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Chemical and Biological Pharmaceutical Engineering Research Center, School of Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, Jiangsu 221004, China
Department of Chemistry, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China
a r t i c l e
i n f o
Article history:
Received 11 November 2011
Received in revised form 27 December 2011
Accepted 27 December 2011
Available online 6 January 2012
Keywords:
Hydroxychalcones
Radical scavenging activity
DFT
OH bond dissociation enthalpy
Ionization potential
a b s t r a c t
The molecular structure and radical scavenging activity of six new synthesized hydroxychalcones have
been explored by using density functional theory (DFT) with the B3LYP exchange correlation functional.
The minimum energy conformations were obtained from the energy scan, then a further geometry optimization was performed at the B3LYP level with 6-31 + G basis set. For radicals and cations, the geometry optimizations and frequency calculations were also done at the UB3LYP/6-31 + G level. The
homolytic OH bond dissociation enthalpy (BDE) and the adiabatic ionization potential (IP) were determined both in gas phase and in solvents using PCM model. The geometry structure, radical, electron character and the frontier molecular orbital were analyzed to explore the key factors that inuence the radical
scavenging activity of the hydroxychalcones. Based on BDE and IP values, it was revealed that compound
3 is expected to be more efcient hydrogen atom and electron donors than others, B-ring of hydroxychalcones is the active center and the hydrogen atom transfer (HAT) appears as a major mechanism in antioxidant action. The calculated results are in good agreement with experimental values.
2012 Elsevier B.V. All rights reserved.
1. Introduction
Free radicals, reactive oxygen species (ROS), and reactive nitrogen species (RNS) are implicated in numerous pathological conditions such as inammation, metabolic disorders, cellular aging,
reperfusion damage, atherosclerosis, and carcinogenesis [15].
Therefore, there is increasing interest in the protective and preventive function of foods and their constituents against oxidative damage caused by free radicals.
Polyphenol compounds such as protocatechuic acid, caffeic acid
and a variety of avonoids are present in fruits and vegetables and
are an integral part of the human diet. It is already known that
dietary polyphenols show potent antiradical ability. The radical
scavenging abilities of these compounds depend greatly on the number and arrangement of phenolic hydroxyl groups. Recently, theoretical methods especially density functional theory (DFT) method,
have been successfully used to evaluate chemical properties, such
as bond dissociation enthalpy (BDE) and the adiabatic ionization
potential (IP) of polyphenol compounds and to elucidate the
structureactivity relationship (SAR) for phenolic antioxidants
[615]. Furthermore, the study of the electronic and molecular
properties is of great importance that helps to understand the mechanism of the antioxidant activity of these compounds.
Corresponding authors. Tel.: +86 516 83262137 (Y. Xue), +86 516 83262136 (Y.
Liu).
E-mail addresses: xzmcysxue@sina.com (Y. Xue), njuliuyi2003@gmail.com (Y.
Liu).
2210-271X/$ - see front matter 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.comptc.2011.12.020
Chalcones (or 1,3-diaryl-2-propen-1-ones) are natural compounds that are largely distributed in plants, fruits, and vegetables
(see Fig. 1). They are precursors in avonoid biosynthesis: the
enzymatic cyclization of the 6-hydroxychalcones leads to the formation of avanones, and subsequently to a large number of avonoid groups, including avones, avonols, dihydroavonols,
aurones, and isoavones [16]. The presence of a a,b-unsaturated
bond and the absence of the central C-ring are two specic characteristics of chalcones, making these compounds chemically different from the other avonoids. Chalcone derivatives generate strong
interest stemming from their broad spectrum of pharmacological
activities, such as anti-ulcer, anti-cancer, antimitotic, anti-inammatory, anti-malarial, anti-fungal, anti-HIV and antioxidant activities [1724].
Hydroxychalcones, as an important part of chalcones family, are
widespread among natural and synthesized chalcones and have
attracted an increased attention. In the last decade a large number
of reports have been published on the benecial effects of hydroxychalcones, especially the antioxidant activity [2529]. These experimental results have shown that hydroxychalcones are efcient for
the scavenging of various radicals including DPPH radical. Moreover, some of them, such as 2,3,4,6-tetrahydroxychalcone, exhibit
more potent radical-scavenging activity than vitamin C and
a-tocopherol [27].
Apart from the experimental studies, a few theoretical investigations mainly based on DFT have also been performed on the
antioxidant activity of hydroxychalcones to elucidate the SAR. Cotelle et al. [30] investigated the redox properties of a series of
R2
R1
5
4
A
3
6'
1'
9
O8
10
5'
B
2'
4'
3'
75
electron to the free radical. Again, the radical cation arising from
the electron transfer must be stable, so it does not react with substrate molecules. In this case, the adiabatic ionization potential (IP)
is the most signicant energetic factor for the scavenging activity
evaluation. Molecules with the low IP and BDE values are expected
to have high activity. Thus, in the present study BDE and IP values
were used as the main molecular descriptors to elucidate the radical scavenging activity of the investigated compounds.
The homolytic BDE values of the OH bond were calculated as
the differences in the enthalpy of the reactants at 298.15 K and
1.00 atm with the use of the following equation:
R4
R3
2
3
4
5
hydroxychalcones by cyclic voltammetry and theoretical calculation. Kozlowski and co-workers [31] have reported a detailed study
of conformational, electronic and antioxidant properties of a series
of natural hydroxychalcones by B3P86/6-31 + G calculations.
Their results demonstrated the importance of the H atom transfer
mechanism to explain their capacity to scavenge the free radicals.
Furthermore, the active sites were identied as the 6-OH group
and the 3,4-dihydroxy-catechol. The calculated results obtained
by Chen et al. [32] shown that the 2,4,30 ,40 -tetrahydroxychalcone
(butein) can serve as a powerful antioxidant against DPPH radical.
Despite these advances in experimental and theoretical works,
an understanding of the relationship between the structure and
antioxidant activity and the antioxidant mechanism is still lacking.
Very recently, Zhou et al. [33] have synthesized six hydroxychalcones 16 (see Fig. 1) and evaluated their antioxidant activity by
several antioxidant assays. In the present work, the structural
and electronic properties of these hydroxychalcones and their
radicals were investigated at DFT level, with the aim to further
shed light on the structureradical scavenging activity relationship
of these compounds and provide new clue for antioxidant development. Specically, the homolytic bond dissociation enthalpy (BDE)
of OH bonds, adiabatic ionization potential (IP), HOMO orbital
distribution and spin density in free radicals were calculated. With
the current work we hope to add knowledge on the structureradical scavenging activity of hydroxychalcones and stimulate the
interest for further research and exploitation of such avonoids
for food or other applications.
2. Methods
In the literature, two main mechanisms by which antioxidants
can play their protective role were proposed and widely analyzed
[12]. The rst one is referred as H-atom transfer (HAT, Eq. (1)) from
the antioxidant ArOH that becomes itself a radical. The second one
is referred as one-electron transfer (ET, Eq. (2)) in which the antioxidant gives an electron to the free radical becoming a radical
cation.
R ArOH ! RH ArO
R ArOH ! R ArO
76
groups + PCM) for quercetin [43]. They observed only a slight difference in BDE as compared to a pure PCM calculation, while computational time was dramatically increased. Thus, in the present
paper, calculations were performed with the integral equation formalism polarized continuum model (IEFPCM) [44,45].
Fig. 2. Potential energy curves of hydroxychalcones 16 calculated at the B3LYP/3-21G level in gas phase.
former is more stable than the s-trans one, thus, we decided to focus
on the s-cis conformer for compounds 16. In order to analyze the
torsion around the C1C7 and C10C10 bonds, a fully relaxed torsional potential is computed for 16 at the B3LYP/3-21G level of
theory in vacuo. The potential energy surface scan was performed
around the two bonds (Fig. 1) in steps of 30 by varying the torsion
angles h [C6C1C7C9] and u [C9C10C10 C60 ] from 0 to 180.
The plots of the potential energy prole are shown in Fig. 2. It can
be observed that the PES exhibits two unique energy minima for
each hydroxychalcone studied. The pairs of torsional angle values
are h = 0, u = 0 for the global minimum and h = 0(180),
u = 180(0) for the local minimum (see Table 1). The energy difference between the two conformers of each hydroxychalcone is very
low, with the largest value of only 0.72 kcal/mol.
At the minimum energy conformations obtained from the energy scan, further geometry optimization was performed with
the B3LYP/6-31 + G basis set. Geometry optimizations on the radicals were performed, starting from the optimized structure of the
parent molecule, after the H atom was removed from the 3, 4, 30
and 40 positions. No geometrical parameter constraint was imposed during the optimization, except those favoring the stabilizing effects due to hydrogen bonding between two adjacent OH
groups. The optimized structures of the most stable conformers
of neutral form of hydroxychalcones are shown in Fig. 3 along with
the pattern of intramolecular hydrogen bonds (IHBs). It has been
Table 1
The energy as a function of torsional angle of the six hydroxychalcones at the B3LYP/
3-21G level.
Comp.
M1
M2
DE (kcal/mol)
E (hartree)
E (hartree)
1
2
3
4
5
6
0
0
0
0
0
0
0
0
0
0
0
0
800.04804
800.04574
949.65063
725.24378
725.2432
800.0437
0
0
0
180
180
0
30
180
180
0
180
180
800.04690
800.04572
949.65048
725.24344
725.24291
800.04345
0.72
0.01
0.09
0.21
0.18
0.16
77
found that the neutral species of molecules 1, 2 and 3 are characterized by IHB which contributes to the stability. The optimized
geometrical parameters for neutral molecules and its radicals are
shown in Table 2. From the data of bond distances and bond angles,
it can be seen that no signicant geometrical change has been observed when going from the neutral molecule to the phenoxy
(ArO) and the cation (ArOH+) radicals obtained after hydrogen
and electron abstraction, respectively. Most of the bond distances
are exhibiting double bond character and at the same time shorter
than single bonds. From the data of dihedral angle in Table 2, it can
also be seen that compounds 1 and 3 with o-dihydroxyl groups in
A-ring are completely planar, while others have some degree of
deviation from the planarity due to the torsion between A-ring
and the plane of enone system. The planarity of 1 and 3 is further
indication of possible extended conjugation and their stronger
antioxidant activities.
3.2. BDE computation. The inuence of solvents
The hydrogen donating ability of the wide class of polyphenols
and the ability of these compounds to form the radical forms are
characterized by BDE. The BDE corresponds to the OH bond
breaking (H abstraction), thus this parameter describes the stability of the hydroxyl bonds. The molecules with lower values of BDE
are endowed with higher antioxidant activity. Table 3 presents the
calculated BDE values in gas phase and solvents (ethanol and
water) by applying B3LYP/6-31 + G method.
For a compound possessing more than one phenolic hydroxyl,
its radical-scavenging activity is determined by the one with the
lowest OH BDE. On the basis of the calculated OH BDEs (Table
3), the hydrogen donating ability of hydroxychalcones follows
the order: 3 > 2 > 1 > 6 > 5 > 4, which is fully consistent with the
galvinoxyl radical (GO)-scavenging rate constant obtained from
experimentally kinetic measurement [33]. Moreover, among the
phenolic hydroxyls at different positions, the hydroxyl at position
40 in compound 3 has the lowest OH BDE, 72.9, 78.5 and
78.8 kcal/mol in gas phase, ethanol and water, respectively (Table
3). These results indicate that there are some correlations between
Fig. 3. Optimized structures of hydroxychalcones 16 calculated at the B3LYP/6-31 + G level in gas phase.
180.0
178.8
178.9
180.0
179.1
179.0
179.0
177.7
180.0
178.8
178.9
180.0
180.0
180.0
179.2
178.9
179.5
179.2
179.2
177.5
179.1
178.9
179.3
179.6
0.1
6.5
5.7
0.0
4.9
5.9
5.2
17.5
0.0
5.1
4.2
0.0
0.0
0.0
5.5
5.5
13.5
3.9
4.2
25.9
4.6
4.3
4.3
4.7
179.9
161.7
162.6
179.9
165.1
165.3
166.1
172.4
179.9
162.3
163.6
179.8
179.8
180.0
170.7
162.5
159.6
166.8
167.9
173.2
166.8
162.7
171.8
174.1
127.9
128.0
128.0
127.7
128.2
127.8
127.5
126.9
128.2
128.3
128.2
127.6
127.7
127.6
128.0
128.0
127.5
128.2
127.4
126.8
128.2
128.2
127.4
127.5
120.3
120.3
120.3
119.1
120.3
120.2
120.2
118.9
120.2
120.1
120.1
120.1
120.1
119.0
120.4
120.3
118.9
120.3
120.2
119.1
120.3
120.3
120.2
118.8
119.8
119.5
119.2
119.4
119.6
120.1
120.2
123.0
119.6
119.3
119.1
120.2
120.1
120.6
119.9
118.9
120.4
119.5
120.3
123.6
119.5
118.8
120.5
121.6
0.971
0.9667
0.9695
0.9715
0.9666
0.9668
0.9665
0.9662
0.9707
0.9746
0.9819
0.9678
0.9701
0.9702
0.9732
0.9666
0.9823
0.9659
0.9660
0.9685
0.9699
0.9835
0.9659
0.9693
0.9655
0.9655
0.9656
0.9698
0.9656
0.9843
0.9746
0.9823
0.9699
0.97
0.9834
1.4964
1.5067
1.5037
1.5024
1.5039
1.5009
1.4997
1.4776
1.4980
1.5079
1.5043
1.4931
1.4919
1.4907
1.4963
1.5008
1.4893
1.5047
1.4994
1.4715
1.5047
1.5017
1.4919
1.485
1
1-radical-a
1-radical-b
1-cation
2
2-radical-a
2-radical-b
2-cation
3
3-radical-a
3-radical-b
3-radical-c
3-radical-d
3-cation
4
4-radical
4-cation
5
5-radical
5-cation
6
6-radical-a
6-radical-b
6-cation
1.4838
1.4815
1.4796
1.4772
1.4811
1.4878
1.4853
1.5014
1.4805
1.4778
1.4762
1.4870
1.4845
1.4865
1.4857
1.4788
1.4822
1.4811
1.4846
1.4956
1.4811
1.4755
1.4861
1.4921
1.2346
1.2304
1.2325
1.2292
1.2331
1.2308
1.232
1.2313
1.2354
1.2314
1.2339
1.2342
1.2351
1.2304
1.2333
1.2337
1.2295
1.2329
1.2324
1.2343
1.2329
1.2348
1.2339
1.2301
1.3499
1.3512
1.3517
1.371
1.3518
1.35
1.3595
1.3713
1.3521
1.3539
1.354
1.3491
1.3601
1.3681
1.3495
1.3518
1.3745
1.3519
1.3633
1.3796
1.3519
1.3541
1.3629
1.3747
1.4636
1.4619
1.4615
1.4375
1.4584
1.4615
1.4439
1.4302
1.4579
1.4555
1.4557
1.4642
1.4433
1.4349
1.4638
1.4614
1.4334
1.4584
1.4376
1.4227
1.4584
1.4557
1.4379
1.4273
0.9659
0.982
0.9761
0.9697
0.9699
0.97
0.9843
119.4
118.8
119.0
118.8
119.0
119.1
119.2
120.1
119.4
118.9
119.0
119.4
119.4
119.1
119.2
119.1
118.9
119.2
119.4
121.0
119.2
119.1
119.4
118.9
D(7,9,10, 10 )
D(8,7,9,10)
D(6,1,7,8)
A(9,10, 10 )
A(7,9,10)
A(1,7,8)
A(1,7,9)
O(4)-H
O(3)-H
O(2)-H
O(1)-H
R(10,10 )
R(9,10)
R(7,8)
R(7,9)
R(1,7)
Parameters
Table 2
The selected geometrical parameters of the six hydroxychalcones and its radicals at the (U) B3LYP/6-31 + G level.
0.1
2.9
3.0
0.0
1.8
2.8
1.6
5.6
0.1
1.8
1.8
0.0
0.0
0.0
2.9
3.0
4.2
0.6
1.0
6.5
1.7
1.8
1.1
1.1
D(9,10, 10 ,60 )
78
the two parameters, namely, the lower the OH BDE is, the more
active is the hydroxychalcones to scavenge galvinoxyl radical.
In the present study compounds 13, bearing o-dihydroxyl
groups on the two aromatic A and B rings, presented lower BDE
values (72.978.1 kcal/mol), in comparison to those of compounds
46 bearing no such groups (80.984.6 kcal/mol). Comparing 2
with 5, or 1 with 4, we nd that the presence of o-dihydroxyl group
on aromatic rings decreases the OH BDE by about 8 kcal/mol (Table 3). The reason can be found in the fact that the radical arising
from H-atom removal is stabilized by the formation of the IHB with
the vicinal hydroxyl, as evidenced from theoretical calculations
[12], suggesting that the BDE of catechol is 9.1 kcal/mol lower than
that of phenol. It is noteworthy that the very important role of odihydroxyl groups has previously been discussed for other polyphenol compounds, based on experimental data as well as theoretical calculations [4852]. In the 30 -OH and 40 -OH radicals of
compounds 1, 2 and 3, we also observe H-bonding between the
remaining OH group and the neighboring phenolic oxygen atom.
After the OH bond is broken in the parent compound, the radical
is able to rearrange to the more stable conformation, corresponding to the formation of a new H-bond, as shown in Fig. 4. A decrease of 8.7 kcal/mol in energy is observed between the
molecule without (Fig. 4a) and with (Fig. 4b) this new H-bond.
Moreover, the potential energy surface scan at B3LYP/6-31G level
of theory (Fig. 4c) shows that the barrier height for the rotation of
OH in the radical is only ca. 5.8 kcal/mol, so this rearrangement
can occur at room temperature. The IHB enthalpy in 2 is estimated
to be 8.5 kcal/mol, which is similar to that of phenolic radical of
catechol by theoretical calculations, 8.09.6 kcal/mol [12,52,53].
From the gas phase BDE values, it can be found that lesser
amount of energy is required for breaking the hydroxyl groups
on B-ring with respect to the corresponding hydroxyl groups on
A-ring. As exemplied in compounds 5 and 4, 40 -OH in the B-ring
had a lower BDE value than 4-OH in the A-ring in both gas phase
and solvents. This clearly conrms that HAT from the B-ring is easier than that of A-ring, which is congruent with experimental
results; i.e. compound 5 is more active in the GO-scavenging reaction than is compound 4 [33].
In compound 1, 4-OH had a lower BDE value than 3-OH, and
hence the HAT reaction should rst occur in 4-OH. Similarly, the
BDE value of 30 -OH for compound 2 was relatively high; thus, the
hydrogen abstraction from 40 -OH is more favorable than that from
30 -OH. Furthermore, the BDE values (Table 3) for all the radicals of
compound 3 give the following sequence for the present OH groups:
40 < 30 < 4 < 3. These results clearly show that p-hydroxyl group has
stranger radical-scavenging activity than m-hydroxyl group.
When the solvents were taken into consideration an increase in
the range of 2.15.9 kcal/mol was obtained for BDE values. A close
inspection on the BDE values in structurally related aurones [54]
revealed a similar phenomenon, i.e., an increasing of the BDE values in going from gas phase to solvent. This nding indicates that
in polar solvents, such as ethanol and water, the antioxidants studied have a lower ability to hydrogen transfer than in gas phase. It is
noticeable that the order of BDE values calculated for the solvent
phase is the same as that for the gas phase but small difference
is observed from the values of the radicals of 3. The hydrogen
abstraction from 4-OH in 3 is more favorable than that from 3OH in gas phase, while reversed case is found in water.
From Table 3, it can be seen that the BDE values of each of the
OH groups present in all radicals of hydroxychalcones are similar
to, or smaller than, those of phenol calculated at the same level
of theory. This indicates that most of the phenolic hydroxyls have
stronger hydrogen donating ability than phenol. It can also be seen
from Table 3 that the BDE of 40 -OH group in 3 (72.9 kcal/mol in gas
phase) is similar to that of the HPMC (72.3 kcal/mol), a model for
the antioxidant a-tocopherol lacking the phytl (C16H33) tail. This
79
1
2
3
4
5
6
BDE (kcal/mol)
Radicals
Gas
Ethanol
Water
Gas
Water
3-OH
4-OH
30 -OH
40 -OH
3-OH
4-OH
30 -OH
40 -OH
4-OH
40 -OH
4-OH
40 -OH
78.1
77.3
75.9
73.2
78.0
77.1
76.1
72.9
84.6
81.1
84.3
80.9
83.4
75.1
72.3
81.3
81.0
79.8
77.3
81.8
81.7
81.4
78.5
87.7
83.4
87.1
83.0
85.4
81.6
81.3
80.0
77.6
82.0
82.1
81.8
78.8
87.9
83.4
87.4
83.0
85.7
176.2
134.5
29.8 0.9
172.9
128.9
69.5 3.3
168.7
128.3
93.2 2.2
180.1
175.9
172.9
140.7
133.0
131.9
0.13 0.01
0.30 0.01
0.32 0.01
190.7
202.1
154.2
136.8
Phenol
Vit.C analogueb
HPMCc
(a)
(b)
(c)
-803.830
Energy (hartree)
a
b
K (M1s1)a
IP (kcal/mol)
-803.835
-803.840
(a)
-803.845
-803.850
(b)
B3LYP/6-31G*
-803.855
-20
20
40
60
Fig. 5. HOMO shapes of hydroxychalcones 16 in gas phase calculated at the B3LYP/6-31 + G level.
80
-0.15
HO
0.07
0.02
0.37
O
O
0.32
0.33
0.28
-0.11
0.09
HO
0.23
0.20
-0.01
-0.12
0.30
0.34
-0.16
1r-a
1r-b
0.34
0.31
-0.06
O
0.34
-0.18
OH
O
0.32
0.28
0.33
0.02
-0.11
OH
0.23
0.09
HO
0.20
OH
-0.12
0.30
0.34
OH
-0.16
3r-b
3r-a
0.06 OH
O 0.34
0.02
HO
0.19
0.08
OH
0.24
HO
-0.17
0.29
0.29
-0.07
-0.13
HO
3r-d
0.28
0.36
-0.23
0.33
0.44
-0.18
-0.21
4r
0.36
-0.23
0.33
0.44
-0.19
-0.11
0.40
0.33
-0.22
5r
OH
-0.12
0.32
O
0.39
O
-0.13
3r-c
0.33
-0.02
0.35
-0.16
0.30
-0.13
0.28
O
0.21
HO
0.39
O
OH
0.08
2r-b
-0.15
0.27
2r-a
0.37
-0.01
0.33
-0.15
HO
0.07
-0.09
0.27
0.02
0.13
0.28
O
0.17
0.08
OH
-0.14
0.26
HO
0.33
-0.21
-0.17
O
6r-a
0.32
O
-0.18
-0.10
0.40
0.31
-0.21
6r-b
Fig. 6. Spin density distribution in the phenoxy radicals of hydroxychalcones 16 in gas phase calculated at the B3LYP/6-31 + G level.
means that hydroxychalcone 3 should be of comparable antioxidant activity with a-tocopherol, which is a biological reference
81
4. Conclusions
Free radical-scavenging activity of various phenolic antioxidants is also strictly related to the distribution of the HOMO orbital. The molecules with a lower energy of the HOMO orbital have
weaker electron donating ability. Besides, the electronic density
distribution in these orbitals permits prediction of the most probable sites in the molecules investigated which can be easily attacked by free radicals and other reactive agents. More active
redox sites of these molecules are characterized by high density
of the HOMO orbital. Analysis of Fig. 5 shows that HOMO orbitals
of the six compounds present different distribution that depend
on the position and number of substituted OH groups. For compounds 1 and 4, which are bearing OH groups on A-ring, the HOMO
orbitals are almost delocalized on the whole molecule, whereas in
compounds 2 and 5 bearing OH groups on B-ring, the HOMO orbitals are mainly localized on 3-phenylpropenal and phenolic oxygen
atom. As far as compounds 3 and 6 are concerned, the HOMOs are
essentially outspreaded on 3-phenylpropenal and OH groups on Bring with a smaller contribution on A-ring. The contribution to the
82
Acknowledgements
Financial support for this work was provided by Natural Science
Foundation of Jiangsu Province (No. BK2009523), Natural Science
Foundation of Education Ministry of Jiangsu Province (No.
09KJB350003, 11KJB350005), Priority Academic Program Development of Jiangsu Higher Education Institutions, Laboratory of Biological Therapy for Cancer of Xuzhou Medical College (C0903),
the Special Fund for the Presidents Project of School of Pharmacy
(2010YKJ003), Innovative Practice Training Program for Students
of Jiangsu Higher Education Institutions and Innovative Practice
Training Program for Students of School of Pharmacy.
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