Transition Metal Chemistry
https://doi.org/10.1007/s11243-022-00503-w
Synthesis, structural characterization and anticancer properties
of p‑cymene Ru(II) complexes with 2‑(N‑methyl‑1H‑1,2,4‑triazol‑3‑yl)
pyridines
Yulia M. Ohorodnik1 · Sikalov A. Alexander1 · Dmytro M. Khomenko1,2 · Roman O. Doroshchuk1,2 ·
Ilona V. Raspertova1 · Sergiu Shova3 · Maria V. Babak4 · Rostyslav D. Lampeka1
Received: 26 March 2022 / Accepted: 14 May 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022
Abstract
The structures of new p-cymene Ru(II) complexes with 2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine and 2-(1-methyl-1H-1,2,4triazol-5-yl)pyridine were established based on the results of elemental analysis; IR and NMR spectra; and X-ray diffraction studies. Their anticancer activity, tested on human ovarian cancer cell lines A2780 (cisplatin-sensitive) and A2780cis
(cisplatin-resistant), is also reported.
Introduction
A significant number of scientific papers deal with p-cymene
ruthenium complexes based on the chelating N–N ligands
and particularly 2-pyridine-azoles. Among them are 2-pyridine derivatives of 1,2,3-triazole [1], 1,2,4-triazole [2, 3],
thiazole [4, 5], pyrazole [6], benzoxazole [7], benztiazole
[2], indole [8] and the most wide spread benzimidazole
[9–16]. A limited number of cytotoxicity studies of complexes based on 2-(1,2,4-triazol-5-yl)pyridines forced us to
carry out investigations related to this class of compounds.
* Sergiu Shova
shova@icmpp.ro
* Rostyslav D. Lampeka
rostlamp@gmail.com
Dmytro M. Khomenko
https://www.enamine.net
Roman O. Doroshchuk
https://www.enamine.net
1
Department of Chemistry, Kyiv National Taras Shevchenko
University, Volodymyrska st. 64, Kyiv 01601, Ukraine
2
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094,
Ukraine
3
“Petru Poni” Institute of Macromolecular Chemistry, Aleea
Gr. Ghica Voda 41A, 700487 Iasi, Romania
4
Drug Discovery Lab, Department of Chemistry,
City University of Hong Kong, 83 Tat Chee Avenue,
Hong Kong SAR 999077, People’s Republic of China
Generally, the wide use of 1,2,4-triazole-derived ligands
arises from specific features of their structure, properties and
from the possibility of introducing a plethora of substituents
into triazole ring. Position of donor atoms in the substituents
provides the ability to influence coordination behavior of the
ligand. In this way, it is possible to obtain both complexes
with bridging ligands and chelates [17]. Moreover, structural chemistry of p-cymene Ru(II) complexes with 2-pyridile-1,2,4-triazole systems is much better known and thus
some prediction about coordination mode of title ligands
could be made. The coordination chemistry of Ru complexes
with 2-(N-methyl-1H-1,2,4-triazol-5-yl)pyridine was a target of intensive research since the mid-1990s [18–26]. But
only two of the three possible isomers of proligands have
been investigated. Complexes of 2-(1-methyl-1H-1,2,4triazol-5-yl)pyridine (L1) remain unexplored. As concerns
2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (L2), both merand fac-Ru(L2)3(PF6)2 were obtained and characterized
[21]. But it should be noted that mainly it was used for the
synthesis of mixed ligand coordination compounds together
with bpy [18, 19, 22, 26] and CO [20, 25]. During the investigation, it was established that depending on the conditions
L2 can provide both N1 and N4 for coordination with ruthenium. Fanni et al. showed that N1 isomer readily rearranges
to N4 in the photolysis conditions [18, 19]. In the same article, the authors proposed a possible route for the obtaining of complexes with methylated ligands by alkylation of
coordinated triazole. Generally, above mentioned research
regarding L2 and its N4 methylated isomer (L3) were mainly
focused on elucidation structure and some physicochemical
13
Vol.:(0123456789)
Transition Metal Chemistry
properties. Thus, investigation of cytotoxic activity of ruthenium complexes with 2-(N-methyl-1H-1,2,4-triazol-5-yl)
pyridines could be considered as challenging and actual
goal. 2-(1-Methyl-1H-1,2,4-triazol-3-yl)pyridine is a typical
chelating ligand. Compared to 2,2-bipyridine, 2-(1H-1,2,4triazol-3-yl)pyridines are stronger σ-donors and weaker
π-acceptors [13].
In this paper, we describe the synthesis and structures of
new p-cymene Ru(II) complexes with 2-(1-methyl-1H-1,2,4triazol-3-yl)pyridine and 2-(2-methyl-1H-1,2,4-triazol-5-yl)
pyridine. Their antitumor properties are also delineated.
Experimental section
General
All reagents were obtained commercially unless otherwise
noted and used as received. 2-(1,2,4-Triazol-5-yl)pyridine
was prepared by known procedure [27]. All solvents used
were laboratory reagent grade. Elemental analyses were
carried out with Perkin-Elmer 2400 CHN Analyzer. Melting points (°C, uncorrected) were measured with Opti Melt
Automated Melting Point System (MPA 100). 1D (1H and
13
C) and 2D (1H,1H COSY; 1H,1H NOESY; 1H,13C HSQC;
1 13
H, C HMBC) NMR spectra were recorded on a Varian
UnityPlus 400 spectrometer (at 400.4 MHz and 100.7 MHz
for 1H and 13C nuclei, respectively): internal standard—
signal of residual solvent protons (DMSO-d6—2.50 ppm)
and carbons (DMSO-d6—39.5 ppm). The IR spectra (KBr,
discs) were recorded with Spectrum BX Perkin-Elmer
spectrometer.
X‑Ray experimental
Crystals of 1 and 2 suitable for single-crystal X-ray diffraction studies were obtained using slow diffusion of methyltert-butyl ether vapours into a methanol solution of complex. X-ray diffraction measurements were carried out with a
Rigaku Oxford Diffraction XCALIBUR E CCD diffractometer equipped with graphite-monochromated MoKα radiation. The unit cell determination and data integration were
carried out using the CrysAlis package of Oxford Diffraction [28]. The structures were solved by Intrinsic Phasing
using Olex2 [29] software with the SHELXT [30] structure
solution program and refined by full-matrix least squares on
13
F2 with SHELXL-2015 [31] using an anisotropic model for
non-hydrogen atoms. The mean value for |E2 − 1| was 0.815
indicating that the probability of centrosymmetric structure is of 35.5%. The structure was initially solved in Pnma
space group and refined to R = 0.0541 giving good molecular
geometry. Nevertheless, the further analysis of the ΔF maps
has revealed that i-propyl group and bidentate ligand L1 are
disordered over two equivalent positions at the site of symmetry m. In subsequence attempt, the structure solution and
refinement in non-centrosymmetric Pna21 space group have
been performed. The i-propyl group remained disordered in
two resolvable positions, while no disorder of the L1 ligand
was observed. Furthermore, the value of R decreased to
0.0416 in this space group. All H atoms attached to carbon
were introduced in idealized positions with ­dCH = 0.96 Å.
The molecular plots were obtained using the Olex2 program. Table 1 provides a summary of the crystallographic
data together with refinement details for compounds. The
geometric parameters are summarized in Table S1. The
supplementary crystallographic data can be obtained free
of charge via http://​www.​ccdc.​cam.​ac.​uk/​conts/​retri​eving.​
html or from the Cambridge Crystallographic Data Centre,
CCDC: 2088900 for 1, 2088901 for 2.
Synthesis of proligands and coordination
compounds
2-(1-Methyl-1H-1,2,4-triazol-5-yl)pyridine (L 1) and
2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (L 2 ).
Table 1 Crystal data and details of data collection for 1 and 2
Compound
1
2
Empirical formula
Fw
space group
a [Å]
b [Å]
c [Å]
V [Å3]
Z
ρcalcd[g ­cm–3]
crystal size [mm]
T [K]
μ[mm‒1]
R1[]
wR2[b]
GOF[c]
C18H25.5Cl2N4O1.75Ru
497.89
Pna21
15.3098(8)
14.5400(7)
9.7038(5)
2160.11(18)
4
1.531
0.25 × 0.15 × 0.15
293
0.991
0.0416
0.0736
1.022
C18H22Cl2N4Ru
466.36
Pna21
13.1620(6)
15.3179(7)
9.7000(4)
1955.65(15)
4
1.581
0.30 × 0.25 × 0.25
293
1.083
0.0633
0.0641
1.095
a
b
R1 = Σ||Fo| −|Fc||/Σ|Fo|
wR2 = {Σ[w(Fo2 − Fc2)2]/Σ[w(Fo2)2]}1/2
GOF = {Σ[w(Fo2 − Fc2)2]/(n − p)}1/2, where n is the number of reflections and p is the total number of parameters refined
c
Transition Metal Chemistry
2-(1,2,4-Triazol-5-yl)pyridine (10.0 g, 68.0 mmol) was
added to the suspension of potassium carbonate (14.0 g,
101.0 mmol) in DMF (200.0 mL) followed by the addition
of iodomethane (11.2 g, 79.0 mmol). The resulting mixture was stirred at room temperature until the completion
of the reaction (monitored by NMR). Obtained solution
was filtered off and concentrated under reduced pressure.
The residue was dissolved in ­H2O (100.0 mL) and extracted
with ­CHCl3 (3 × 100 mL). The combined organic layers were
dried over N
­ a2SO4, filtered off and evaporated in vacuo. The
obtained solid was subjected to column chromatography
­(SiO2, MTBE as an eluent, Rf (L1) = 0.63, Rf (L2) = 0.39) to
afford 2-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (L1) and
2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (L2).
2-(1-Methyl-1H-1,2,4-triazol-5-yl)pyridine (L1): yield
4.9 g (45%). M.p. = 58 °C. 1H NMR (400 MHz, DMSO-d6):
δ 8.72 (d, J = 4.1 Hz, 1H, Py-H6), 8.12 (dd, J = 7.9, 0.8 Hz,
1H, Py-H3), 8.03 (s, 1H, ­Htr), 7.99 (td, J = 7.8, 1.7 Hz, 1H,
­ H3) ppm. 13C
Py-H4), 7.51 (m, 1H, Py-H5), 4.26 (s, 3H, C
6
1
NMR (101 MHz, DMSO-d ): δ 151.59(C ), 150.56 ­(C6),
149.54(C7), 147.86 (­ C5), 138.14(C3), 124.97 (­ C2), 123.87
­(C4), 38.92 (­ C8) ppm. IR (KBr): 3457, 3097, 29.52, 2019,
1814, 1711, 1592, 1489, 1412, 1292, 1232, 1172, 1095,
1010, 907, 805, 736, 685, 633, 522, 403 ­cm−1. Elemental
analysis: Anal. Calcd. for ­C8H8N4: C, 59.99%; H, 5.03%; N,
34.98%. Found: C, 59.42%; H, 4.81%; N, 35.07%.
2-(1-Methyl-1H-1,2,4-triazol-3-yl)pyridine (L2): yield
4.68 g (43%) M.p. = 76 °C. 1H NMR (400 MHz, DMSO-d6):
δ 8.63 (d, J = 4.1 Hz, 1H, Py-H6), 8.57 (s, 1H, ­Htr), 8.03 (d,
J = 7.9 Hz, 1H, Py-H3), 7.88 (t, J = 7.7 Hz, 1H, Py-H4), 7.40
(dd, J = 6.7, 5.4 Hz, 1H, Py-H5), 3.94 (s, 3H, C
­ H3) ppm. 13C
6
6
NMR (101 MHz, DMSO-d ): δ161.58 ­(C ), 150.16 ­(C1),
149.98 ­(C7), 146.20 ­(C5), 137.39 ­(C3), 124.28 ­(C2), 121.83
­(C4), 36.56 (­ C8) ppm. IR (KBr): 3447, 3068, 1778, 1670,
1598, 1517, 1426, 1336, 1282, 1228, 1146, 1047, 993, 803,
740, 668, 623, 488 ­cm−1. Elemental analysis: Anal. Calcd.
for ­C8H8N4: C, 59.99%; H, 5.03%; N,34.98%. Found: C,
59.64%; H, 4.78%; N, 35.11%.
[(η 6-p-Pr iC 6H 4Me)Ru(L)Cl]Cl (General method).
­[RuCl2(p-cymene)]2 (0.245 g, 0.4 mmol) was dissolved in
methanol (10 mL). Then respective proligands (0.128 g,
0.8 mmol) were added to the solutions. The reaction mixtures were stirred for 4 h at ambient temperature. Methanol
was then distilled off yielding orange residues. The suspensions of the latter in methanol:methyl-tert-butyl ether (1:9)
mixture were stirred for several days at room temperature.
Then the solid residues were filtered off and dried.
[(η 6-p-Pr iC 6H 4Me)Ru(L 1)Cl]Cl (1): yield 242 mg
(65%) M.p. = 95 °C. 1H NMR (400 MHz, DMSO-d6): δ
9.68 (d, J = 3.7 Hz, 1H, Py-H6), 9.3 (s, 1H, H
­ tr), 8.40 (m,
3
4
1H, Py-H ), 8.33 (m, 1H, Py-H ), 7.84 (m, 1H, Py-H5),
6.25 (d, J = 5.1 Hz, 2H, ­Cbenzene-H), 6.03 (d, J = 5.0 Hz, 2H,
­Cbenzene-H), 4.37 (s, 3H, 1L-CH3), 2.68 (m, 1H, CH from
i-Pr of p-cymene), 2.12 (s, 3H, ­CH3 from p-cymene), 1.05
(d, J = 7.2 Hz, 1H, ­CH3 from i-Pr of p-cymene), 1.02 (d,
J = 6.5 Hz, 1H, ­CH3 from i-Pr of p-cymene) ppm. 13C NMR
(101 MHz, DMSO-d6): δ 157.48 ­(C1), 151.97 (­ C6), 151.74
­(C7), 143.34 ­(C5), 140.65 ­(C3), 128.39 ­(C2), 125.43 ­(C4),
104.73 ­(C12), 101.53 (­ C9), 84.94, 84.37, 84.18, 82.20 (­ C10,
­C11, ­C13, ­C14), 40.48 (­ C8), 30.91 (­ C16), 22.41, 22.16 (­ C17,
­C18), 18.63 (­ C15) ppm. IR (KBr); 3410, 3060, 2970, 2880,
2386, 1620, 1509, 1466, 1389, 1302, 1230, 1012, 886,
797, 748, 705 ­cm−1. Elemental analysis: Anal. Calcd. for
­C18H22Cl2N4Ru: C, 46.36%; H, 4.75%; N, 12.01%. Found:
C, 46.04%; H, 4.59%; N, 12.27%.
[(η6-p-PriC6H4Me)Ru(L2)Cl]Cl (2): yield 265 mg (71%)
M.p. = 197 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.12
(s, 1H, ­Htr), 9.51 (d, J = 4.9 Hz, 1H, Py-H6), 8.22 (m, 1H,
Py-H4), 8.13 (m, 1H, Py-H3), 7.75 (t, 1H, Py-H5), 6.19 (m,
2H, ­Cbenzene-H), 5.99 (m, 2H, C
­ benzene-H), 4.11 (s, 3H, C
­ H3
from 2L-CH3), 2.65 (m, 1H, CH from i-Pr of p-cymene), 2.09
(s, 3H, C
­ H3 from p-cymene), 1.00 (m, 2H, C
­ H3 from i-Pr of
p-cymene) ppm. 13C NMR (101 MHz, DMSO-d6): δ160.10
­(C6), 156.56 ­(C1), 149.18 ­(C7), 146.28 ­(C5), 141.01 ­(C3),
128.03 ­(C2), 122.48 ­(C4), 104.16 ­(C12), 101.31 ­(C9), 84.81,
84.15, 83.57, 82.36 ­(C10, ­C11, ­C13, ­C14), 38.69 ­(C8), 30.81
­(C16), 22.37, 21.99 (­ C17, ­C18), 18.63 (­ C15) ppm. IR (KBr):
3424, 3035, 2964, 2924, 2870, 1868, 1622, 1518, 1452,
1359, 1288, 1228, 1145, 1014, 893, 806, 756, 713 ­cm−1.
Elemental analysis: Anal. Calcd. for C
­ 18H22Cl2N4Ru: C,
46.36%; H, 4.75%; N, 12.01%. Found: C, 45.97%; H, 4.44%;
N, 12.13%.
Cell lines and culture conditions Human ovarian cancer
cell lines A2780 (cisplatin-sensitive) and A2780cis (cisplatin-resistant) were purchased from ATCC. Adherent cells
were grown in tissue culture 25-cm2 flasks (Greiner BioOne) at 37 °C in a humidified atmosphere of 95% air and
5% ­CO2. Experiments were performed on cells within 30
passages. All drug stock solutions were prepared in DMSO,
and the final concentration of DMSO in medium did not
exceed 1% (v/v) at which cell viability was not inhibited.
The amount of actual Ru concentration in the stock solutions
was determined by ICP-OES.
Inhibition of cell viability assay The cytotoxicity of the
compounds was determined by colorimetric microculture
assay (MTT assay). The cells were harvested from culture
flasks by trypsinization and seeded into Cellstar 96-well
microculture plates (Greiner Bio-One) at the seeding density of 6 × ­104 cells per well. After the cells were allowed
to resume exponential growth for 24 h, they were exposed
to drugs at different concentrations in media for 72 h. The
drugs were diluted in complete medium at the desired concentration and 100 μL of the drug solution was added to
each well and serially diluted to other wells. After exposure
for 72 h, drug solutions were replaced with 100 μL of MTT
in media (5 mg ­mL−1) and incubated for additional 75 min.
13
Transition Metal Chemistry
Scheme 1 Synthesis of triazole ligands and their complexes
Subsequently, the medium was aspirated and the purple
formazan crystals formed in viable cells were dissolved in
100 μL of DMSO per well. Optical densities were measured
at 570 nm with a microplate plate reader. The quantity of
viable cells was expressed in terms of treated/control (T/C)
values by comparison to untreated control cells, and 50%
inhibitory concentrations ­(IC50) were calculated from concentration–effect curves by interpolation using GraphPad
Prism software (version 5.01). Evaluation was based on
means from at least three independent experiments, each
comprising three replicates per concentration level.
Results and discussion
Synthesis
Complexes 1 and 2 were produced starting from equimolar
amounts of [(η6-p-PriC6H4Me)RuCl2]2 and corresponding proligands using standard procedure [10] to form ionic
chelate compounds of the composition [(η6-p-PriC6H4Me)
Ru(L)Cl]Cl. Complexes are yellow precipitates soluble in
alcohols, acetonitrile, DMF and DMSO and insoluble in
hexane and ether (Scheme 1).
13
Crystal structure
The results of X-ray diffraction study for 1 and 2 are shown
in Fig. 1. Two isostructural species crystallize in non-centrosymmetric space group Pna21 with one complex cation
and one chloride counter-anion in the asymmetric part of
the unit cell. There are no co-crystallized solvate molecules
in the crystal 2, while compound 1 crystallizes with 1.75
water molecules per organometallic unit. Both complexes
show the expected half-sandwich pseudo-octahedral “threelegged piano-stool” geometry (η6-p-cymene as the site and
bidentate pyridyl-triazole ligand and chlorine atom as three
legs). The Ru–N bond distances (Table S1) are comparable
to those of similar ruthenium complexes with pyridyl-triazole ligands [18, 23, 25]. The distance between the ruthenium and the centroid of η6-p-cymene is of 1.6762(5) for 1
and 1.6678(5) Å for 2, which is consistent with those found
for earlier reported complexes with related ligands [32, 33].
The crystal packing is driven by an extended system of intermolecular hydrogen bonding involving O–H···Cl, O–H···O.
O–H···N and C–H···Cl short contacts. The H-bonds parameters are listed in Table S2. It determined the presence of a
dense and complex 3D supramolecular architecture, where
the formed cavities are filled by chloride counter-anions and
water solvate molecules. A partial view of the crystal packing for 1 and 2 is shown in Figure S10 and S11, respectively.
Transition Metal Chemistry
Fig. 1 X-ray molecular structure of [(η6-p-PriC6H4Me)Ru(L1)Cl]+(1) (a) and [η6-p-PriC6H4Me)Ru(L2)Cl]+(2) (b) complex cations with
selected labeling and thermal ellipsoids at 40% probability. Selected bonds and angles:
Ru–N1
Ru–N2
Ru–Cl1
N2–Ru1–Cl1
N1–Ru1–Cl1
N1–Ru1–N2
Table 2 Chemical shifts
of protons of ligands and
coordination compounds of
ruthenium
1
2
2.086(12)
2.101(10)
2.4003(17)
84.1(4)
85.7(4)
75.74(19)
2.128(4)
2.074(5)
2.3986(15)
82.11(12)
82.11(12)
76.40(16)
Proton
Chemical shift, δ (ppm)
L
H6
H5
H4
H3
H2
H1
1
8.72
7.51
7.99
8.12
8.03
4.26
∆δ (ppm)
2
1
9.68
7.84
8.33
8.40
9.30
4.38
Chemical shift, δ (ppm)
0.96
0.33
0.34
0.27
1.27
0.12
L
2
8.63
7.40
7.88
8.02
8.57
3.94
9.51
7.75
8.22
8.13
10.12
4.12
∆δ (ppm)
0.88
0.25
0.34
0.11
1.55
0.18
13
Transition Metal Chemistry
Fig. 2 1H,1H NOESY spectra of 2 in DMSO-d6
Fig. 3 UV–Vis absorption
spectra of acetonitrile solution
of 1 and 2
13
Transition Metal Chemistry
Table 3 UV–Vis absorption data of complexes in acetonitrile
–4
Complex
λmax/nm (ε/10 ­M
1
2
274 (0.7858)
269 (0.86)
−1
−1
­cm )
336 (0.2878)
314 (0.354)
Table 4 Cytotoxicity of ligands L1 and L2 and corresponding ­RuII
complexes in comparison with cisplatin
Compound
L1
1
L2
2
Cisplatin
IC50 [μM]a
RFb
A2780
A2780cis
345 ± 43
86 ± 19
330 ± 48
34 ± 10
0.22 ± 0.03
445 ± 50
125 ± 47
486 ± 17
77 ± 12
4.3 ± 0.8
1.3
1.5
1.5
2.3
19.5
a
50% inhibitory concentrations ­(IC50) in human ovarian cancer cell
lines A2780 and A2780cis, determined by means of the MTT assay
after exposure for 72 h; Values are means ± standard deviations
obtained from at least three independent experiments
b
Resistance factor (RF) is determined as ­IC50(A2780cisR)/IC50(A2780)
NMR and UV–Vis spectroscopy
1
H NMR spectra of title compounds are characterized by
sharp signals indicating the absence of dynamic processes
in solutions (Fig S3, S6 SI). Coordination of proligands
by Ru(II) leads to significant shift of almost all signals in
1
H NMR spectra. Assignment of proton signals in NMR
spectra was made using the data of 1H-1H COSY experiment. Expectedly, the most significant downfield shifts
are observed for triazole (­ H2) and o-pyridine (­ H6) protons
(Table 2).
Abovementioned changes in NMR spectra of complexes
are results of their identical coordination mode. Theoretically, L1 could form metallochelates only by binding through
­NPy and ­N4Trz, whereas L2 could chelate also through N
­ 2Trz.
2
But abovementioned significant downfield shift of ­H confirms that coordination mode of proligands with involving of
­N4Trz remains unchanged in both cases after dissolution. This
assumption is also proved by 1H-1H NOESY spectra of title
complexes particularly by the absence of cross-peak between
p-cymene protons and N-methyl of proligand in 2 (Fig. 2).
Taking into account that 1 and 2 have “piano chair”-type
structure, direct dipole–dipole interaction between proligand
and p-cymene moiety is presented. This results in appearing of cross-peaks in NOESY spectrum of 1 due to spatial
interaction between H
­ 2Trz and almost all p-cymene protons.
Latter also shows the same contacts with ­H6Py, which are
observed in two-dimensional matrix of NOESY spectra.
Therefore, it could be concluded that coordination mode
of ligand remains the same in solution of DMSO as in crystalline state, i.e., [(η6-p-iPrC6H4Me)Ru(L1)]+ particles have
“piano chair”-type structure with ­NPy, ­N4Trz coordination
mode of pyridile-triazole ligand.
The UV–Vis spectra of both complexes (Fig. 3, Table 3)
show absorption band approximately at 270 nm, assigned
to ligand-centered π → π*/n → π* transitions [32, 33]. The
spectrum of 1 exhibits a broad band centered at around
336 nm assigned to a metal-to-ligand charge transfer
(MLCT) involving triazole ligand. This band is observed at
314 nm for complex 2.
Anticancer activity
The anticancer activity of novel ligands and corresponding
complexes was tested in cisplatin-sensitive ovarian cancer
cell line A2780 and its cisplatin-resistant analogue A2780cis
by means of the colorimetric MTT assay with an exposure
time of 72 h. The results are presented in Table 4, and the
concentration–effect curves are shown in Figure S12. As
expected, cisplatin demonstrated excellent cytotoxicity in a
cisplatin-sensitive cell line, which dropped by ≈ 20-fold in
a cisplatin-resistant cell line. Novel compounds also demonstrated slightly reduced cytotoxicity in a cisplatin-resistant
cell line; however, the resistance factors (RFs) were significantly lower than for cisplatin. Ligands L1 and L2 were
devoid of anticancer activity, while their coordination to a
Ru(II) center resulted in fourfold to tenfold increase of anticancer activity.
Conclusion
Two novel p-cymene Ru(II) complexes based on 2-(1,2,4-triazol-5-yl)pyridine derivatives were structurally characterized both in solid state and in solution. In both cases, X-ray
showed formation of ionic chelate compounds of the same
composition. The fact that compounds remain stable in
solution, which was unambiguously showed using NMR,
enforced us to investigate their anticancer activity. The coordination of the ligands to a Ru center resulted in the significant improvement of cytotoxicity in both cisplatin-resistant
and cisplatin-sensitive cell lines. The resistance factors of
novel compounds were significantly lower the resistance
factor of cisplatin, indicating their potential for treatment of
cisplatin-resistant cancers.
Supplementary Information The online version contains supplementary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 11243-0​ 22-0​ 0503-w.
13
Transition Metal Chemistry
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