centers. This may predict high role for VO atoms in the application feature
interested in this research due to their contribution in electronic transition between frontiers
(HOMO & LUMO) which facilitate charge transfer process. Electronegativity (χ), chemical
potential (μ), global hardness (η), global softness (S), global electrophilicity index (ω) and absolute
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softness (ϭ) were calculated referring to standard equations [43,44]. Toxicity and reactivity for
compounds can be evaluated from electrophilicity index (ω). This index gives clear view about
expected biological attitude for tested hydazonoyl in comparing with their VO(II) complexes. Also,
measures the constancy of compound which taken extra negative charge from environment. As well
as, the constancy and reactivity for compounds can be tested from two opposite indexes (η and ϭ )
[45,46].
3.6.2.1 Essential quantum parameters
Essential quantum parameters calculated for all compounds under investigation count on frontier
energy gaps, were displayed at Table 8. The data belong to ligands reveal the following notice; i)
degree of converged softness recorded for ligands offer their compatible flexibility towards
coordination. ii) Electrophilicity index (χ) and electronic chemical potential (μ) index have two
different signs. This is evidence for the ability of compounds to acquire electrons from surrounding
with priority for HL1, HL4 and HL5derivatives. While, data attributing to VO(II) complexes reveal
the following notice; i) frontier energy gaps are completely reduced from original ligands which
represent red shift observed for electronic transition by influence of vanadyl atoms. This reduction
is favored with biological efficiency[47]. ii) Enhancement for absolute softness values in comparing
with ligands offers well predication for biological activity. From calculated energy gaps, Hammett's
relation displays significant effect of p- substituent on ΔE values for ligands or their complexes by
two reverse features (Fig. 7).
3.6.2.2. Some log file parameters
Some log files data were aggregated in Table 9. A comparative view for computing data of ligands
and their complexes offers the following; i) the calculated charges over donor atoms (O12, N8 and
N7) represent general reduction in most complexes while, somewhat rise may refer to their
contribution in HOMO and LUMO levels by intensive way. ii) Bond lengths for coordinating
groups in complexes suffer more or less reduction, which may point to presence of intra-ligand
hydrogen bonding before complexation. Such eliminates an observable elongation after removing of
H-bonding due to complexation. iii) Oscillator strength values (range 0-1) of complexes are
minimized than the free ligands values. This may be the indicator for the ease absorption or
reemission of electromagnetic radiations inside complexes[48]. The values are far from 1, in
agreement with high excitation values needed for electronic transitions. iv) Also, enhancement of
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dipole moment values for complexes over ligands indicates high polarity of covalent bonds
surrounds two central atoms.
3.6.3 QSAR calculations
Optimized structures obtained through HyperChem (8.1) program, display essential QSAR
parameters(Table 10). This study gives further view about properties concluded from Gaussian09
software. Log P values calculated are arranged by; HL2 (1.8)˃ HL5 (1.7) ˃ HL1 (1.64) ˃ HL4 (1.42)
˃ HL3 (0.65). Partition coefficient (log P) is attached strongly with biological feature of computed
compound by a reverse relation. This means that, the high biological activity will be expected from
HL3 ligand, while the reverse may be expected from HL2 [28].
3.6.4. Docking interpretation
Science of drug design is a field faced great revolution in last few decades to give a broad view
about such essential industry. Advanced methods were established to dive visually inside infected
cells during drug treatment. Such, to clarify its interaction process with cell protein to build a good
view. Autodock 4.2 tools software was used for this approach. 1sm3, 4uy9 and 5j6a are protein
receptors for, breast, colon and liver carcinoma while 2ki2 is CT-DNA receptor. All ligands were
treated towards four receptors individually and the data represent little difference in between five
derivatives. The computed energies over PDB files (a format using Gaussian09 soft ware) were
tabulated in Table 11. Dissociation constant (pKa) calculated is considered the biopharmaceutical
measure for drug-likeness compounds. This constant help in understanding the ionic form of drug
along the pH range. High pKa values (˃ 10) reflect their ionization which facilitate their diffusion
across cell membrane to give a well inhibition process. Also, highly reduced energies were recorded
for 1sm3 and 2ki2 receptors. Such predicts the high interaction towards breast carcinoma and CT-
DNA in comparing with 4uy9 and 5j6a (Fig. 8,7S)[49]. Positive sign for electrostatic energy
recorded for 2ki2 docking, clarify high stability of interacting complexes toward CT-DNA. HP
plots(Fig. 9,8S) as well as 2D plots verify high interaction towards 1sm3 and 2ki2 receptors through
high surface area contributed with intensive H-bonding. While, a moderate interaction efficiency
was recorded with 4uy9 and 5j6a proteins. This study offer proposal for promising interaction
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towards breast carcinoma and CT-DNA while, a moderate activity is expected with colon and liver
carcinoma.
3.7. Antitumor efficiency
Results confirmed that the complexes exhibit more cytotoxicity impact against (HEPG2. MCF-7,
HCT116) comparing to their ligands. The IC50 values have been given in Table 12 and displayed in
Figure 10,9S. Cytotoxicity considered as good anti-cancer parameter if the influence induced
apoptotic pathways inside the cell. Apoptotic may be detected by many parameters like the
activation of Caspase family, DNA fragmentation or morphology of the cell. Depending on that,
this study tried to identify, if the complexes can induce cells to apoptotic or not by means of
morphological parameter. To achieve this goal, cells were treated with IC50 for selected high
impacted complexes (HL3-5). MCF-7 breast cancer was the selected cell line. After treatment with
IC50 of selected complexes, MCF-7cells were incubated for 24 hours. Cells were fixed using Carnoy
fixative and stained by fluorescent stain[50]. The evaluation was based on the nucleus shape,
nucleus density, foci presence and number of cells. Results clearly showed that, nucleus remained
their regular shape, no condensation and no degradation for detected for nucleus (Fig. 2A). Lack of
micronucleus inside cytoplasm revealed that, ligands and VO(II) complexes are not clastogenic
agents which may consider as very good feature. Also cells were kept their ability to form foci
which means that the complexes may have no impact to penetrate layers and have no ability to solve
cell-to-cell connections. This can be considered as advantage for the complexes because they do not
help cells to spread where they can kill in situ (Fig. 2B). In terms of cell numbers, photos have
confirmed the compatibility and harmony with the data proposed by SRB assay. In the light of
previous results and discussion, ligands and complexes may consider as in situ cytotoxic but not
genototoxic.
4. Conclusion
New VO(II) complexes were prepared from hydazonoyl ligands. All the complexes have the same
structural formula may refer to fixed nucleus used. The square- pyramidal configuration is the
general structural form proposed. The isolated complexes are found comfortably in nanometer range
which expect their distinguish application in different fields. Theoretical implementation introduce
the best configurations for all compounds under investigation. CT-DNA binding constants were
calculated using spectrophotometric relations. . Binding constant (Kb)values are in agreement with
electron drawing character for p-substituent which offer high Kb values. Also variable Hammett's
relations were drawn. Antitumor activity was tested over all compounds and cytotoxicity was
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clearly appeared with most compounds especially with HL4 and HL5 and their complexes against
three carcinoma used.
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Fig. 1A. Structures for, hydrazonoyl ligands (HL1-5), (HOPH, HMPH, HMoPH, HCPH and HBPH)
18

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Fig. 1B. Optimized structures for hydrazonoyl ligands (HL1-5)
Fig. 2A.Morphological feature of cell and cell nucleus of MCF-7 breast cancer with DNA binding
Fig. 2B. The arrow indicates the formation of foci of MCF-7 breast cancer despite the treatment by
IC50 of different impacted complexes
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Fig. 3 . 1HNMR for HL1and HL4 ligands ( as examples)
Fig. 4 . Geometry optimization for VO(II)-HL(1-5) complexes (A-E, respectively)
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Fig. 5. X-ray diffraction patterns for HL4, HL5 and their complexes
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Fig. 6A. Frontier molecular orbital's of HOMO(1)and LUMO(2) pictures for hydrazonoyl ligands
22

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Fig. 6B. Frontier molecular orbital's of HOMO(1) and LUMO(2) pictures for VO(II)-HL (1-5)
ligands (A-E, respectively)
Fig. 7. Hammett's relation between effect of p- substituent (σ R) and energy gaps (ΔE )for ligands and their
VO(II) complexes
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Fig.8 . High interacting Protein- inhibitor complexes for ; HL1, HL2, HL3, HL4 and HL5 with 1sm3 and
2ki2 receptors,( A1-E1 and A2-E2, respectively
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Fig. 9 . High interacting hp plot for ; HL1, HL2, HL3, HL4 and HL5 ligands with 1sm3 and 2ki2 receptors,( A1-E1
25

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and A2-E2, respectively
Fig.10 . Dose response curves of HL4,5 ligands and their VO(II) complexes against MCF-7, HCT-116
and HEPG-2 cancer cells, cells were treated with various concentrations of ligands and complexes
incubated for 72 hrs. %5 CO2.
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Table 1. Significant analytical and physical data for hydrazonoyl ligands (HL1-5) and their VO(II)
complexes.
Compounds
Color Elemental analysis (%) Calcd (Found)
(Empirical formula )
C
H
N
Cl
SO4
M
1) HOPH(C9H9N2OCl)(HL1)(196.64)
4.61(4.60)
18.03(18.03)
----
Faint
54.97(54.95)
14.25(14.26)
yellow
2)[(VO)2
(SO4)2(HOPH)(H2O)]H2O(558.66)
Dark
green 19.35(19.34)
2.34(2.34) 5.01(5.02)
6.35(6.34)
16.83(16.82)
6.00(6.01)
34.39(34.37) 18.23(18.22)
-----
3)
5.74(5.75)
Faint
HMPH(C10H11N2OCl)(HL2)(210.66)
57.02(57.02)
13.30(13.31)
yellow
Dark
4)[(VO)2 (SO4)2( HMPH
)(H2O)]2H2O(590.70)
2.90(2.91) 4.74(4.74)
5.34(5.31)
green 20.33(20.32)
32.52(32.51) 17.25(17.24)
-----
5)
Faint
HMoPH(C10H11N2O2Cl)(HL3)(226.66)
52.99(52.89)
12.36(12.37) 15.64(15.63)
yellow
Dark
6)[(VO)2
2.57(2.56) 4.76(4.77)
6.02(6.03)
(SO4)2(HMoPH)(H2O)]H2O(588.68)
green 20.40(20.41)
32.63(32.63) 17.31(17.30)
-----
7) HCPH(C9H9N2OCl2)(HL4)(231.08))
3.92(3.91)
Faint
46.78(46.81)
12.12(12.11) 30.68(30.69)
4.72(4.73)
yellow
Dark
8)[(VO)2
(SO4)2(HCPH)(H2O)]H2O(593.10)
green 18.23(18.23) 2.29(2.2.8)
11.96(11.95) 32.39(32.38) 17.18(17.19)
9)HBPH(C H N OBrCl)(HL5)(275.54)
3.29(3.28)
-----
Faint
9
9
2
39.23(39.30)
10.17(10.18) 12.87(12.88)
yellow
10)[(VO)2
(SO4)2(HBPH)(H2O)]2H2O(655.58)
Dark
green 16.49(16.47)
2.31(2.32) 4.27(4.25)
5.41(5.40)
29.30(29.31) 15.54(15.54)
Table 2. Significant IR spectral bands (cm-1) for hydrazonoyl ligands and their VO(II) complexes
δr(H2O),δw(H2O)
Compounds
δNH υ
C=O C=Nas(SOs(SO4)
NH, OH

M-O M-N
V=O
4)
1) HL1, HOPH
3249
1495 1683 1534---- ---- ------
14821632 15241260 120 753, 638
1524 1676 1595----- ---- ------
14801630 15701250 112 757, 638
1518 1674 1540----- ---- -----
---- -----
963 614
----
----
549
----
B. c. 3471
2)[(VO)2 (SO4)2( HOPH )(H2O)]H2O
3) HL2, HMPH
3244
B.c. 3449
943 614
----
545
----
4)[(VO)2 (SO4)2( HMPH )(H2O)]2H2O
5) HL3, HMoPH
3228
B.c. 4508 1480 1628 15301250 131 753, 638
996 617
-----
560
----
6)[(VO)2 (SO4)2( HMoPH )(H2O)]H2O
7) HL4, HCPH
3242
B. c. 3506 14901630 15101250 128 753, 637
3241 1504 1681 1536---- ---- -----
1507 1682 1537----- ---- -----
991 616
-----
553
-----
525
8)[(VO)2 (SO4)2( HCPH )(H2O)]H2O
9)HL5, HBPH
B.c. 3408 14901643 15101224 155 755, 632
944 622
10)[(VO)2 (SO4)2(HBPH )(H2O)]3H2O
27

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B. c. Broad centered
Table. 3. 1HNMR and 13CNMR data for hydrazonoyl ligands
δ (m, Ar)
δ (s,
NH)
δ(CH3),
OCH3
δ(2C,Ar),(C- δ (2C,Ar)
Br)
δ (2C,Ar),(C-O) δ (=C- δ (C=O)
compound δ
Cl)
(s,CH3),OCH3
HL1
HL3
HL4
HL5
2.50
7.02-7.47
10.68
10.59
10.78
10.77
25.82
115.32
115.06
116.89
123.25,
123.30
116.62
129.77
143.00 188.38
2.48, 3.74
2.50
6.94 (d)
7.40 (d)
7.39 (d)
7.45 (d)
7.39 (d)
7.52 (d)
25.75,
55.75
25.84
122.27,136.61 155.81 188.09
123.98,126.87 129.64
124.08 132.51
142.01 188.39
142.42 188.42
2.50
25.85
117.31,
114.81
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Table 4. Electronic transitions for hydrazonoyl ligands and their VO(II) complexes
Compounds
μ(eff) d-d transition Intraligand and
bands
(nm)
------
charge transfer/nm
(BM)
-----
1) HL1, HOPH
290, 320, 400
280, 380,
1.65
-----
620
2)[(VO)2 (SO4)2(HOPH )(H2O)]H2O
3) HL2, HMPH
----
625
300, 320, 430
300,320, 380
1.66
4)[(VO)2 (SO4)2(HMPH
)(H2O)]2H2O
5) HL3, HMoPH
-----
1.66
----
620
290, 330, 400, 420
300, 320, 350, 380, 420
6)[(VO)2 (SO4)2(HMoPH
)(H2O)]H2O
7) HL4, HCPH
------
----
300, 370, 400
1.67
----
620
----
300, 310, 360, 430
300, 400, 420
8)[(VO)2 (SO4)2(HCPH )(H2O)]H2O
9)HL5, HBPH
1.65
620
290, 350, 370, 450
10)[(VO)2 (SO4)2(HBPH
)(H2O)]3H2O
29