Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155

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Spectrochimica Acta Part A: Molecular and Biomolecular

Spectroscopy
journal homepage: www.elsevier.com/locate/saa

Investigation of anticancer properties of caffeinated complexes via

computational chemistry methods
Koray Sayin ⁎, Ayhan Üngördü
Department of Chemistry, Faculty of Science, Cumhuriyet University, 58140 Sivas, Turkey

a r t i c l e i n f o a b s t r a c t

Article history: Computational investigations were performed for 1,3,7-trimethylpurine-2,6-dione, 3,7-dimethylpurine-2,6-dione,

Received 27 September 2017 their Ru(II) and Os(III) complexes. B3LYP/6-311++G(d,p)(LANL2DZ) level was used in numerical calculations.
Received in revised form 22 November 2017 Geometric parameters, IR spectrum, 1H-, 13C and 15N NMR spectrum were examined in detail. Additionally, contour
Accepted 1 December 2017
diagram of frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP) maps, MEP contour and
Available online 6 December 2017
some quantum chemical descriptors were used in the determination of reactivity rankings and active sites. The
Keywords:
electron density on the surface was similar to each other in studied complexes. Quantum chemical descriptors
Caffeine were investigated and the anticancer activity of complexes were more than cisplatin and their ligands. Additionally,
Transition metal complexes molecular docking calculations were performed in water between related complexes and a protein (ID: 3WZE). The
Computational study most interact complex was found as Os complex. The interaction energy was calculated as 342.9 kJ/mol.
Anticancer properties © 2017 Elsevier B.V. All rights reserved.
Molecular docking

1. Introduction
Investigation for new cancer drugs is an important field for researcher.
Searching for cancer drugs has been attractive for many years. The first
study in this field has been done by Rosenberg et al. in 1965 [1]. In their
study, the interaction between Pt complex and E. coli (Escherichia coli)
has been investigated [1]. Then, significant of Pt complexes increased.
Disadvantages of platinum complexes over anticancer studies have been
observed and new metal complexes used as anticancer drugs has been
started to investigate [2–5]. Anti-cancer drugs may be organic or inorgan-
ic molecules [2–9]. Although ruthenium and osmium elements are toxic,
ruthenium and osmium complexes have been investigated as anti-cancer
drugs [10–13]. In this respect, they have the same properties as the
platinum complexes. Caffeine is popular substance and mainly found in
cola, tea, energy drinks and coffee. Caffeine has the positive and negative
effect on the living. Caffeine is metabolized in the liver into three metab-
olites which are paraxanthine, theobromine and theophylline [14].
There are limited computational studies in literature over complexes
which have anti-cancer properties, caffeine and its derivatives. Computa-
tional researches have many advantages compared to the experimental
studies [15]. In this paper, we focus on caffeine, theobromine, their
tautomers, their ruthenium complexes and osmium complex. Schematic
diagram of mentioned complexes is represented in Scheme 1. Atomic
labeling of mentioned complexes is shown in Scheme 1, too.
In Scheme 1, molecule (I) and (III) correspond to theobromine and
caffeine, respectively. Additionally, molecule (I)–(II) and (III)–(IV) are
⁎ Corresponding author.
E-mail addresses: krysayin@gmail.com, ksayin@cumhuriyet.edu.tr (K. Sayin).
tautomers of each other, separately. Naturally, molecule (I) and (III)
are more stable than molecule (II) and (IV), respectively. But, some
complexes containing molecule (II) and (IV) have been investigated
by Clarke et al. [16,17]. As experimentally, complex VII has been synthe-
sized by Clarke et al. in 1993 [16]. A structural isomer of complex V has
been synthesized by Krentzien et al. in 1975 [17]. There is no any data
about complex V and VI in literature. Additionally, biological properties
and anticancer properties of caffeinated compounds have been investi-
gated by the researcher from the beginning [18–21].
The aims of this paper are the investigations of structural,
electronical and biological properties of mentioned compounds. For
these purposes, related compounds are performed at B3LYP/6-
311++G(d,p) and B3LYP/6-311++G(d,p)(LANL2DZ) levels for com-
pound I–IV and complex V–VII, respectively. Some quantum chemical
descriptors which are mainly used by the computational researchers
are used to investigate anti-cancer activity. Additionally, the effect of
complexation on the anti-cancer properties is investigated by quantum
chemical parameters which are energy of the highest occupied molecu-
lar orbital (EHOMO), energy of the lowest unoccupied molecular orbital
(ELUMO), energy gap between LUMO and HOMO (EGAP), absolute
hardness (η), absolute softness (σ), absolute electronegativity (χ),
chemical potential (CP), electrophilicity index (ω), nucleophilicity
index (N), additional electronic charges (ΔNmax), global softness (S).
Mentioned descriptors of caffeine and its derivate are calculated at
B3LYP/6-311 ++G(d,p) level in the gas phase and water. Interaction
energies between vascular endothelial growth factor receptor 2
(VEGFRTK) (ID: 3WZE) and mentioned complexes are calculated by
molecular docking calculations in water. The anti-cancer activity of
caffeine, theobromine and their complexes are examined in detail. The

https://doi.org/10.1016/j.saa.2017.12.013
1386-1425/© 2017 Elsevier B.V. All rights reserved.
148 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155
Scheme 1. Schematic representation of mentioned compounds with atomic labeling.
difference between caffeine and caffeinated complexes was tried to be
mentioned.
2. Computational Details
Quantum chemical calculations of related complexes were per-
formed by using GaussView 5.0.8 [22], Gaussian 09 AML64-G09
Revision-D.01 programs [23] and ChemBioDraw Ultra Version
(13.0.0.3015) [24]. Calculations were done at B3LYP/6-311 -
++G(d,p)(LANL2DZ) level for studied complexes and B3LYP/6-
311++G(d,p) level was used for organic molecules in this study. No
imaginary frequencies were observed in computational results for the
whole complexes. Gauge-including-atomic-orbital (GIAO) method
with B3LYP/6-311 ++G(d,p)(LANL2DZ) level was used to calculate
NMR spectra for studied molecules [25,26]. In calculations, LANL2DZ
basis set was used for metal atoms and 6-311++G(d,p) was used for
the rest atoms. In calculations, 28 core electrons were frozen in rutheni-
um atoms and 60 core electrons were frozen in osmium atom due to the
LANL2DZ basis set. There are π electrons in organic compounds and het-
eroatoms and we add diffuse and polarized basis set. We tried to select
big basis set for atoms except metal atoms to examine more accurate
the electronical and biological properties. 6-311 ++G(d,p) basis set
was selected. Additionally, LANL2DZ was used for metal atoms like
many computational researchers. Molecular docking calculations were
performed by Hex 8.0.0 program in water [27]. Additionally, some
quantum chemical parameters which are energy of the highest occu-
pied molecular orbital (EHOMO), energy of the lowest unoccupied molec-
ular orbital (ELUMO), energy gap between LUMO and HOMO (EGAP),
absolute hardness (η), absolute softness (σ), absolute electronegativity
(χ), chemical potential (CP), electrophilicity index (ω), nucleophilicity
index (N), dipole moment (μ), additional electronic charges (ΔNmax),
global softness (S), are calculated by using following equations [28–37].:
I ¼ −EHOMO
A ¼ −ELUMO
EGAP ¼ ELUMO −EHOMO
I−A ELUMO −EHOMO
η¼ ¼ ð4Þ
2 2
1 Frontier Molecular Orbitals (FMOs) of Organic Compounds
σ¼
n
jI þ Aj −EHOMO −ELUMO
χ¼ ¼ ð6Þ
2 2
CP ¼ −χ
CP2
ω¼ ð8Þ
2η
1
N¼ ð9Þ
ω
CP
ΔNmax ¼ − ð10Þ
η
1
S¼ ð11Þ
2η
3. Results and Discussion
3.1. Ground State Optimization of Organic Compounds
Mentioned molecules are optimized in the gas phase and optimized
structures of related molecules are given in Fig. 1.
Stability of investigated molecules can be determined by using total
energy (ETOTAL), enthalpy (H) and Gibbs free energy (G) which are
known as thermodynamic parameters. These parameters are calculated
for mentioned molecules and given in Table 1. Molecule (I) is more sta-
ble than molecule (II). The energy differences between mentioned mol-
ecules are calculated as 133.7, 100.3 and 137.7 kJ/mol in total energy,
enthalpy and Gibbs free energy, respectively. As for the molecule (III)
and (IV), the energy differences between of them are calculated as
133.5, 133.5 and 135.1 kJ/mol in total energy, enthalpy and Gibbs free
energy, respectively. According to these results, molecule (III) is more
stable than molecule (IV). These results are expected situation. Because
caffeine and theobromine are mainly found in natural products in tea,
cacao plant, etc. Some structural parameters of related molecules are
ð1Þ given in Table 1. There are significant differences around N10 and C11
atoms. The bond lengths (N10\\C11) are longer in the molecule (II)
ð2Þ and (IV). Additionally, there are important differences in bond angles
containing N10 and C11 atoms. Especially, C11 atom is stretched to
ð3Þ
outward in the molecule (II) and (IV). These results may be increased
the chemical reactivity of molecules.
3.2. Molecular Electrostatic Potential (MEP) Map, MEP Contour and
ð5Þ
MEP maps, MEP contours and FMOs are calculated for investigated
molecules. MEP maps and contours are represented in Supp. Fig. S1 in
the supplemental material.
According to Supp. Fig. S1, there are yellow or red zones around the
ð7Þ oxygen atoms of all molecules in MEP maps. This result implies that the
 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155 149

Theobromine Theobromines Tautomer

(I) (II)
Caffeine Caffeines Tautomer

(III) (IV)
Fig. 1. Optimized structures of studied molecules at B3LYP/6–311++G(d,p) level in gas phase.

activities of oxygen atoms are similar to each other. Especially, this re- than those of molecule (I) and (III). Since there is a hydrogen atom in
sult can be seen easily from MEP contours. There are red lines around molecule (I) and (III). This situation in molecule (II) and (IV) causes
the oxygen atoms at same volume in MEP contours. Red and yellow the delocalization of electrons on molecule surface. So, the activity of
regions are appropriate to nucleophilic attack. But localized electron oxygen atoms decreases and the activity of C11 atoms increases.
densities of molecule (II) and (IV) are more than those of molecule (I) Contour diagrams of frontier molecular orbitals which are the highest
and (III). According to this outcome, Chemical activities of molecule occupied molecular orbitals (HOMO) and the lowest unoccupied molec-
(II) and (IV) are expected as higher than those of molecule (I) and ular orbitals (LUMO) are calculated and represented in Supp. Fig. S2.
(III). Electron density of C11 atom in molecule (II) and (IV) are more According to Supp. Fig. S2, there are two colors, yellow and tur-
quoise. There are two electrons in HOMO and mainly localized in yellow
Table 1 zones. As for the LUMO, if molecule accepts electron, these electrons will
Calculated some structural parameters of studied molecules. be localized to yellow zones. There are not big zones (yellow or tur-
Molecule (I) Molecule (II) Molecule (III) Molecule (IV) quoise) environment of N10 atom in molecule (I) and (III). In these
molecules, oxygen atoms are active to any chemical interaction. As for
Bond lengths (Å)
N1\\C2 1.407 1.418 1.417 1.429 the molecule (II) and (IV), it was found that the carbon atom (C11)
\O7
C2\ 1.221 1.217 1.224 1.220 was also active in addition to oxygen atoms. These results show that
\N12
C3\ 1.386 1.402 1.388 1.404 C11 atom increases the activity of molecules. As a result, C11 atoms is
\N5
C4\ 1.379 1.372 1.375 1.367 more active than heteroatoms. It is expected that Ligand coordinated
\N10
C4\ 1.356 1.370 1.357 1.371
N5\\C9 1.465 1.461 1.465 1.461
to metal atoms from C11 atom like synthesized complexes.
\O8
C6\ 1.216 1.215 1.218 1.217
N10\\C11 1.329 1.392 1.328 1.392 3.3. Ground State Optimization of Complexes
C11\\N12 1.354 1.351 1.354 1.354
N1\\C14 – – 1.469 1.470
Complex V, VI and VII are optimized at mentioned level in vacuo and
Bond angles (°) optimized structures of related molecules are given in Fig. 2. Selected
\N1\
C2\ \C6 129.856 130.276 126.757 127.147 structural parameters of related complexes are given in Table 2.
N1\\C2\\O7 121.831 120.852 122.421 121.529
In computational results, there are no significant differences among
N1\\C6\\O8 121.769 122.644 121.331 122.084
\N5\
C6\ \C9 118.464 119.663 118.317 119.664 the structural parameters of studied complexes. These results imply
\N10\
C4\ \C11 104.079 112.549 103.909 112.397 that structural properties of related complexes are similar to each other.
\N12\
C3\ \C11 105.741 112.595 105.692 112.543 The geometric structure of related complexes is distorted octahedral. Ex-
C11\\N12\\C13 127.453 123.269 127.271 123.090 perimental structural parameters are represented in parenthesis at
N10\\C11\\N12 113.567 102.563 113.610 102.611
Table 2. Experimental and calculated results are compared each other.
150 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155

Complex V Complex VI Complex VII

Fig. 2. Optimized geometric structures of related complexes at same level of theory in vacuo.

Scatter graphs are plotted for complex V and VII. Correlation coefficients
(R2) are calculated from these graphs. R2 value is calculated as 0.9966 and
0.9463 for complex V and VII, respectively. These results imply that there
are good agreements between experimental and calculated results.
3.4. IR Spectra
IR spectra are significant spectral technique in the determination of
functional groups. IR spectrum of studied complexes are calculated at
same level of theory and represented in Supp. Fig. S3. Some peaks are
labeled and calculated harmonic frequencies of these peaks are given
in Table 3. Additionally, reported experimental frequencies of complex
VII are given in Table 3, too.
According to the Supp. Fig. S3, IR spectra of ruthenium and osminium
complexes are different to each other. There are two N\\H stretching
frequencies in Ru complexes while there are three N\\H stretching
frequencies in Os complex. The differences between Ru and Os com-
plexes can be easily understood from Supp. Fig. S3 and Table 3. As exper-
imental and computational frequencies are compared, there are some
differences results. The source of this difference is the frequency types.
Experimental frequencies are anharmonic while calculated results are
Table 2
Calculated structural parameters of mentioned complexes at B3LYP/6-311-
++G(d,p)(LANL2DZ) level in vacuo.
harmonic frequencies. Generally, there is an agreement between exper-
imental and calculated frequencies. In addition to these spectrum, IR
spectrum of molecule (II) and (IV) are calculated and represented in
Supp. Fig. S4. There no much differences between IR spectrum of ligand
and its complexes except complex VII. Especially, intensity of C_O
stretching frequencies decreases with complexation. Some frequencies
of molecule (II) and (IV) are given in Supp. Table S1.
3.5. NMR Spectra
Chemical shifts values of hydrogen, carbon and nitrogen atoms in
studied complexes are calculated by using GIAO method in vacuo. In
addition to these calculations, tetramethylsilane is calculated at the
same level of theory to evaluate the chemical shift values of carbon
and hydrogen atoms. The similarity of optimized structures of Ru and
Os complexes are investigated by using chemical shift values of
mentioned atoms. Calculated 13C NMR and 15N NMR results are given
in Table 4 and 1H NMR results are given in Table 5.
According to Table 4, chemical shifts of aromatic and aliphatic carbon
atoms are calculated in the range of 115–243 ppm and 29–39 ppm, re-
spectively. In addition to these results, chemical shift values of nitrogen
atoms in the ring are calculated in the range of 47–126 ppm and
235–265 ppm for other nitrogen atoms. Additionally, NMR spectrum of
molecule (II) and (IV) are calculated at B3LYP/6-311++G(d,p) level.

Complex Vc Complex VI Complex VIId Table 3

Some calculated stretching frequencies (cm−1) of studied complexes at same level of
Bond lengths (Å)a, b
theory.
M1\\N2 2.261 (2.071) 2.262 2.263 (2.172)
M1\\N3 2.170 (2.120) 2.170 2.183 (2.129) Peaks Frequencies (cm−1) Modesa
M1\\N4 2.170 (2.108) 2.170 2.192 (2.112)
M1\\L5 2.495 (2.350) 2.497 2.191 (2.125) Complex V
M1\\L6 2.525 (2.427) 2.524 2.184 (2.127) a 3601 νN\
\H

M1\\C7 2.024 (2.030) 2.024 1.977 (2.039) b 3361 νN\

\H

Bond angles (°)a, b c 1789 νC_O

N2\\M1\ \N3 88.17 (84.9) 88.20 86.26 d 1560 νC_C, νC\
\N

N2\\M1\ \N4 88.21 (91.7) 88.25 87.25 e 1214 τN\

\H

N2\\M1\ \L5 176.08 (176.2) 176.15 85.33 Complex VI

N2\\M1\ \L6 85.57 (85.8) 85.62 87.95 a 3566 νN\
\H
N2\\M1\ \C7 176.08 (176.0) 176.15 178.11 b 3369 νN\
\H
N3\\M1\ \N4 175.86 (175.5) 175.92 173.39 c 1722 νC_O
N3\\M1\ \L5 88.52 (85.1) 88.18 92.75 d 1567 νC_C, νC\
\N
N3\\M1\ \L6 90.84 (96.0) 91.01 88.06 νN\
e 1406 \C, νN_C
N3\\M1\ \C7 91.84 (94.0) 91.70 95.25 f 1214 τN\
\H
N4\\M1\ \L5 88.94 (87.2) 89.29 87.96
N4\\M1\ \L6 90.90 (91.7) 90.70 90.45 Complex VIIb
N4\\M1\ \C7 91.91 (89.0) 91.96 91.20 a 3529 νN\
\H
\M1\
L5\ \L6 166.76 (176.2) 166.70 173.17 b 3253 (3213) νN\
\H
\M1\
L5\ \C7 102.72 (93.4) 102.75 95.70 c 3180 νN\
\H
\M1\
L6\ \C7 90.51 (90.3) 90.53 90.97 d 1755 (1680, 1697) νC_O
a e 1562 νC_C, νC\
\N
M: Ru or Os.
b f 1052 νN\
\C, νN_C
L: Cl or NH2.
c g 753 τN\
\H
Experimental values belong to isomer of complex V are given from Ref. 17 and given in
a
parenthesis. Vibration modes: ν, stretching; τ, wagging.
d b
Experimental values belong to complex VII are given from Ref. 16 and given in Experimental values belong to complex VII are given from Ref. 16 and given in
parenthesis. parenthesis.
 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155 151

Table 4 by MEP contours. In MEP contour, there are red lines around the oxygen
13
C and 15N NMR results of related molecules at same level of theory in gas phase. and chlorine atoms in mentioned complexes except Os complex. In Os
Complex V Complex VI Complex VII complex, there are red lines environment of oxygen atoms. Electron den-
13
C NMR results
sity on surface are similar to each other in complexes. The determining
C7 243.301 242.242 224.195 the active complex is difficult via MEP maps and contours.
C9 147.956 146.34 145.255 Contour diagrams of frontier molecular orbitals which are the
C10 116.491 117.065 115.547 highest occupied molecular orbitals (HOMO) and the lowest unoccu-
C12 39.451 39.666 32.311
pied molecular orbitals (LUMO) in studied complexes are calculated
C13 154.957 156.278 155.885
C15 153.459 154.943 154.206 and represented in Fig. 4.
C19 29.047 29.791 31.569 According to Fig. 4, there are three colors, green, yellow and tur-
C20 – 29.17 29.172 quoise. There are two electrons in HOMO and mainly localized in yellow
15
N NMR results and green zones. As for the LUMO, if molecule accepts the electron,
N2 235.986 235.685 273.081 these electrons will be localized to yellow and green zones.
N3 261.767 261.121 263.67
N4 262.188 262.272 265.262
N5 – – 263.428
3.7. Investigation of Anticancer Activity of Studied Complexes and their
N6 – – 265.259
N8 64.647 65.986 76.426 Ligands
N11 47.773 47.097 71.649
N14 83.567 80.711 81.093 Anticancer investigations are an important field for the researcher.
N16 124.967 126.046 126.645
These type investigations can be done as experimentally or computa-
tionally. In computational chemistry, some special parameters which
are listed in “Computational Details” are used to determine the antican-
Chemical shift values of carbon and hydrogen atoms in molecule (II) and cer properties. These parameters are calculated at B3LYP/6–311 -
(IV) are given in Supp. Table S2. According to Table 5 and Supp. Table S2, ++G(d,p)(LANL2DZ) level in vacuo and water. These results are
the chemical shift values of carbon atoms mainly increases with com- given in Table 6. Additionally, mentioned parameters of caffeine and
plexation. The same results is seen for hydrogen atoms. theobromine are calculated at B3LYP/6-311 ++G(d,p) level in vacuo
and given in Table 6, too.
3.6. Molecular Electrostatic Potential (MEP) Map, MEP Contour and Fron- The first parameter is EHOMO. If EHOMO is high, the compound can
tier Molecular Orbitals (FMOs) of Complexes easily give electron to appropriate acceptor structure. This result implies
that biological activity increases with increasing of EHOMO. According to
MEP maps, MEP contours and contour diagram of FMOs are impor- EHOMO, the activity ranking should be:
tant to determine the chemical mechanism in reaction. For this purpose, Complex VII N Complex VI N Complex V N Molecule I N Molecule II N
they must calculate elaborately in appropriate calculation level. MEP Cisplatin.
maps and MEP contours are calculated for investigated molecules and The second parameter is ELUMO. If its value is low, the molecule can
represented in Fig. 3. accept electrons from an appropriate molecule and this result shows
According to Fig. 3, there are yellow or red zones around the oxygen that activity increases with decreasing of ELUMO. According to the energy
and chlorine atoms of investigated complexes in MEP maps. These re- of LUMO, the biological activity ranking should be as follow:
gions are active in the nucleophilic attack. The same results are supported Cisplatin N Molecule II N Molecule I N Complex V N Complex VI
N Complex VII.
The third parameter is energy gap between LUMO and HOMO. Elec-
Table 5 tron freedom is important in the determination of biological reactivity.
1
H NMR results of related molecules at B3LYP/6-311++G(d,p) (LANL2DZ) level in gas
Mentioned activity increases with decreasing of EGAP values. The activity
phase.
ranking should be:
Complex V Complex VI Complex VII Complex VII N Complex V N Complex VI N Cisplatin N Molecule I
N2H 5.8583 5.8703 2.8193 N Molecule II.
N2H′ 5.8913 5.8913 3.1253 The other parameters are chemical hardness and softness. The coor-
N2H″ 6.7493 6.7953 3.6503 dination tendencies of molecule towards appropriate structure can be
N3H 4.3993 4.3243 0.7143
N3H′ 4.7063 4.6953 3.2273
discussed with the HSAB (hard–soft–acid–base) approximation. The
N3H″ 4.7723 4.8403 2.5993 rule is that hard acids prefer to coordinate to hard bases and soft acids
N4H 4.3833 4.4143 0.5783 to soft bases. Hard molecules have big EGAP and soft molecules have
N4H′ 4.6973 4.7253 3.0273 small EGAP. The biological structure such as a cell, enzyme, etc. are soft.
N4H″ 4.7893 4.7533 3.6213
Biological activities of soft molecules are therefore higher than hard
N5H – – 0.3513
N5H′ – – 3.0853 molecules. According to global softness values, the ranking should be
N5H″ – – 3.8513 as follow:
N6H – – 0.9003 Complex VII N Complex V N Complex VI N Cisplatin N Molecule I
N6H′ – – 2.6113 N Molecule II.
N6H″ – – 3.0223
N8H 16.2163 16.1493 9.4453
Other parameters are global electronegativity and chemical poten-
C12H 7.6613 7.7073 6.7383 tial. Small values of global electronegativity or high values of chemical
C12H′ 7.6763 7.7433 6.8123 potential imply that electron delocalized the whole structure and so
C12H″ 9.8823 9.8913 7.3013 molecule can easily give electrons to coordinate appropriate structure.
N14H 10.8193 – –
The biological activity ranking should be as follow:
C19H 6.7623 6.8233 6.4543
C19H′ 6.7683 6.8383 6.4603 Complex VII N Complex VI N Complex V N Molecule I N Molecule II N
C19H″ 8.6323 8.8353 8.8393 Cisplatin.
C20H – 6.7443 6.6513 The eighth and ninth parameters are electrophilicity and nucleo-
C20H′ – 6.7463 6.6653 philicity indexes, respectively. According to these parameters,
C20H″ – 8.6323 8.4713
biological activity increases with increasing of nucleophilicity index
152 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155

MEP maps MEP contour

-2 -2
-5,651x10 +5,651x10

(V)

-2 -2
-5,494x10 +5,494x10

(VI)

-2 -2
-4,338x10 +4,338x10

(VII)

Fig. 3. MEP maps and contours of studied complexes at same level of theory.

and decreasing of electrophilicity index. The activity ranking should
be as follow:
Complex VI N Complex VII N Complex V N Molecule I N Molecule II N
Cisplatin.
The tenth parameter is ΔNmax. ΔNmax is related to charges of com-
pounds. The biological activity of compound increase with increasing
of ΔNmax values. The last parameter is global softness. This parameter
can be evaluated like chemical softness. The increasing of value of this
parameter implies that biological activity of the compound is the in-
creasing. According to above explanations, biological activity rankings
should be as follow:
Complex VII N Complex V N Complex VI N Cisplatin N Molecule I
N Molecule II.
According to above ranking, anticancer properties of caffeine and
theobromine mainly are less than cisplatin. Therefore, it is not
expected to show anticancer properties of caffeine and theobromine.
As for the complexes, their anticancer activities are more than
cisplatin and their ligands. It is found that complexation increases
the anticancer activity. There are two caffeine complexes and a theobro-
mine complex. In these complexes, complex VII has higher anticancer
activity than other complexes in both gas phase and water. It is seen
easily from above ranking that Os complex is a good candidate for
cancer drugs.
In literature, it is reported that compounds with caffeine exhibit
anti-cancer properties. Biological properties of caffeinated compounds
have been investigated by experimental investigations [18–21]. We in-
vestigate the interaction of mentioned complexes with vascular endo-
thelial growth factor receptor 2 (VEGFRTK) (PDB code: 3wze) to
understand on the potency of mentioned complexes. The molecular
docking is performed by simulation of our three novels into the binding
site of the protein. The previous literature demonstrates that blocking of
VEGFRTK is one of the anticancer mechanisms [38]. Therefore, the
 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155 153

HOMO LUMO
-0.130 +0.130 -6.188x10-2 +6.188x10-2

(V)

-0.142 +0.142 -6.494x10-2 +6.494x10-2

(VI)

-2 -2
-4,982x10 +4,982x10 -4.851x10-2 +4.851x10-2

(VII)

Fig. 4. Contour diagrams of FMOs of investigated complexes.

docking study is carried out to investigate the possible binding confor- are represented in Fig. 5. Interaction energies are calculated for complex
mations for mentioned complexes to the (VEGFR) active binding site. V, VI and VII as −305.9, −335,8 and −342.9 kJ/mol, respectively. Ac-
Molecular docking calculations are performed in water phase via HEX cording to these results, the most effective molecule is complex VII.
program. Docking structures between 3WZE and mentioned complexes There is a well agreement in the determining of the best candidate for
drugs. Complex VII is found as the number one bot quantum chemical
descriptor and molecular docking calculations. In addition to these re-
sults, one of the important thing is the determining the general activity
Table 6
Calculated quantum chemical parameters of related molecules at same level of theory. ranking. Unfortunately, there is no general ranking in quantum chemi-
cal descriptors. According to molecular docking calculations, the activity
Parameters Complex Complex Complex Molecule Molecule cisplatin
ranking is found as follow:
V VI VII I III
Complex VII N Complex VI N Complex V.
EHOMOa −5.124 −5.105 −1.940 −6.395 −6.475 −6.618 According to above ranking is, these results are in the agreement
ELUMOa −1.230 −1.133 −1.039 −1.306 −1.396 −1.970
with the energy of HOMO, electronegativity and chemical potential
EGAPa 3.894 3.972 0.902 5.089 5.079 4.647
ηa 1.947 1.986 0.451 2.545 2.539 2.324 are decisive descriptors for studied complexes.
σb 0.514 0.504 2.218 0.393 0.394 0.430 If the contour diagrams of HOMO for each complex is examined,
χa 3.177 3.119 1.489 3.851 3.936 4.294 electrons are mainly delocalized on the surface of complex VII. How-
CPa −3.177 −3.119 −1.489 −3.851 −3.936 −4.294
ever, electrons in HOMO of other complex are mainly belong to metal
ωa 2.592 2.450 2.461 2.914 3.050 3.967
Nb 0.386 0.408 0.406 0.343 0.328 0.252 atoms. Therefore, these complexes do not interact like complex VII.
ΔNmax 1.632 1.571 3.304 1.513 1.550 1.848 These results are in the agreement with Fig. 5. Heteroatoms and
Sb 0.257 0.252 1.109 0.196 0.197 0.215 around the amines in complex VII are active site and interact with
a
In eV. protein while complex V and VI are interact with related protein
b
In eV−1. from chloride atoms.
154 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155
Complex V
Complex VI
Complex VII
Fig. 5. Interactions between protein and mentioned complexes.
4. Conclusions
Quantum chemical calculations of 1,3,7-trimethylpurine-2,6-
dione, 3,7-dimethylpurine-2,6-dione and their tautomers are
performed at B3LYP/6-311 ++G(d,p) level in gas phase. Electronic
structures are determined by fully optimizations. Thermodynamic
parameters are used to determine the most stable structure between
molecule (1)–(2) and (3)–(4), separately. Chemical reactivity of
mentioned molecules are investigated by geometric parameters,
MEP maps, MEP contour and contour diagram of FMOs. As a result,
it is found that activities of molecule (II) and (IV) are higher than
those of molecule (I) and (III).
Quantum chemical calculations of Ru and Os complexes are per-
formed at B3LYP/6–311++G(d,p)(LANL2DZ) level in vacuo. Electronic
and spectral properties of related complexes are examined in detail. The
similarity of mentioned complexes is demonstrated by structural
parameters, IR results, 1H\\, 13C and 15N NMR results. Additionally,
MEP maps, MEP contours and contour diagrams of FMOs are calculated
and examined in detail. There are yellow or red zones around the
heteroatoms in studied complexes in MEP maps and contours. General-
ly, the electron density on surface are similar to each other in com-
plexes. These results imply that the determining the active complex is
difficult via MEP maps and contours. Anticancer properties of related
complexes, caffeine, theobromine and cisplatin are investigated by
using some quantum chemical descriptors. According to quantum
chemical descriptors, anticancer properties of caffeine and theobromine
mainly are less than cisplatin and anticancer activities of studied com-
plexes are more than cisplatin and their ligands. Complex VII has higher
anticancer activity than other complexes in both gas phase and water.
Additionally, molecular docking calculations are performed between
studied complexes and a protein (ID: 3WZE). According to these analy-
ses, Os complex is a good candidate for cancer drugs.
Acknowledgments
The numerical calculations reported in this paper are performed at
TUBITAK ULAKBIM, High Performance and Grid Computing Center
(TRUBA Resources).
 K. Sayin, A. Üngördü / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 193 (2018) 147–155
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.saa.2017.12.013.
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