Synthesis of ionic liquid-based Ru(II)–phosphinite complexes and evaluation of their antioxidant, antibacterial, DNA-binding, and DNA cleavage activities

Article abstract of DOI:10.1007/s11696-018-00670-0

Abstract: Two Ru(II) complexes were synthesized by reaction of phosphinite-functionalized imidazolium salts [(Ph₂PO)C₇H₁₁N₂Cl]Cl (1) and [(Cy₂PO)C₇H₁₁N₂Cl]Cl (2) with

Full text of DOI:10.1007/s11696-018-00670-0

Chemical Papers
https://doi.org/10.1007/s11696-018-00670-0
ORIGINAL PAPER
Synthesis of ionic liquid‑based Ru(II)–phosphinite complexes
and evaluation of their antioxidant, antibacterial, DNA‑binding,
and DNA cleavage activities
Nermin Meriç · Cezmi Kayan · Khadichakhan Rafkova2,3 · Alexey Zazybin2,3 · Veysi Okumuş · Murat Aydemir ·
1
1
4
1
Feyyaz Durap1
Received: 3 September 2018 / Accepted: 13 December 2018
©
Institute of Chemistry, Slovak Academy of Sciences 2019
Abstract
Two Ru(II) complexes were synthesized by reaction of phosphinite-functionalized imidazolium salts [(Ph PO)C H N Cl]
2
7
11
2
6
Cl (1) and [(Cy PO)C H N Cl]Cl (2) with 1/2 equivalent of [Ru(η -p-cymene)(µ-Cl)Cl] in anhydrous CH Cl and under
2
7
11
2
2
2
2
argon atmosphere. The complexes were then isolated as analytically pure substances and characterized using multinuclear
NMR and infrared spectroscopies and elemental analysis. The Ru(II) compounds were used to study their biological assay.
For this purpose, radical scavenging, reducing power, antibacterial activity, DNA binding, and DNA cleavage activity were
fully studied. The maximum 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH) scavenging (78.9%) and reducing power were
obtained from compound 4 at the concentration of 200 µg/ml. The compounds were also tested against three Gram-positive
and three Gram-negative bacteria, and they were found to be more eꢀective against Gram-positive bacteria. In addition, both
compounds showed excellent DNA binding and DNA cleavage activity.
Graphical abstract
Extended author information available on the last page of the article
Vol.:(0
1
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Chemical Papers
Keywords Ionic liquid · Phosphinite · Ruthenium · Antibacterial · DNA binding · DNA cleavage
Introduction
as biological agents is constantly increasing. As far as we
know, there are not many reports on biological agents using
chiral Ru(II) phosphinites, which have been employed suc-
cessfully tested as anticancer, antibacterial, and antioxidant
agents (Appelt et al. 2017). Free radicals can damage lipids,
proteins, and DNA, leading to an increase in cancer rates.
Fortunately, antioxidants have the ability to scavenge free
radicals. Studies on the binding and cleavage of DNA to
small molecules and antioxidant activities of new synthe-
sized compounds are very important for the design of new
anticancer drugs (Aziz and Elbadawy 2014; Deepika et al.
2016). We report here, for the ꢁrst time, the synthesis and
characterization of two ruthenium(II) compounds based
ionic liquids and theirs radical scavenging, reducing power,
antibacterial activity, DNA binding, and DNA cleavage
activity.
After years of exponential development, the ꢁeld of ionic
liquids (ILs) has attained a substantial degree of maturity in
many aspects, such as preparation, puriꢁcation, and phys-
icochemical characterization (Hallett and Welton 2011;
Prediger et al. 2013). It has been known that ionic liquids
(
ILs) can be functionalized easily by incorporating several
functional moieties into the IL structure to design diꢀerent
functionalized ILs (FILs), which dually maintain the char-
acters of the incorporated functionalities as well as those
of the ILs (Luska and Moores 2011; Vicente et al. 2012;
Andrieu et al. 2010). An important factor for eꢀective use
of ILs as solvents in green chemistry is to enable clean and
eꢂcient syntheses of the ILs, so that an additional waste is
not introduced into the overall process (Bonhote et al. 1996;
Holbrey et al. 2002, 2003a, b). Furthermore, ionic liquids
including hydroxyl moiety have interesting properties such
as high hydrophilicity and a potential for enzyme stabiliza-
tion (Holbrey et al. 2003a, b). Metal-containing ionic liquids
are regarded as promising new materials which combine the
properties of ionic liquids with additional intrinsic magnetic,
spectroscopic, or catalytic properties, depending on the
incorporated metal ion (Chiappe et al. 2012).
Experimental
Materials and methods
Unless, otherwise, stated, all reactions were carried out
under an atmosphere of argon using the conventional
Schlenk glassware, solvents were dried using the established
procedures and distilled under argon immediately prior to
use. Analytical grade and deuterated solvents were pur-
chased from Merck. Epichlorohydrin, 1-methylimidazole,
The phosphorus-based FILs have long been investigated
to design the ionic organometallic compounds and applica-
tion to homogeneous catalysis (Luska et al. 2012; Brauer
et al. 2001; Abdellah et al. 2010; Canac et al. 2012; Barthes
et al. 2013). It has been found that, while the coordinating
P(III) atom is vicinal to the positive-charged imidazolium
ring, the corresponding phosphine FILs possess π-acceptor
character as well as ϭ-donor (You et al. 2013; Zhou et al.
6
PPh Cl, PCy Cl, and [Ru(η -p-cymene)(µ-Cl)Cl] are pur-
2
2
2
chased from Fluka, and were used as received. The infrared
1
spectra were measured by a Perkin Elmer Lambda 25. H
1
3
31
1
(400.1 MHz), C NMR (100.6 MHz), and P-{ H} NMR
spectra (162.0 MHz) were recorded on a Bruker AV400
spectrometer, with δ referenced to external TMS and 85%
H PO , respectively. Elemental analysis was carried out
2012; Wang et al. 2013; Chen et al. 2013). In addition, it has
been well known that phosphinites have diꢀerent chemical,
electronic, and structural features in comparison with phos-
phines. For instance, the metal–phosphorus bond is often
stronger for phosphinites than the corresponding phosphine
owing to the existence of electron withdrawing P–OR group.
Moreover, the empty ϭ*-orbital of the phosphinite P(OR)
3
4
on a Fisons EA 1108 CHNS-O instrument. Melting points
were recorded by a Gallenkamp Model apparatus with open
capillaries.
R is stabilized, rendering it a better acceptor (Galka and
2
Synthesis and characterization of ligands and their
complexes
Kraatz 2003; Aydemir et al. 2011; Işık et al. 2013; Meriç
et al. 2014a, b; Ak et al. 2015a, b).
Metallo drugs have emerged as an important area of med-
ical chemistry due to their therapeutic use of metal-based
pharmaceuticals. Platinum-based drugs used as chemother-
apeutic agents show high systemic toxicity and resistance
problems (Naveen et al. 2018). It has been reported that
Ru(II)-based compounds are important therapeutic agents
and less toxic than platinum-based compounds (Devagi et al.
General procedure for the synthesis of phosphinites (1
and 2)
A dry and degassed CH Cl (20 ml) solution of 1-(3-chloro-
2
2
2
-hydroxypropyl)-3-methylimidazolium chloride under
argon atmosphere (0.100 g, 0.474 mmol) was cooled to
78 °C in acetone and dry ice bath. To the cooled solution,
was added dropwise a hexane solution of n-BuLi (0.296 ml,
−
2
018). For this reason, the interest in ruthenium compounds
1
3

Chemical Papers
2
0
.474 mmol). After the addition, the mixture was stirred
(–CH Cl), 52.34 (NCH ), 77.32 (d, J=22.7 Hz, –CHOP),
2
2
at − 78 °C for 1 h and for an additional 30 min at room
temperature. The reaction solution was cooled to − 78 °C
again, and a solution of chlorodiphenylphosphine for 1 or
chlorodicyclohexylphosphine for 2 (0.474 mmol) in CH Cl
123.05, 123.43 (–NCHCHN–), 138.67 (–(CH )NCHN–);
3
1 13
assignment was based on the H– C HETCOR, DEPT,
1
1
31
1
and H– H COSY spectra; P-{ H} NMR (162.0 MHz,
CDCl -d , ppm): δ 148.76 (s, OPCy ); IR, (KBr): υ 2923,
2
2
3
1
2
−1
(
10 ml) was added dropwise to the reaction medium. Stirring
2850 (aliphatic C–H), 1446 (P-Cy), 1059 (O-P) cm ;
was maintained for further 1 h at −78 °C. Then, the cooling
bath was removed and the mixture was stirred for another
C H N OCl P (407.36 g/mol): calcd. C 56.02, H 8.16, N
1
9
33
2
2
6.88; found C 55.83, H 8.01, N 6.70.
1
h at room temperature. Precipitated lithium chloride was
6
removed by ꢁltration under argon, and then, the volatiles
were evaporated in vacuo to leave viscous oily phosphinite
ligand 1 or 2. The experimental details were in given in a
reference by Aydemir et al. (2014).
Synthesis of [Ru((Ph PO)–C H N Cl)(η ‑p‑cymene)Cl ]Cl,
2 7 11 2 2
3
1
1
(3) Yield 0.154 g, 86.5%. M.p.: 110–112 °C P-{ H} NMR
(162.0 MHz, CDCl -d , ppm): δ 124.23 (s, Ru-OPPh ); IR,
3
1
2
(KBr): υ 3053 (aromatic C–H), 1435 (P-Ph), 1047 (O-P),
−
1
5
32 (Ru–P) cm ; C H N OCl PRu (701.46 g/mol):
29 35 2 4
General procedure for the synthesis of ruthenium
complexes (3 and 4) (Chiappe et al. 2012)
calcd. C 49.66, H 5.03, N 3.99; found C 49.34, H 4.96, N
1
3.89. H NMR (400.1 MHz, CDCl -d , ppm): δ 9.53 (s,
3
1
1
H, –(CH )NCHN–), 7.14–7.93 (m, 12H, P(C H ) +–
3
6
5 2
6
[
[
(
Ru(η -p-cymene)(µ-Cl)Cl] (0.12 mmol) and
NCHCHN–), 5.43 (br, 2H, aromatic protons of p-cymene),
5.23 (br, 2H, aromatic protons of p-cymene), 4.81 (br, 1H,
–CHOP), 4.61 (br, 1H, NCH , (a)), 4.48 (br, 1H, NCH ,
2
(Ph PO)–C H N Cl]Cl, 1 or [(Cy PO)–C H N Cl]Cl, 2
2
7
11
2
2
7
11
2
0.24 mmol) were dissolved in 25 ml of dry CH Cl under
2
2
2
2
argon atmosphere and stirred for 30 min at room tempera-
ture. The volume of the solvent was then reduced to 0.5 ml
before addition of petroleum ether (10 ml). The precipitated
product was ꢁltered and dried in vacuo yielding 3 or 4 as a
clear red solid.
(b)), 3.94 (s, 3H, NCH ), 3.42 (br, 2H, –CH Cl), 2.46 (m,
3
2
1H, CH of p-cymene), 1.83 (s, 3H, CH Ph of p-cymene),
3
3
13
0.99 (d, 6H, J=6.8 Hz, (CH ) CHPh of p-cymene);
C
3
2
NMR (100.6 MHz, CDCl -d , ppm): δ 17.22 (CH Ph of
3
1
3
p-cymene), 22.16, 22.23 ((CH ) CHPh of p-cymene),
3
2
3
0.01 (CH of p-cymene), 37.36 (NCH ), 44.57 (CH Cl),
3
2
1
2
[
(
(Ph PO)C H N Cl]Cl (1) Yield 0.180 g, 96.3%. H NMR
50.92 (NCH ), 75.11 (d, J=22.9 Hz, –CHOP), 86.77 (d,
2
7
11
2
2
2
400.1 MHz, CDCl -d , ppm): δ: 10.14 (s, 1H, –(CH )
J
=5.0 Hz, aromatic carbons of p-cymene), 88.89 (d,
3
1
3
31P–13C
2
2
NCHN–), 7.13–7.78 (m, 12H, P(C H ) +–NCHCHN–),
J31P–13C =7.0 Hz, aromatic carbons of p-cymene), 89.35 (d,
6
5 2
4
1
–
.94 (m, 1H, NCH , (a)), 4.71 (br, 1H, –CHOH), 4.57 (m,
J
=4.0 Hz, aromatic carbons of p-cymene), 92.56
=6.0 Hz, aromatic carbons of p-cymene),
2
31P–13C
2
H, NCH , (b)), 3.91 (m, 1H, –CH Cl, (a)), 3.85 (m, 1H,
(d, J
2
2
31P–13C
1
3
CH Cl, (b)), 3.80 (s, 3H, NCH ); C NMR (100.6 MHz,
96.31, 111.15 (quaternary carbons of p-cymene), 122.60,
2
3
3
CDCl -d , ppm): δ 36.55 (NCH ), 45.14 (–CH Cl), 52.52
123.17 (–NCHCHN–), 128.34 (d,
J
=10.1 Hz,
3
1
3
2
31P–13C
2
4
(
NCH ), 78.45 (d, J=23.1 Hz, (–CHOP), 122.59, 122.90
m-P(C H ) )), 131.91 (d, J
=6.1 Hz, p-P(C H ) ),
2
6
5 2
31P–13C
6
5 2
3
2
(
–NCHCHN–), 129.53 (d, J
=10.1 Hz, m-P(C H ) ),
133.84 (d,
J
=12.6 Hz, o-P(C H ) ), 137.87 (d,
3
1P–13C
6
5 2
31P–13C
6
5 2
2
1
1
31.41 (p-P(C H ) ), 135.26 (d,
J
=19.6 Hz,
J
=52.3 Hz, i-P(C H ) ), 139.70 (–(CH )NCHN–);
6
5 2
31P–13C
31P–13C
6
5 2
3
1
1
13
o-P(C H ) )), 140.65 (d, J
=47.8 Hz, i-P(C H ) ),
assignment was based on the H– C HETCOR, DEPT, and
6
5 2
31P–13C
6
5 2
1
1
1
1
38.17 (–(CH )NCHN–); assignment was based on the H–
H– H COSY spectra.
3
1
3
1
1
31
1
C HETCOR, DEPT, and H– H COSY spectra; P-{ H}
NMR (162.0 MHz, CDCl -d , ppm): δ 118.46 (s, OPPh );
6
Synthesis of [Ru((Cy PO)–C H N Cl)(η ‑p‑cymene)Cl ]Cl,
3
1
2
2
7
11
2
2
3
1
1
IR, (KBr): υ 3053 (aromatic C–H), 1434 (P-Ph), 1060 (O-P)
(4) Yield 0.163 g, 93.1%. M.p.: 106–108 °C P-{ H}
−1
cm ; C H N OCl P (395.27 g/mol): calcd. C 57.74, H
NMR (162.0 MHz, CDCl -d , ppm): δ 154.25 (s, Ru-
1
9
21
2
2
3
1
5
.35, N 7.09; found C 57.48, H 5.15, N 6.96.
OPCy ); IR, (KBr): υ 2926, 2852 (aliphatic C–H), 1446
2
−1
(
P-Cy), 1057 (O-P), 528 (Ru–P)cm ; C H N OCl PRu
29 47 2 4
1
[
(
(Cy PO)–C H N Cl]Cl (2) Yield 0.183 g, 94.8%. H NMR
(713.56 g/mol): calcd. C 48.81, H 6.64, N 3.93; found C
2
7 11 2
1
400.1 MHz, CDCl -d , ppm): δ 10.48 (s, 1H, –(CH )
48.53, H 6.51, N 3.83. H NMR (400.1 MHz, CDCl -d ,
3
1
3
3
1
NCHN–), 7.64, 7.45 (2xs, 2H, –NCHCHN–), 4.84 (m,
ppm): δ 9.81 (s, 1H, –(CH )NCHN–), 7.66, 7.08 (2xs,
3
3
1
H, NCH , (a)), 4.53 (m, 1H, NCH , (b)), 4.16 (br, 1H, –
2H, –NCHCHN–), 5.64 (d, 2H, J = 3.8 Hz, aromatic
2
2
3
CHOP), 4.10 (s, 3H, NCH ), 3.83 (m, 1H, –CH Cl, (a)),
protons of p-cymene), 5.61 (d, 2H, J = 3.8 Hz, aromatic
3
2
3
.68 (m, 1H, –CH Cl, (b)), 1.00–1.95 (m, 22H, protons of
protons of p-cymene), 5.34–5.36 (m, 1H, –CHOP), 4.72
(m, 1H, NCH , (a)), 4.43 (m, 1H, NCH , (b)), 4.02 (s,
2
1
3
P(C H ) ; C NMR (100.6 MHz, CDCl -d ,ppm): δ 26.20,
6
11 2
3
1
2
2
2
6.27, 26.64, 26.85, 26.98, 27.21 (CH of P(C H ) ), 37.20
3H, NCH ), 3.83 (m, 1H, –CH Cl, (a)), 3.26 (m, 1H, –
2
6
11 2
3
2
1
(
d, J=15.1 Hz, CH of P(C H ) ), 36.77 (NCH ), 44.05
CH Cl, (b)), 2.81 (m, 1H, –CH of p-cymene), 2.12 (s, 3H,
6
11 2
3
2
1
3

Chemical Papers
CH Ph of p-cymene), 1.28–1.36 (m, 22H, P(C H ) ),
Finally, at 700 nm, the absorbance was evaluated against
the blank. As positive control, α-tocopherol was used.
3
6
11 2
3
13
0
.87 (d, 6H, J = 6.5 Hz, (CH ) CHPh of p-cymene);
C
3
2
NMR (100.6 MHz, CDCl -d , ppm): δ 18.77 (CH Ph of
3
1
3
p-cymene), 22.33, 22.48 ((CH ) CHPh of p-cymene),
Antibacterial activity
3
2
2
6.25, 26.94, 27.21, 27.85, 28.48, 29.06 (CH of
2
P(C H ) ), 30.83 (CH of p-cymene), 37.38 (NCH ),
Antibacterial activities of the compounds were assessed
through disc diꢀusion method making use of nutrient agar
medium (Khan and Asiri 2012). Escherichia coli (ATCC
10536), Legionella pneumophila subsp. pneumophiia
(ATCC 33152), and Pseudomonas aeruginosa (ATCC 9027)
were used as Gram-negative bacteria, and Staphylococcus
aureus (ATCC 6538), Bacillus cereus, and Enterococcus
hirae (ATCC 10541) were used as Gram-positivebacteria for
antibacterial activity of compounds. Blank antibiotic discs
were spread by 15 μL of the compounds (500 µg/ml) and
discs were placed on the solidiꢁed medium inoculated with
the bacteria in petri dishes. Streptomycin (10 µg) and tetra-
cycline (30 µg) were used as positive control, and blank disc
impregnated with DMSO was used as negative control. The
petri dishes were incubated with bacterial cultures for 24 h at
37 °C. After incubation time, the antibacterial activity of the
compounds was evaluated using zone inhibition technique.
6
11 2
3
1
4
4
9
6.00 (–CH Cl), 46.35 (d, J = 29.7 Hz, CH of P(C H ) ),
2
6
11 2
2
9.79 (NCH ), 74.50 (d, J = 24.2 Hz, –CHOP), 84.86,
2
0.33 (aromatic carbons of p-cymene), 96.28, 110.99
(
quaternary carbons of p-cymene), 122.40, 122.42 (–
NCHCHN–), 139.09 (–(CH )NCHN–); assignment was
3
1
13
1
1
based on the H– C HETCOR, DEPT, and H– H COSY
spectra.
Biological assays
Chemicals
All the materials (DPPH, Calf Thymus (CT) DNA,
supercoiled plasmid DNA pBR322, dimethyl sulfoxide
(
DMSO), methanol, α-tocopherol, and trolox) used in the
biological test work were supplied from Sigma (Sigma-
Aldrich GmbH, Steinheim, Germany).
DNA binding and DNA cleavage activity
Binding and cleavage of DNA with compounds were studied
through agarose gel electrophoresis. For DNA-binding activ-
ity, stock solution of CT-DNA (conc: 20 µg/ml) diluted 1:10
ratio with sterile distilled water and 5 µl diluted DNA was
treated with the 8 µl Ru (II) compounds in DMSO (50, 100,
and 200 µg/ml). For DNA cleavage activity, stock solution
of supercoiled pBR322 DNA (conc: 1.0 µg/ml) diluted 1:10
ratio with sterile distilled water and 5 µl diluted DNA was
treated with the 8 µl Ru (II) compounds in DMSO (100 µg/
ml). To determine both activities, the mixture of solutions
was incubated at 37 °C for 4 h in the dark, and then, 3 µl
DNA loading dye was added. The samples were loaded sepa-
rately on 0.8% agarose gel containing 7 µl ethidium bromide
DPPH radical scavenging activity
The free radical scavenging activities of the Ruthenium (3
and 4) compounds were studied through the DPPH assay
method (Ağırtaş et al. 2014). The compounds stock solu-
tion was diluted to ꢁnal concentrations of 25, 50, 100,
1
50, and 200 µg/ml in DMSO. 2.0 ml methanol solution
of DPPH was added to 0.5 ml of diꢀerent concentrations
of compounds and solution mixture incubated at 25 ºC in
the dark for an hour. The absorbance was then measured at
5
17 nm using the spectrophotometer. Trolox was utilized
as a positive control.
(
0.05%). Electrophoresis was applied for 60 min at 80 V in
TAE buꢀer (50 mM Tris base, 50 mM acetic acid, 2 mM
EDTA, and pH:7.8). The gel was visualized under UV light
and photographed (Ağırtaş et al. 2017; Keypour et al. 2015).
Reducing power
The reducing power activity of ruthenium compounds
was evaluated as reported by Oyaizu (1986). All the com-
pounds were prepared (25–200 µg/ml) in DMSO (0.5 ml).
Results and discussion
0
0
.5 ml of 200 mM sodium phosphate buꢀer (pH 6.6) and
.5 ml of potassium ferricyanide (1%) were added, and the
Synthesis of the ligands and complexes
mixed solution was incubated for 20 min at 50 °C. Then,
0
.5 ml of trichloroacetic acid (10%) was mixed, and the
mixed solution was centrifuged at 1000 rpm for 10 min.
.0 ml sterilized water and 0.4 ml ferric chloride (0.1%)
were mixed with the upper part of the solution (1.0 ml).
Phosphinite-based ionic liquids can play a dual role both
as reaction medium and also as potential complexing agent
through the phosphinite group that they bear (Iranpoor et al.
2007). Recently, the preparation of imidazolium-based phos-
phinite ionic liquids and their applications were reported
1
1
3

Chemical Papers
(
Iranpoor et al. 2006, 2010; Valizadeh and Gholipour 2010;
organic and inorganic compounds (Baykara et al. 2015).
To assess the antioxidant activity, the decrease in absorb-
ance is used by reducing the amount of DPPH in the
medium. The results of radical scavenging activity as a
percentage are shown in Fig. 2. As seen from the results,
both compounds exhibited high activity even at low con-
centrations. Compound 4 (78.9%) showed a better activity
than compound 3 (66.1%) at concentration of 200 µg/ml. It
is well known that compounds having diꢀerent functional
groups such as –SH, –COOH, –N, –OH, –S–, and –O– can
show antioxidant activity. Compounds 3 and 4 are only
diꢀerent from each other about the group on the phospho-
rus atom. In compounds 4, the Cy (cyclohexyl group) on
the phosphorus atom may show a better antioxidant activ-
ity than compound 3 which has the rigid planar phenyl
group on the phosphorus atom. It is reported that Ru(II)
complexes demonstrated good radical scavenging activity
using DPPH (Appelt et al. 2017). Our compounds showed
similar scavenging activity with these results. Trolox, used
as a positive control, exhibited higher free radical scaveng-
ing activity than two compounds at all concentrations. As
a result, compounds with radical scavenging activity may
be used as promising therapeutic agents in conditions such
as aging, cardiovascular diseases, and cancer, which are
caused by stress-related pathological problems (Ejidike
and Ajibade, 2015).
Valizadeh and Halili 2012; Valizadeh et al. 2011). Attract-
ing features of this type of compounds prompted us to focus
on phosphinite-based ionic liquids (Aydemir et al. 2014;
Meriç et al. 2014a, b; Elma Karakaş et al. 2016). In the pre-
sent study, IL-OPR (R:Ph, Cy) phosphinites were prepared
2
from the two-step reaction of 1-methylimidazole, epichlo-
rohydrin, and chlorodiphenylphosphine or chlorocyclohex-
ylphosphine (Aydemir et al. 2014; Meriç et al. 2014a, b)
in 95–97% yields (Scheme 1) (Chen 2010; Hauptman et al.
1
998; Ruhlan et al. 2008; Hariharasarma et al. 1999; Esquius
et al. 2002; Ak et al. 2015a, b; Elma et al. 2013).
6
Reactions of [Ru(η -p-cymene)(µ-Cl)Cl] with
2
[
(Ph PO)–C H N Cl]Cl, 1 or [(Cy PO)–C H N Cl]Cl (2)
2
7
11
2
2
7
11
2
in CH Cl in a ratio of 1/2:1 at room temperature gave red
2
2
6
complexes, [Ru((Ph PO)–C H N Cl)(η -p-cymene)Cl ]
2
7
11
2
2
6
Cl, (3) and [Ru((Cy PO)–C H N Cl)(η -p-cymene)Cl ]
2
7
11
2
2
Cl, (4). The coordination of the ligand through the P donor
3
1
1
was conꢁrmed by the P-{ H} NMR spectroscopy (Fig. 1).
(
Ak et al. 2013; Aydemir et al. 2010a, b; Milton et al. 2004;
Zhang et al. 2003; Aydemir et al. 2014).
DPPH radical scavenging activity
The DPPH method is known as a simple, easy, and fast
method to measure the radical scavenging activity of
Scheme 1 Synthesis of the, [(Ph PO)–C H N Cl]Cl, (1), [(Cy PO)–
pounds. (1) 1equiv. Ph PCl or Cy PCl, 1equiv. n-BuLi, CH Cl ; (2)
2
7
11
11
2
2
2
2
2
2
2
6
6
C H N Cl]Cl, (2), [Ru((Ph PO)–C H N Cl)(η -p-cymene)Cl ]Cl,
1/2equiv. [Ru(η -p-cymene)(µ-Cl)Cl] , CH Cl
2 2 2
7
11
2
2
7
2
6
(
3) and [Ru((Cy PO)–C H N Cl)(η -p-cymene)Cl ]Cl, (4) com-
2 7 11 2 2
1
3

Chemical Papers
Fig. 1 The 31P-{ H} NMR spectra of complexes [Ru((Ph PO)–C H N Cl)(η -p-cymene)Cl ]Cl, (3) and [Ru((Cy PO)–C H N Cl)(η -p-
1
6
6
2
7
11
2
2
2
7
11
2
cymene)Cl ]Cl, (4)
2
1
20
00
0.8
3
3
4
4
1
Trolox
Alpha-tocopherol
0
.6
8
6
4
2
0
0
0
0
0
0.4
0
.2
0
2
5
50
100
150
200
2
5
50
100
150
200
Concentraꢀon (µg/ml)
Concentraꢀon (µg/ml)
Fig. 2 Radical scavenging activities percent of the Ru(II) compounds
Fig. 3 Reducing power of the ruthenium compounds
Reducing power
Table 1 Inhibition zone of Ru compounds against bacteria
Reducing power and antioxidant activity are associated
and can provide us with signiꢁcant data about antioxidant
activity. Compounds with reducing power which are elec-
tron donors can reduce oxidative intermediates in the lipid
peroxidation process; for this reason, they may be used as
primary and secondary antioxidants (Zhang et al. 2017). The
reducing power of Ru (II) compounds is shown in Fig. 3.
The reducing power of compounds depends on the concen-
tration, and both compounds showed high activity. When
the two compounds are compared, the 4 has more reduc-
ing power activity. Among the test materials, the highest
reducing power capability was attained from α-tocopherol
as 0.719 at 200 µg/ml, and this is followed by 4 as 0.547 and
Bacteria
Ruthenium compounds and standard antibi-
otic discsa
3
4
S
TE
S. aureus
B. cereus
E. hirae
E. coli
P. aeruginosa
L. pneumophila
12
15
14
7
10
8
11
12
10
7
9
10
16
18
19
24
22
15
24
20
22
23
14
21
S streptomycin (10 µg), TE tetracycline (30 µg)
a
Inhibition diameter in millimeters
3
as 0.436 at the same concentration. The reason for these
activity diꢀerences may be due to the diꢀerence in func-
tional groups of complexes as described in DPPH radical
scavenging activity section.
1
3

Chemical Papers
Antimicrobial activity
from the agarose gel well. The results showed that
both compounds demonstrated excellent DNA-binding
capability.
The inhibition zones of the Ru(II) compounds against three
Gram-negative and three Gram-positive bacteria are given
in Table 1. According to the results, compounds 3 and 4
were observed to have antibacterial activity against all tested
bacteria and 7–15 mm inhibition zones obtained from them.
Both Ru(II) compounds were found to be more eꢀective
against Gram-positive bacteria. This diꢀerence in the activ-
ity of diꢀerent compounds against diꢀerent bacterial spe-
cies may be caused by the permeability of bacterial cells
or the diꢀerence in ribosomes (İlhan et al. 2014). Devagi
et al. (2018) studied four Ru (II) complexes antimicrobial
activity against three Gram-positive bacteria (S. aureus, E.
hirae, and B. subtilis) and found the inhibition zones in the
range of 4–9 mm. Our compounds showed inhibition zones
against Gram-positive bacteria in the range of 10–15 mm.
Although the compounds were active against all tested bac-
terial strains, they were not as eꢀective as the standard strep-
tomycin and tetracycline.
DNA cleavage activity
A one-strand scission of the intact supercoil DNA (Form
I) led to an open circular form (Form II) and double-strand
scission led to a linear form (Form III). The lowest move-
ment is the Form II and the fast movement is the Form I,
and also Form III moves in between. The agarose gel pic-
ture displays the cleavage of supercoiled plasmid pBR322
DNA is shown in Fig. 5. According to the ꢁgure, one
band (Form I) was observed for the control which was not
exposed to compounds (Lane C), and three bands (Form I,
II, and III) were observed for the samples incubated with
Ru (II) compounds (Lane 1 and 2). In this study, it was
clearly observed that the Ru (II) compounds showed two-
strand cleavage activity of supercoiled DNA.
DNA‑binding activity
In this study, DNA-binding activity was assessed by gel
electrophoresis and CT-DNA was used for this purpose.
It has been reported that the charge, ꢃexibility, and size of
DNA play an important role in its movement on the aga-
rose gel. The binding of DNA to the compounds causes it
to move more slowly on the gel, because the bound DNA
turns into a larger structure than the free DNA, and the
total charge of DNA is reduced (Anjomshoa et al. 2015).
Figure 4 shows the extent of DNA-binding activity with
three concentrations (50, 100, and 200 µg/ml) of two Ru
(
II) compounds. The DNA exposed to a concentration of
5
0 and 100 µg/ml of the tested compounds were found
Fig. 5 DNA cleavage of Ru complexes. Lane C, Control, pBR 322
DNA; Lane 1, pBR 322 DNA+100 μg/ml of 3; Lane 2, pBR 322
DNA+100 μg/ml of 4
to move less than the control, and the DNA exposed to
the 200 µg/ml concentration showed almost no movement
Fig. 4 DNA binding of Ru
complexes. Lane M, DNA
Marker; Lane C, Control,
CT-DNA; Lane 1, CT-
DNA+50 μg/ml of 3; Lane 2,
CT-DNA+50 μg/ml of 4; Lane
3
, CT-DNA+100 μg/ml of 3;
Lane 4, CT-DNA+100 μg/
ml of 4; Lane 5, CT-
DNA+200 μg/ml of 3; Lane 6,
CT-DNA+200 μg/ml of 4
1
3

Chemical Papers
C -symmetric ferrocenyl phosphinite ligands for asymmet-
Conclusions
2
ric transfer hydrogenations of aromatic ketones. Tetrahedron
Asymmetry 26:1307–1313. https://doi.org/10.1016/j.tetas
y.2015.10.002
In summary, we have synthesized phosphinite-based ionic
liquids [(Ph PO)–C H N Cl]Cl, (1), [(Cy PO)–C H N Cl]
Andrieu J, Harmand L, Picquet M (2010) Firsts lysidinyl- and lysi-
dinium-triphosphines Pd(II) complexes. Polyhedron 29:601–605.
https://doi.org/10.1016/j.poly.2009.07.055
2
7
11
2
2
7
11
2
Cl (2), and their Ru(II) complexes Ru((Ph PO)–C H N Cl)
2
7
11
2
6
(
(
η -p-cymene)Cl ]Cl (3), and [Ru((Cy PO)–C H N Cl)
2
2
7
11
2
Anjomshoa M, Hadadzadeh H, Fatemi SJ, Torkzadeh-Mahani M
(2015) A mononuclear Ni(II) complex with 5,6-diphenyl-3-(2-
pyridyl)-1,2,4- triazine: dNA- and BSA-binding and anticancer
activity against human breast carcinoma cells. Spectrochim Acta
A Mol Biomol Spectrosc 136:205–215. https://doi.org/10.1016/j.
saa.2014.09.016
6
η -p-cymene)Cl ]Cl (4). The compounds were character-
2
ized using several techniques such as multi nuclear NMR,
IR spectroscopy, and microanalysis. Two ruthenium com-
plexes were studied for biological assays such as free radical
scavenging, reducing power, antibacterial, and DNA-bind-
Appelt P, da Silva JP, Fuganti O, Aquino LEN, Sandrino B, Wohnrath
K, Santos VAQ, Cunha MAA, Veiga A, Murakami FS, Back DF,
de Araujo MP (2017) New heterobimetallic ruthenium (II) com-
ing and DNA cleavage activity. Especially, the compound
6
[
Ru((Cy PO)–C H N Cl)(η -p-cymene)Cl ]Cl demon-
2
7
11
2
2
plexes [Ru(N-S)(bipy)(dppf)]PF : synthesis, molecular structure,
6
strated highest free radical scavenging and reducing power
activity. They were determined to be more eꢂcient against
Gram-positive bacteria than Gram-negative bacteria. Fur-
thermore, both compounds showed very good DNA bind-
ing and DNA cleavage activity. According to the results of
this study, our compounds can be considered as a type of
drug treatment for the cancer therapy with DNA-binding
and cleavage activities.
electrochemistry, DFT, antioxidant and antibacterial potential. J
Organomet Chem 846:326–334. https://doi.org/10.1016/j.jorga
nchem.2017.07.005
Aydemir M, Meriç N, Baysal A, Gümgüm B, Toğrul M, Turgut Y
(
2010a) A modular design of ruthenium(II) catalysts with chi-
ral C -symmetric phosphinite ligands for eꢀective asymmetric
2
transfer hydrogenation of aromatic ketones. Tetrahedron Asym-
metry 21:703–710. https://doi.org/10.1016/j.tetasy.2010.04.002
Aydemir M, Meriç N, Durap F, Baysal A, Toğrul M (2010b) Asym-
metric transfer hydrogenation of aromatic ketones with the
ruthenium(II) catalyst derived from C symmetric N, N′-bis[(1S)-
2
Acknowledgements Partial support from Dicle University Research
Fund (Project numbers: FEN.17.023 and FEN.17.019) is gratefully
acknowledged. The authors would also like to thank the Ministry of
Education and Science of the Republic of Kazakhstan for the ꢁnancial
support (IRN: AP05132833, BR05236800 and BR05236302).
1
-benzyl-2-O-(diphenylphosphinite)ethyl]ethanediamide. J Orga-
nomet Chem 695:1392–1398. https://doi.org/10.1016/j.jorga
nchem.2010.02.003
Aydemir M, Meriç N, Baysal A, Turgut Y, Kayan C, Şeker S, Toğrul
M, Gümgüm B (2011) Asymmetric transfer hydrogenation of
6
acetophenone derivatives with novel chiral phosphinite based η -
p-cymene/ruthenium(II) catalysts. J Organomet Chem 696:1541–
1
546. https://doi.org/10.1016/j.jorganchem.2010.12.027
Aydemir M, Raꢁkova K, Kystaubayeva N, Pasa S, Meriç N, Ocak YS,
Zazybin A, Temel H, Gurbuz N, Özdemir İ (2014) Ionic liquid
based Ru(II)–phosphinite compounds and their catalytic use in
transfer hydrogenation: X-ray structure of an ionic compound
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Aꢀliations
Nermin Meriç · Cezmi Kayan · Khadichakhan Rafkova2,3 · Alexey Zazybin2,3 · Veysi Okumuş · Murat Aydemir ·
1
1
4
1
Feyyaz Durap1
2
*
*
Cezmi Kayan
Institute of Chemical and Biological Technologies, Satbayev
University, Almaty, Kazakhstan
cezmik@dicle.edu.tr
3
4
Murat Aydemir
School of Chemical Engineering, Kazakh-British Technical
University, Almaty, Kazakhstan
aydemir@dicle.edu.tr
Department of Biology, Faculty of Science and Art,
University of Siirt, 56100 Siirt, Turkey
1
Department of Chemistry, Faculty of Science, University
of Dicle, 21280 Diyarbakir, Turkey
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3