Tunable Anticancer Activity of Furoylthiourea-Based RuII–Arene Complexes and Their Mechanism of Action

Article abstract of DOI:10.1002/chem.202004954

Fourteen new Ru^II–arene (p-cymene/benzene) complexes (C1–C14) have been synthesized by varying the N-terminal substituent in the furoylthiourea ligand and satisfactorily characterized by using analytical and spectroscopic techniques. Electrosta

Full text of DOI:10.1002/chem.202004954

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&
Antitumor Agents
Tunable Anticancer Activity of Furoylthiourea-Based RuII–Arene
Complexes and Their Mechanism of Action
Srividya Swaminathan,[a] Jebiti Haribabu,[a] Naveen Kumar Kalagatur,[b] Maroli Nikhil,[c]
Nithya Balakrishnan,[a] Nattamai S. P. Bhuvanesh,[d] Krishna Kadirvelu,[b]
Ponmalai Kolandaivel,[e] and Ramasamy Karvembu*[a]
Abstract: Fourteen new RuII–arene (p-cymene/benzene)
complexes (C1–C14) have been synthesized by varying the
N-terminal substituent in the furoylthiourea ligand and satis-
factorily characterized by using analytical and spectroscopic
techniques. Electrostatic potential maps predicted that the
electronic effect of the substituents was mostly localized,
with some influence seen on the labile chloride ligands. The
as N-terminal substituent) and C13 (Ru–benzene complex
containing C6H4(CF3) as N-terminal substituent) showing the
highest activity among each set of complexes, and hence
they were chosen for further study. These complexes
showed different behavior in aqueous solutions, and were
also found to catalytically oxidize glutathione. They also pro-
moted cell death by apoptosis and cell cycle arrest. Further-
structure–activity relationships of the Ru–p-cymene and Ru– more, the complexes showed good binding ability with the
benzene complexes showed opposite trends. All the com-
plexes were found to be highly toxic towards IMR-32 cancer
cells, with C5 (Ru–p-cymene complex containing C6H2(CH3)3
receptors Pim-1 kinase and vascular endothelial growth
factor receptor 2, commonly overexpressed in cancer cells.
Introduction
Although platinum-based drugs gained importance in
cancer treatment, they came with serious drawbacks.[3] In a
search for alternatives, scientists began to explore options with
other metal ions. Ruthenium complexes came foremost with
desirable properties, which made them exciting candidates for
medicinal applications. They were found to be selectively
active toward cancer cells over normal cells, and to mimic iron
in binding to biological molecules.[4] The antineoplastic ruthe-
nium frameworks that have entered clinical trials mostly in-
volve RuIII species, imidazolium (imidazole)(dimethyl sulfoxide)-
tetrachlororuthenate(III) (NAMI-A), indazolium trans-tetrachloro-
bis(1H-indazole)ruthenate(III) (KP1019) and sodium trans-tetra-
chlorobis(1H-indazole)ruthenate(III) (KP1339; Figure 2).[5] Nu-
merous pharmaceutical chemists are exploring RuII scaffolds in
preclinical studies that are at several stages of development.
Namely, RuII–arene compounds containing ethylenediamine
(en) or 1,3,5-triaza-7-phosphaadamantane (PTA) ligand have
shown efficient antineoplastic activity. Another promising RuII
therapeutic, TLD1433, has entered phase 1 and phase 2a clini-
cal trials for non-muscle invasive bladder cancer treatment by
photodynamic therapy (PDT).[6]
The growth of research in the field of medicinal chemistry has
been highly beneficial for the well-being of humans. In a study
that proved to be a boon to mankind, Barnett Rosenberg acci-
dentally discovered the cytotoxic nature of cisplatin,[1] a plati-
num-based compound that gained approval from the Food
and Drug Administration (FDA) in 1978 and went on to
become a widely used anticancer drug. After its discovery, the
research on platinum-based anticancer drugs flourished, which
led to the discovery of various new therapeutics, a couple of
which were approved for the global market (Figure 1).[1,2]
[a] S. Swaminathan, Dr. J. Haribabu, N. Balakrishnan, Prof. R. Karvembu
Department of Chemistry, National Institute of Technology
Tiruchirappalli 620015, Tamil Nadu (India)
E-mail: kar@nitt.edu
[b] Dr. N. K. Kalagatur, Dr. K. Kadirvelu
DRDO-BU Centre for Life Sciences, Bharathiar University Campus
Coimbatore 641046, Tamil Nadu (India)
[c] Dr. M. Nikhil
Centre for Condensed Matter Theory, Department of Physics
Indian Institute of Science, Bangalore 560012, Karnataka (India)
[d] Dr. N. S. P. Bhuvanesh
Department of Chemistry, Texas A & M University
College station, Texas 77842 (USA)
[e] Prof. P. Kolandaivel
Periyar University, Salem 636011, Tamil Nadu (India)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202004954.
Figure 1. Globally approved platinum-based anticancer drugs.
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Figure 3. Aroylthiourea-based RuII–arene complexes reported by our group.
Results and Discussion
Figure 2. Ruthenium compounds in clinical trials.
Synthesis
Metals combined with organic motifs are becoming increas-
ingly dominant with their vast number of applications.[7–10] In
the pharmaceutical industry, although many drugs in the
market are seemingly organic in nature, organometallic com-
pounds offer various benefits over their organic counterparts.
They demonstrate a wide range of oxidation states, lipophilic
character, redox properties, structural diversity, kinetic stability,
an ability to bind to biomolecules and the opportunity to tune
ligands to control the kinetic properties. In this regard, ligand
selection needs to be carefully planned for the development
of organometallic drugs.[11–14] Aroylthioureas are known to ex-
hibit antibacterial, antifungal, and anticancer properties. Our
group has been actively investigating the biological properties
of NiII, PdII and CuII complexes of aroylthiourea ligands.[15,16]
More recently, we have diverted our efforts towards aroylth-
iourea-based RuII–arene complexes, which have resulted in po-
tential anticancer agents (Figure 3).[17–19]
The ligands L1–L7 were synthesized from 2-furoyl chloride, po-
tassium thiocyanate and the respective amines according to a
previously reported procedure (Scheme 1).[16] Among these li-
gands, L6 and L7 are new, and they were characterized by ele-
mental analysis and UV/Vis, FTIR and NMR spectroscopy.
The RuII–arene complexes were synthesized by adding the
[Ru(arene)Cl2]2 (arene=p-cymene or benzene) precursor to a
solution of the corresponding ligand in toluene (Scheme 2). A
few drops of methanol were added to promote the solubility
of the metal precursor.[19] The reaction was allowed to proceed
for 4 h, after which the ligand spot in TLC had completely dis-
appeared. The resulting reaction mixture was concentrated
Although the literature contains a significant number of re-
ports on RuII–arene acylthiourea complexes, the structure–ac-
tivity relationships of these compounds have seldom been in-
vestigated. The structures of these compounds are similar to
ruthenium–arene PTA (RAPTA) species, which make them inter-
esting candidates for anticancer applications, because the
latter are rapidly evolving as lead compounds for the treat-
ment of cancer. Hence, in this study, we have explored the
RuII–arene complexes of furoyl-based thiourea ligands for their
anticancer properties, with the perspective that furan deriva-
tives are important pharmaceutical compounds. Various sub-
stituents (electron-donating/electron-withdrawing/steric/differ-
ent aliphatic chain length) on the terminal nitrogen were se-
lected to study their effects.[20,21] As a result, 14 RuII–p-cymene
or RuII–benzene complexes with furoylthiourea ligands were
synthesized. They were characterized and evaluated for their
solution behavior, GSH binding and anticancer activity.
Scheme 1. Synthesis of the furoylthiourea ligands.
Scheme 2. Synthesis of the RuII–arene complexes.
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under reduced pressure, and then hexane was added until a
solid formed. The precipitate was filtered, washed thoroughly
with hexane and dried under vacuum. The complexes were ob-
tained in good yields (70–79%). Crystals of C1–C4, C6, C8 and
C14 were grown in DMF/chloroform solution, and their struc-
tures were solved by single-crystal XRD analysis.
and 5.79–5.21 ppm (C1–C7). The benzene complexes (C8–C14)
each showed a sharp singlet corresponding to the six protons
in the range 5.98–5.62 ppm.
The 13C NMR spectra of the complexes showed a signal due
to the thioamidic carbon (C=S) in the most shielded region
(185.4–178.8 ppm), whereas the amidic carbon (C=O) signal
was observed in the range 162.6–157.7 ppm. All the aromatic
carbon atoms were observed in the expected region. The ali-
phatic carbon atoms of the p-cymene, that is, the methyl
carbon attached to the aromatic ring, the isopropyl carbon
and the two methyl carbons attached to the isopropyl carbon,
displayed signals in the ranges 30.5–30.3, 22.3–21.9 and 18.4–
18.2 ppm, respectively (C1–C7). In the spectra of the com-
plexes with benzene as the arene moiety (C8–C14), an intense
signal corresponding to the six carbon atoms was observed at
around 92.8–85.3 ppm (see Figures S23–S54 in the Supporting
Information). The 19F NMR spectra of the compounds contain-
ing CF3 were recorded and a single sharp peak was observed
for all in the range 60.5–61.5 ppm (see Figures S19, S22, S35,
S38, S51 and S54).
Spectroscopic characterization
The compounds were initially characterized by elemental anal-
ysis and UV/Vis and FTIR spectroscopy (see Figures S1–S16 and
1
Tables S1 and S2 in the Supporting Information).[17–19] The H
and 13C NMR spectra of the ligands L6 and L7, aside from their
aromatic protons and carbon atoms being observed in their re-
spective regions, showed amide and thioamide NÀH protons
as singlets in the ranges 12.53–12.50 and 11.62–11.45 ppm, re-
spectively. The thioamidic and amidic carbon signals were seen
at around 179.5–178.4 and 157.9–156.9 ppm, respectively. Each
of the trifluoromethyl carbon atoms showed four signals in the
13C NMR spectra in the range 126.3–119.9 ppm as a result of
spin–spin coupling between the carbon and fluorine atoms
(see Figures S17–S22).[17,18]
The mass spectra of the complexes showed a base peak cor-
responding to the [MÀ2H+À2ClÀ+H+]+ fragment, in agree-
ment with the data reported for similar types of complexes in
the literature (see Figures S55–S68 in the Supporting Informa-
tion).[17–19]
1
In the H NMR spectra of the complexes, the three aromatic
protons of the furan ring were observed as two doublets and
a doublet of doublets in the ranges 8.11–7.60 and 6.79–
6.49 ppm, respectively. The terminal N substituents of the li-
gands, apart from the aromatic protons, which were observed
in their respective regions, displayed signals as follows: the
methylene protons were seen as a doublet at 4.86–4.79 ppm
(C2 and C9), the CH2CH2 protons as a doublet of doublets
(3.94–3.92 ppm) and triplet (3.03 ppm; C3 and C10), and the
CH2CH3 protons as a multiplet and triplet at 2.62 and 1.22 ppm
(C4 and C11), respectively. The signals due to the ortho- and
para-methyl protons of C5 and C12 appeared at 2.25 and
2.14 ppm as singlets, respectively. The aliphatic segments of
the p-cymene ligand showed characteristic signals, that is, a
doublet corresponding to the six protons of the isopropyl
methyl groups at 1.35–1.19 ppm, a multiplet at 3.02–1.63 ppm
due to the CÀH proton and a singlet at 2.29–2.09 ppm caused
by the methyl protons. Similarly, the aromatic protons of the
p-cymene ring appeared as doublets in the ranges 5.83–5.32
Molecular structures
The structures of C1–C4 and C6 (Ru–p-cymene complexes),
and C8 and C14 (Ru–benzene complexes) were determined by
single-crystal XRD analysis. The complexes showed a pseudo-
octahedral geometry around the ruthenium ion with a piano
stool form (Figure 4 and Tables S3 and S4 in the Supporting In-
formation).[22–24] On going from C1 (2.405 Š) to C3 (2.4206 Š),
there was a noticeable increase in the RuÀS bond length,
owing to the distancing of the phenyl group from the thiocar-
bonyl (C=S) moiety. This increase was also observed in the
case of C4 (2.4065 Š), in which electron-donating ethyl groups
are attached at the ortho positions of the terminal phenyl
moiety, from which it can be concluded that the RuÀS bond
becomes weaker in such cases. In contrast, the RuÀS bond was
Figure 4. Crystal structures of the complexes C1–C4, C6, C8 and C14.
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shorter in C6 (2.4025 Š), and still shorter in C14 (2.3875 Š)
compared with their parent complexes C1 and C8 (2.406 Š), re-
spectively, which signifies the strengthening of the bond in the
presence of electron-withdrawing group(s). The RuÀC bond
lengths in the arene rings showed similar trends.
ligand is mostly observed as a localized effect.[21] The ESP of
the ligand exposed enhanced/diminished electronic charge
density on the terminal N to which the substituent was at-
tached. There was no significant effect observed for complexes
C1–C3 and C8–C10. The electron-donating groups in com-
plexes C4, C5, C11 and C12 generated a more negative ESP
within the terminal N-substituted aromatic ring, whereas the
complexes with electron-withdrawing substituents (C6, C7,
C13 and C14) provided a more positive ESP within the ring.
The calculations also showed that the chloride ligands of C6,
C7, C13 and C14 (containing electron-withdrawing substitu-
ents) displayed a less negative ESP than those of C4, C5, C11
and C12 (containing an electron-donating substituent).
It is interesting to note that the RuÀS bond in benzene com-
plex C8 was longer than that in its p-cymene analogue C1.
This may be because the electron-donating groups on p-
cymene reduce its p-accepting ability, which result in longer
RuÀarene and shorter RuÀS bonds (Table 1).
In addition, an increase in the Cl-Ru-Cl angle was observed
upon moving from C1 (87.548) to C3 (87.968), which might be
attributed to the fact that the bulky phenyl group is further
away from the metal center, thereby allowing the chloride li-
gands to assemble freely in space. Further proof for this was
observed in a contrasting manner when the same angle was
lower in C4 (86.958) due to the steric effect of the ethyl groups
present in both of the ortho positions of the phenyl substitu-
ent. Comparing the Cl-Ru-Cl angles of C1 (87.548) and C6
(91.968), and C8 (86.858) and C14 (87.798), the angle showed a
noticeable increase with the electron-withdrawing group(s) at-
tached to the terminal N of C6 and C14, which may be due to
the shortening of the RuÀS bond in these complexes placing
the sulfur atom and chloride ligands in a crowded environ-
ment. The NÀH bond distances (0.88 Š) in all the complexes
were almost the same. All the bond lengths and angles of
these complexes are in good agreement with those of similar
compounds reported in the literature.[17–19]
Anticancer potential
The in vitro anticancer activities of the complexes were evalu-
ated by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-
zolium bromide) assay in five different cancer cell lines (A431-
epidermoid carcinoma, HeLa-cervix, HepG2-liver, IMR-32-neuro-
blastoma and SW40-colorectal cancer; Figure 5) and one
normal cell line (Vero; see Figure S72 in the Supporting Infor-
mation).[31,32]
The IC50 values of the complexes are compiled in Table 2.
The complexes showed highest activity in the human neuro-
blastoma cell line (IMR-32) with the lowest IC50 values deter-
mined for complexes C5 (11.34Æ0.42 mm) and C13 (11.84Æ
0.66 mm). Although the anticancer potential of the complexes
was lower than that of the positive control cisplatin, it was
comparable to or even greater than those of other reported
complexes after an incubation period of just 24 h.[33–36] We
could see that the IC50 values of the complexes mostly de-
creased as the N-substituted phenyl moved away from the fu-
roylthiourea group. Interestingly, for the p-cymene complexes
(C1–C7), electron-donating substituent(s) in the phenyl ring at-
tached to the terminal N lowered the IC50 values of the com-
plexes. In contrast, the electron-withdrawing groups exerted
the same influence in the benzene analogues (C8–C14). The
IC50 values of the complexes in the normal cell line (Vero) were
almost three-fold greater than those observed in the cancer
cell lines, which reveals the selectivity of the complexes.
Owing to their highest activities and contrasting behavior, C5
and C13 were chosen from each set and subjected to further
mechanistic studies.
Table 1. Selected bond lengths in C1–C4, C6, C8 and C14.
Bond lengths [Š]
C1
C2
C3
C4
C6
C8
C14
Ru1ÀCl1
Ru1ÀCl2
Ru1ÀS1
Ru1ÀC13
Ru1ÀC14
Ru1ÀC15
Ru1ÀC16
Ru1ÀC17
Ru1ÀC18
N1ÀH1
2.416
2.431
2.405
2.206
2.203
2.195
2.200
2.185
2.175
0.880
0.880
1.704
1.220
2.418
2.434
2.416
2.189
2.169
2.207
2.169
2.189
2.197
0.880
0.880
1.709
1.225
2.410
2.426
2.420
2.189
2.172
2.187
2.223
2.199
2.162
0.880
0.880
1.709
1.223
2.412
2.439
2.406
2.205
2.177
2.183
2.219
2.188
2.166
0.880
0.880
1.700
1.232
2.403
2.426
2.402
2.189
2.165
2.172
2.212
2.179
2.193
0.880
0.880
1.689
1.218
2.420
2.425
2.406
2.230
2.170
2.173
2.197
2.160
2.183
0.880
0.880
1.713
1.226
2.414
2.408
2.387
2.189
2.183
2.164
2.176
2.173
2.206
0.880
0.880
1.683
1.228
N2ÀH2
S1ÀC1
O1ÀC8
Since the discovery of metal-based anticancer drugs, it has
been of the utmost importance to find the mechanism of op-
eration of these compounds inside the human body.[37–39] Thus,
the mechanistic pathway by which the most active complexes
C5 and C13 cause cell death has been investigated, as detailed
in the following.
Theoretical studies using DFT
The results of density functional theory (DFT) calculations veri-
fied the structures obtained from single-crystal XRD analysis as
well as the diamagnetic character of RuII in the studied com-
plexes (see Figures S69–S71 and Tables S5 and S6 in the Sup-
porting Information).[25–30] The electrostatic potential (ESP) sur-
face diagrams (see Figure S70) revealed that the electron den-
sity is highest on the two chloride ligands, the carbonyl
oxygen and the oxygen of furan.[27,28] The effect of the elec-
tron-donating/withdrawing substituents on the furoylthiourea
Solution behavior of C5 and C13
The solution behavior of C5 and C13 was studied by using UV/
Vis spectrophotometry under a variety of conditions. The UV/
Vis spectra of C5 and C13 at 298 K immediately after dissolu-
tion in water (water/DMSO, 9.9:0.1, v/v; see Figure S74 in the
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Figure 5. Variation in the cell viability [%] of the complexes with change in the N-terminal substituent.
Table 2. IC50 values of the complexes C1–C14 in various cancer and normal cell lines.
Complex
IC50 [mm]
A431
HeLa
HepG2
IMR-32
SW40
Vero
C1
C2
C3
C4
C5
C6
C7
C8
28.5Æ1.2
42.2Æ0.6
43.5Æ0.4
25.1Æ0.5
21.3Æ1.0
50.5Æ0.4
53.8Æ1.6
36.1Æ0.3
39.1Æ1.1
31.3Æ0.7
37.7Æ1.7
33.2Æ1.3
22.6Æ0.7
45.5Æ1.0
9.8Æ0.8
23.3Æ0.8
28.2Æ1.2
26.6Æ1.3
19.2Æ0.6
17.0Æ1.0
31.3Æ0.4
39.0Æ0.9
28.8Æ1.2
29.9Æ0.7
32.2Æ0.1
29.5Æ0.6
27.8Æ0.6
21.8Æ0.7
27.4Æ0.2
6.1Æ0.5
25.5Æ0.1
33.1Æ0.6
31.9Æ0.3
23.3Æ0.5
17.2Æ0.6
34.7Æ1.2
40.1Æ0.2
38.4Æ0.9
28.3Æ1.3
34.6Æ1.5
37.3Æ0.4
35.3Æ0.5
21.7Æ0.6
38.9Æ1.1
7.9Æ0.2
15.0Æ1.0
19.6Æ0.6
15.1Æ0.9
13.9Æ0.9
11.3Æ0.4
18.1Æ0.8
22.3Æ0.1
23.0Æ0.5
20.9Æ0.6
22.2Æ0.9
23.0Æ0.5
17.0Æ0.6
11.8Æ0.7
24.9Æ1.1
5.7Æ0.6
31.4Æ0.1
47.1Æ0.4
54.0Æ1.5
28.2Æ0.7
26.2Æ0.1
52.8Æ1.7
54.9Æ1.3
39.5Æ0.6
56.2Æ1.8
46.4Æ1.0
33.6Æ0.7
38.0Æ1.3
28.8Æ0.4
39.2Æ1.3
7.12Æ0.3
107.2Æ2.3
121.1Æ2.0
119.6Æ3.8
95.9Æ4.0
91.8Æ4.6
121.9Æ3.9
126.3Æ1.7
130.0Æ3.7
112.0Æ2.0
133.3Æ0.4
117.1Æ2.1
134.5Æ1.3
93.8Æ4.1
116.7Æ2.6
16.7Æ1.3
C9
C10
C11
C12
C13
C14
cisplatin
Supporting Information) exhibited a strong absorption band at
around 280 nm that underwent a small hypsochromic shift
while decreasing in intensity over time, concomitant with the
appearance of a new shoulder peak at around 330 nm, the in-
tensity of which increased with time, indicating rapid hydroly-
sis of the complexes, although the exact nature of the hydroly-
sis products was not known until later.[40–42] The hydrolysis pro-
cess seemed to attain equilibrium after 25 min for both com-
plexes.
To investigate the suppression of hydrolysis by chloride ions,
the UV/Vis spectra of C5 and C13 (0.5 mm) were recorded at
298 K in 4 mm NaCl solution. The spectra were essentially the
same as those observed in water, which indicates that a low
chloride concentration did not suppress hydrolysis. However,
the spectra of the complexes dissolved in a higher concentra-
tion of NaCl (100 mm) revealed that the hydrolysis was sup-
pressed (Figure 6). These results indicate that these complexes,
unless metabolized in a different way, for example, by protein
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Figure 6. Time-dependent UV/Vis absorption spectra of C5 and C13 in 4 and 100 mm NaCl at 298 K, recorded at 1 min intervals over a period of 30 min.
binding, may be able to survive the conditions found in the
Table 3. Rate constants and half-lives for the hydrolysis of complexes C5
and C13 in various strengths of NaClO4.
bloodstream, and that hydrolysis may take place inside the
cells in which the chloride concentration decreases to around
4 mm.[41]
[NaClO4] [m] 0.015
0.1
0.25
0.5
C5 kobs [10À3 sÀ1
t1/2,obs [min]
]
]
1.38Æ0.001 1.41Æ0.005 1.35Æ0.002 1.39Æ0.002
The time-dependent absorption spectra (difference spectra)
of C5 and C13 in 100 mm aqueous NaClO4 at 298 K are shown
in Figures S75 and S76 in the Supporting Information. In each
case, the presence of two isosbestic points (C5: 274 and
326 nm; C13: 281 and 324 nm) suggested the hydrolysis of the
chloro complexes. The maximum change in absorption oc-
curred at 285 and 295 nm for C5 and C13, respectively, and
hence these wavelengths were selected for subsequent kinetic
studies.[42] The hydrolysis of C5 and C13 at 298 K in aqueous
NaClO4 (0.015–0.5m) was monitored at the selected wave-
lengths (see Figure S77). In each case, the time-dependent ab-
sorbance followed first-order kinetics; the corresponding rate
constants (kobs) are listed in Table 3. For both complexes, the
rate of hydrolysis was almost independent of ionic strength.
The reverse reaction was too rapid to be studied by UV/Vis
spectrophotometry.
8.4 8.2 8.5 8.3
1.67Æ0.005 1.79Æ0.005 1.63Æ0.006 1.64Æ0.004
6.9 6.5 7.1 7.0
C13 kobs [10À3 sÀ1
t1/2,obs [min]
D2O. The exchangeable protons present in the complexes dis-
appeared immediately after the addition of D2O. Further analy-
1
sis of the H NMR spectra revealed rapid hydrolysis of the com-
plexes, leading to a mixture of compounds with arene loss
(that is, products in which the three coordination sites original-
ly occupied by the arene and chloride ligands were occupied
by solvent molecules). Separate sets of peaks were observed
for the chloride, aqua and arene-loss species (Figure 7). The
loss of the arene was inferred by the presence of resonances
for free p-cymene (dꢀ7.23 ppm (dd)) and benzene (d
ꢀ7.32 ppm (s)) in the aromatic region for C5 and C13, respec-
tively. Almost 85% of the complexes were hydrolyzed within
30 min, and the major hydrolyzed product constituted 75% of
the products. The equilibria appeared to be reached quickly,
The aqueous solution chemistry of C5 and C13 was studied
1
in detail at 298 K over 24 h by H NMR spectroscopy and ESI-
MS spectrometry. Due to the low solubility of the complexes in
water, the NMR studies were conducted in 3:7 (v/v) [D6]DMSO/
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Figure 7. 1H NMR spectra of C5 (bottom) and C13 (top) in 3:7 [D6]DMSO/D2O at 298 K recorded over a period of 24 h. Peak assignments: a, exchangeable pro-
tons of intact chloride complex; b, intact chloride complex; c, predominant hydrolyzed species; d, free arene; *, other aquated/hydrolyzed species.
because the spectra recorded after 12 and 24 h showed insig-
nificant changes in comparison with those recorded after 1 h.
After 24 h, the original complex species accounted for less
than 10% of species, and arene loss of around 7 and 27% was
observed for C5 and C13, respectively (based on peak inte-
grals).[43–46]
ESI-MS analysis of the complexes in 3:7 (v/v) DMSO/H2O
after 24 h revealed the mononuclear [Ru(h6-p-cymene)(L5)(Cl)-
(H2O)]+ to be the major hydrolysis species deriving from C5.
However, the hydrolysis product of C13 was observed to be a
dimer, [{Ru(h6-benzene)}2(L6)(OH)2(H2O)]2+, formed along with
other minor products (see Figures S78 and S79 in the Support-
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ing Information). This might be because benzene as an arene
ligand is known to exhibit a strong trans labilizing effect on
aqua ligands.[44] The rate of hydrolysis of C13 was higher than
that of C5, although the more electron-accepting arene ligand
in the former should lower the hydrolysis rate. However, the
electron-withdrawing CF3 substituent in C13 weakens the
donor ability of the ligand, thereby leading to an increase in
the hydrolysis rate. In summary, the hydrolysis rates are tun-
able within this family of ruthenium–arene complexes, which is
potentially useful in the design of anticancer drugs.[37]
membrane potential (MMP), DNA damage and caspase-3 analy-
ses to further elucidate their mechanism of action on IMR-32
cancer cells.
Bright-field microscopy was preliminarily employed to ex-
plore the micromorphology of the cells in the presence and
absence of the complexes. Cisplatin was employed as a posi-
tive control. The control cells were seen to be healthy, with cell
bodies and dendrites characteristic of neuronal cells. On treat-
ing the IMR-32 cells with IC50 and IC90 concentrations of the
complexes, changes such as the leakage of cellular debris,
damage to the cellular membrane and the formation of apop-
totic bodies were visualized (Figure 8).[19]
Binding with GSH
Cancer cells, which are metabolically altered, have higher
ROS levels than normal cells. Therefore, they tend to reach the
ROS threshold faster and are at a greater risk of undergoing
apoptosis. Hence, a complex that can further promote ROS
production in a cancer cell is probably an excellent drug candi-
date to induce cancer cell death. Keeping this in mind, the
The tripeptide glutathione (g-l-Glu-l-Cys-Gly; GSH) is an abun-
dant (mm) intracellular thiol that is known to cause the detoxi-
fication of heavier transition-metal ions, including several plati-
num and ruthenium anticancer compounds, which have an af-
finity towards sulfur.[47] However, Wang et al. reported a possi-
bly conflicting role of GSH in the mechanism of action of RuII– ROS levels in IMR-32 cells in the presence and absence of the
arene complexes, which may contribute to the lack of cross-re-
sistance for platinum-based therapeutics.[48,49] The interaction
complexes were measured by using the dichlorodihydrofluor-
escein diacetate (DCFH-DA) staining assay (Figure 9).[53–55] Cis-
platin was used as a positive control. An increase in fluores-
cence intensity was observed when the cancer cells were treat-
ed with IC50 and IC90 concentrations of the complexes as com-
pared with the control cells. The fluorescence intensity was
higher with the IC90 concentration for both complexes. Nota-
bly, the complexes showed dose-dependent generation of ROS
(see Figure S81 in the Supporting Information).
1
of complexes C5 and C13 with GSH was studied by H NMR
spectroscopy; the spectra were recorded over a period of 24 h,
after the addition of a known amount of the respective com-
plex in [D6]DMSO to a 10-fold excess concentration of GSH in
D2O (see Figure S80 in the Supporting Information). The experi-
mental conditions were the same as used in the solution sta-
bility studies. The complexes immediately bound to GSH, as in-
dicated by the observed spectral changes in comparison with
the spectrum of free GSH. This could have an important
impact on the biological activity of the RuII–arene com-
plexes.[50] After 12 h, new peaks attributable to the oxidized
product GSSG arose in the spectra of the complexes.[51] Howev-
er, the intensity of these signals was lower in the spectrum of
C5 than in the spectrum of C13. This is perhaps not surprising
because the electron-donating groups attached to furoylth-
iourea decreases its ability to oxidize GSH.[52] On the basis of
these studies, it is plausible that these complexes act as cata-
lysts for the oxidation of GSH to GSSG. This also could explain
why the Ru–p-cymene and Ru–benzene complexes show re-
verse activity on varying the substituents. As benzene is al-
ready a good p-acceptor ligand, the addition of electron-with-
drawing group(s) to the ligand makes the metal ion less elec-
tron-dense, which makes it more susceptible to bind to GSH,
and may reduce the level of GSH/GSSG in the cell, and hence
promote apoptosis. However, the methyl and isopropyl groups
in p-cymene tend to decrease its p-acidic properties, so the
electron-withdrawing substituent in the ligand does not have
much influence. Nevertheless, the presence of electron-donat-
ing groups in the ligand may increase the p-electron cloud of
the planar rings, and subsequently the intercalation and distor-
tion of DNA, leading to apoptosis.
Cell death pathway
Figure 8. Bright-field microscopic images. (A) IMR-32 control cells. Cells treat-
ed with IC50 and IC90 concentrations of (B,C) cisplatin, (D,E) C5 and (F,G) C13,
respectively. The arrows indicate the leakage of cellular debris, damage to
the cellular membrane and the formation of apoptotic bodies.
Complexes C5 and C13 were subjected to bright-field micros-
copy, intracellular reactive oxygen species (ROS), mitochondrial
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crease in the fluorescence intensity was observed. Also, the
fluorescence was lower with the IC90 concentration of the com-
plexes (see Figure S81 in the Supporting Information).
After the loss of MMP, which may have led to the release of
cytochrome c, the next step in the intrinsic apoptosis pathway
would be a cascade of caspases. Cytochrome c is known to ac-
tivate caspase-9 by promoting nucleotide binding to apoptotic
protein activating factor-1 (APAF-1), which in turn leads to the
activation of caspase-3. Hence, caspase-3 analysis was carried
out to prove the overexpression of caspases, which would con-
firm the apoptotic process. We observed a dose-dependent in-
crease in caspase-3 for C5 and C13, which indicates that the
apoptotic process might have occurred in the IMR-32 cancer
cell line.[57] 4’,6-Diamidino-2-phenylindole (DAPI) is a well-
known bright-blue fluorescent, the intensity of which increases
20-fold on binding to double-stranded DNA preferentially at
adenine–thymine (A-T) abundant zones. The fluorescence in-
tensity exhibited by the cells treated with IC50 and IC90 concen-
trations of the complexes was higher than that exhibited by
the control cells, which evidences conclusively that the com-
plexes induced DNA damage and nuclear leakage in the IMR-
32 cancer cells (Figure 11 and Figure S81 in the Supporting In-
formation).[58,59]
Figure 9. DCFH-DA-stained images. (A) IMR-32 control cells. Cells treated
with IC50 and IC90 concentrations of (B,C) cisplatin, (D,E) C5 and (F,G) C13, re-
spectively. *GFP = green fluorescent product.
Having proved that the complexes generate ROS species in
vitro, we next carried out the MMP analysis. A crucial step in
intrinsic apoptosis is the increase in the permeability of the mi-
tochondria, which results in a dramatic loss of its electrical po-
tential, following which cytochrome c may be released.[19,56]
Rhodamine 123 (3,6-diamino-9-[2-(methoxycarbonyl)phenyl]-
xanthylium chloride) is a cationic dye used to measure MMP.
The green fluorescence of rhodamine 123 should decrease
after the addition of a complex, which means that the electri-
cal potential of the mitochondria has reduced. This was ob-
served when the cancer cells were treated with both the com-
plexes and the stain (Figure 10). Again, a dose-dependent de-
Figure 11. DAPI-stained images. (A) IMR-32 control cells. Cells treated with
IC50 and IC90 concentrations of (B,C) cisplatin, (D,E) C5 and (F,G) C13, respec-
tively.
Cell cycle arrest
A cell that undergoes division renews itself in four phases, de-
noted G0-G1, S, G2 and M. The amount of DNA in a cell over
varying periods can be determined by cell cycle analysis. The
IMR-32 cell line was subjected to such analysis for 24 h follow-
ing the addition of complexes C5 and C13 at their IC50 concen-
tration, with cisplatin being used as a positive control.[59]
The cell cycle diagrams depict the progression of the cell
from G0-G1 to the G2-M phase (Figure 12). The percentages of
Figure 10. Rhodamine 123-stained images. (A) IMR-32 control cells. Cells
treated with IC50 and IC90 concentrations of (B,C) cisplatin, (D,E) C5 and
(F,G) C13, respectively.
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Figure 13. Flow cytometric analysis of (A) control cells and cells treated with
the IC50 concentration of (B) cisplatin, (C) C5 and (D) C13.
early apoptosis and viable cells are limited to each quadrant. It
can be seen that cisplatin achieved an apoptosis rate of
10.75% (4.91% of early apoptosis and 5.84% of late apoptosis),
whereas C5 and C13 achieved 10.08% (3.20% of early apopto-
sis and 6.88% of late apoptosis) and 14.17% of apoptosis
(4.78% of early apoptosis and 9.39% of late apoptosis), respec-
tively. Although both complexes gave comparable percentages
of early and late apoptotic cells to those of cisplatin, C13 ex-
hibited better activity than the other two. These results con-
firm that the complexes prompted cancer cell death through
an apoptotic pathway.[59]
Figure 12. Cell cycle analysis of (A) control cells and cells treated with the
IC50 concentration of (B) cisplatin, (C) C5 and (D) C13. (E) Comparison of the
percentages of cell cycle phases of cells treated with the complexes.
Interaction with protein receptors
the G0-G1, S and G2-M phases in the control were found to be
74.86, 18.63 and 6.52%, respectively. When the cells were treat-
ed with the IC50 concentration of the complexes, the percen-
tages decreased for G0-G1 and increased for the S and G2-M
phases with respect to the control. It was observed that the
complexes showed comparable activity to that of cisplatin. No-
tably, the changes in the percentages of cells in the S and G2-
M phases on going from the control to the complexes were
almost two- and four-fold, respectively, which indicates that
the complexes mainly arrest the cell cycle in the latter phases
of the process.
Meggers and co-workers described how the unique shapes of
metal complexes can be exploited for targeting enzymes and
proteins. The RuII–arene complexes are known to exert a
“multi-targeted” approach, that is, not only do they target
DNA, but they also contain vectors to enable them to target
cancer cells selectively and/or moieties that target enzymes,
peptides and intracellular proteins.[60,61] The Pim-1 kinase re-
ceptor has direct involvement in the regulation of cell cycle
progression and apoptosis, and is overexpressed in various
cancers such as prostate cancer, Burkitt’s lymphoma and oral
cancer, in addition to several hematopoietic lymphomas,
whereas its deficiency leads to failure in cell survival and
growth.[62] The principal responder to the vascular endothelial
growth factor signal, which regulates endothelial migration
and proliferation, is vascular endothelial growth factor receptor
2 (VEGFR2).[63] The VEGFR2 receptor has been reported to be
Apoptotic mode of cell death
Cellular apoptosis of C5 and C13 was studied at their IC50 con-
centration, with cisplatin as a positive control. As depicted in
Figure 13, clockwise from top left, dead cells, late apoptosis,
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expressed in carcinomas and lymphomas, in addition to its ex-
pression in endothelial cells and vascular tumors, which makes
it a crucial cell type marker. Hence, these two receptors were
chosen for this study to explore the possible interactions be-
tween complexes C5 and C13 and the receptors. The opti-
mized geometries of complexes C5 and C13 were used to per-
form molecular docking experiments with the Pim-1 kinase
and VEGFR2 receptors (Figure 14).
sites of the receptor. All the interactions of the complexes with
the individual proteins are listed in Table 4. The high binding
energy and presence of electrostatic energy clouds in the
binding sites will lead to structural changes in the receptors,
which inhibit the functions of the proteins.
Conclusions
Fourteen new RuII–p-cymene/benzene complexes C1–C14
have been synthesized and characterized by UV/Vis, FTIR and
NMR spectroscopy as well as by mass spectrometry. The
pseudo-octahedral geometries of the RuII–arene complexes
were confirmed by a single-crystal XRD study, which revealed
that the RuÀS bond weakened as the phenyl ring moved away
from the furoylthiourea core or when there was an electron-
donating group on the terminal N. On the other hand, an elec-
tron-withdrawing group on the terminal N strengthened the
coordination bond. Theoretical calculations revealed that
changes in the N substituent of the furoylthiourea ligand have
a localized effect on the complex system, with minor changes
in the ESPs of the chloride ligands.
All the complexes were screened for their anticancer poten-
tial by means of the MTT assay in five different cancer cell lines
and were found to be highly toxic towards the IMR-32 cell line,
while showing lower toxicity towards a normal cell line. To
study their mechanism of action, complexes C5 and C13 were
subjected to stability studies, and a preliminarily investigation
showed that the complexes underwent rapid hydrolysis. The
reaction followed pseudo-first order kinetics, and the rate for
C13 was found to be higher than that for C5. The dominant
species obtained from the hydrolysis of the former turned out
to be a dinuclear complex, whereas the latter gave a mononu-
clear complex. Complex C13 also proved to be a better cata-
lyst for the oxidation of GSH to GSSG. A series of staining
Figure 14. Molecular docking images for C5 and C13.
The complexes formed hydrogen-bonding interactions with
the surrounding amino acid residues of Pim-1 kinase, as well
as strong electrostatic attractions, namely p–alkyl, p–p and p– assays revealed the presence of ROS species, a reduction in
sulfur interactions, at the binding site. The presence of the
metal ion and high-affinity atoms such as chlorine contributed
to the higher interaction energies of C5. Hydrogen-bonding in-
teractions were also observed with residues of VEGFR2, along
with strong alkyl and p–alkyl interactions at the active binding
the MMP and nuclear damage. Furthermore, the complexes
could arrest the cell cycle. Flow cytometry studies confirmed
the mechanism of cell death to be apoptotic. Interestingly, the
complexes were capable of binding to receptors such as Pim
kinase-1 and VEGFR2, which may help to block their functions.
Table 4. Interactions of C5 and C13 with the receptors Pim-1 kinase and VEGFR2.
Protein
receptor
Hydrogen-bonding interactions
Electrostatic interactions
Binding
Energy
[kcalmolÀ1
]
C5
Pim-1
kinase
Pro87, Met88, Val91, Leu192,
Val90, Trp198, His157, Val91,
Cys158, Cys161
Leu192, Met88, Leu92, Pro81,
Lys94, Val90, Cys161
À10.2
À9.83
À8.91
À9.66
VEGFR2
Thr24, Ser23, Arg927, Ser1098,
Gly1100, Pro1066, Pro1103, Leu1099,
Arg930, Arg27
Ser261, Glu262, Cys263, Leu266,
Trp269, Ala272, Glue283, Thr280,
His287, Ile284
Cys1022, Leu910, Ser882, Met881,
Arg1020, Leu1017, Phe1016, Leu828,
Pro819, His877, Ile890
Lys1060, Ala1101, Pro1066, Leu1027,
Pro1105
C13
Pim-1
kinase
Leu152, Trp146, Phe148, Arg145,
Met290, His25, Leu266, His265,
Trp149
Cys1022, Arg1020, Leu1017, Phe1016,
Leu828, Pro819, His877
VEGFR2
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The study concluded that the anticancer activity of a bifunc-
tional RuII–arene furoylthiourea complex can be tuned by vary-
ing the substituent on the N-terminal moiety.
N-{[3,5-Bis(trifluoromethyl)phenyl]carbamothioyl}furan-2-
carboxamide (L7)
Yield: 86%; m.p. 1618C; colorless; 1H NMR (500 MHz, [D6]DMSO):
d=12.53 (s, 1H; OC-NH), 11.62 (s, 1H; SC-NH), 8.43 (s, 2H; aromat-
ic), 8.10 (s, 1H; aromatic), 7.98 (s, 1H; aromatic), 7.90 (d, J=3.5 Hz,
1H; aromatic), 6.78 ppm (dd, J=3.6, 1.8 Hz, 1H; aromatic);
13C NMR (125 MHz, CDCl3): d=178.4 (C=S), 156.9 (C=O), 146.8,
144.5, 139.1, 132.4, 132.1, 123.8, 119.7, 113.6 (aromatic), 120.0,
120.0, 120.0, 119.9 ppm (CF3); 19F NMR (471 MHz, [D6]DMSO): d=
61.5 ppm; UV/Vis (CHCl3): lmax (e)=286 (24620), 317 nm
(7963 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3271 (m, n(thioamide NÀH)),
3117 (m, n(amide NÀH)), 1677 (s, n(C=O)), 1230 cmÀ1 (s, n(C=S)); el-
emental analysis calcd (%) for C14H8F6N2O2S (382.0210): C 43.99, H
2.11, N 7.33, S 8.39; found: C 43.75, H 2.27, N 7.21, S 8.46.
Experimental Section
Materials and measurements
All the chemicals and solvents were of analytical reagent grade
and used without further purification. Ligands L1–L5 were synthe-
sized according to the previously reported procedure.[19] Elemental
analyses was carried out on a PerkinElmer instrument. UV/Vis spec-
tra were recorded on a Shimadzu UV2600 spectrophotometer. FTIR
spectra were recorded as KBr pellets using a Thermo Scientific
Nicolet iS5 spectrometer. 1H and 13C NMR spectra were recorded
on a Bruker 500 MHz spectrometer. Mass spectra were recorded on
a Thermo Exactive Plus UHPLC-MS spectrometer. A Bruker Quest X-
ray (fixed-Chi geometry) diffractometer was employed for crystal
screening, unit cell determination and data collection. The goniom-
eter was controlled using the APEX3 software suite. Olex2 was em-
ployed for the final data presentation and structure plots.[64–68] All
the other methods related to the kinetic and biological studies are
described in the Supporting Information.
Synthesis of the Ru–p-cymene and Ru–benzene complexes
C1–C14
The metal precursors, namely Ru–p-cymene and Ru–benzene
dimers, required for the preparation of the complexes, were pre-
pared according to the reported procedures.[17–19] To prepare the
complexes, the metal precursor (0.1 mmol, 500–612 mg) was
added to toluene (10 mL) and the mixture stirred for a few min-
utes. A few drops of methanol were then added to promote the
solubility of the precursor.[19] A solution of the ligand (0.2 mmol,
493–765 mg) in toluene (10 mL) was then added dropwise. The re-
sulting mixture was stirred for 4 h to achieve completion of the re-
action, after which it was reduced in volume, and the solid product
was obtained by the addition of hexane. The solid was then fil-
tered and washed with hexane. The complexes were obtained in
good yields of 70–79%.
Deposition Numbers 1986311 (for C1), 1986316 (for C2), 1986315
(for C3), 1986313 (for C4), 1986317 (for C6), 1986310 (for C8), and
1986312 (for C14) contain the supplementary crystallographic data
for this paper. These data are provided free of charge by the joint
Cambridge Crystallographic Data Centre and Fachinformationszen-
trum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
Synthesis of the ligands
[Dichloro(p-cymene){N-(phenylcarbamothioyl)furan-2-car-
boxamide}ruthenium(II)] (C1)
The ligands were synthesized according to the reported procedure
with slight modifications.[15,16,19] Furoyl chloride (1.3052 g, 10 mmol)
was added dropwise to a solution of potassium thiocyanate
(0.971 g, 10 mmol) in acetone (15 mL), and the mixture was heated
at reflux for 1 h. After cooling, a solution of the desired amine
(0.931–2.29 g, 10 mmol; aniline (L1), benzylamine (L2), 2-phenyl-
ethanamine (L3), 2,6-diethylaniline (L4), 2,4,6-trimethylaniline (L5),
4-(trifluoromethyl)aniline (L6) or 3,5-bis(trifluoromethyl)aniline (L7))
in acetone (10 mL) was added dropwise to the mixture, which was
stirred at room temperature for 3 h. The resulting solution was
poured into 1N HCl to neutralize any excess amine, and the solid
product was filtered and washed with water to remove any traces
of KCl. All the ligands were obtained in good yields of 80–90%.
L1 (49 mg, 0.2 mmol) and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol)
were used. Yield: 75%; m.p. 1808C; orange; 1H NMR (500 MHz,
[D6]DMSO): d=12.36 (s, 1H; OC-NH), 11.28 (s, 1H; SC-NH), 8.08 (d,
J=1.0 Hz, 1H; aromatic), 7.86 (d, J=3.5 Hz, 1H; aromatic), 7.67 (d,
J=7.8 Hz, 2H; aromatic), 7.42 (q, J=7.9 Hz, 2H; aromatic), 7.27 (t,
J=7.4 Hz, 1H; aromatic), 6.77 (dd, J=3.6, 1.7 Hz, 1H; aromatic),
5.82 (d, J=6.3 Hz, 2H; aromatic-H of p-cymene), 5.78 (d, J=6.3 Hz,
2H; aromatic-H of p-cymene), 2.86–2.81 (m, 1H; CH(CH3)2 of p-
cymene), 2.09 (s, 3H; C-CH3 of p-cymene), 1.19 ppm (d, J=6.9 Hz,
6H; CH(CH3)2 of p-cymene); 13C NMR (125 MHz, [D6]DMSO): d=
179.1 (C=S), 158.0 (C=O), 148.9, 145.1, 138.4, 129.1, 126.8, 124.8,
119.1, 113.1 (aromatic), 106.8, 100.5, 86.8, 85.9 (aromatic-C of p-
cymene), 30.4, 21.9, 18.3 ppm (aliphatic-C of p-cymene); UV/Vis
N-{[4-(Trifluoromethyl)phenyl]carbamothioyl}furan-2-carbox-
amide (L6)
(CHCl3):
lmax
(e)=288
(22580),
366
(6082),
433 nm
(1290 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3232 (m, n(thioamide NÀH)),
3171 (m, n(amide NÀH)), 1678 (s, n(C=O)), 1178 cmÀ1 (s, n(C=S)); MS
(ESI): m/z calcd for [C22H23N2O2RuS]+: 481.0524 [M À 2H+ À 2ClÀ
Yield: 82%; m.p. 1358C; colorless; 1H NMR (500 MHz, [D6]DMSO):
d=12.50 (s, 1H; OC-NH), 11.45 (s, 1H; SC-NH), 8.10 (s, 1H; aromat-
ic), 7.95 (d, J=8.3 Hz, 2H; aromatic), 7.88 (d, J=3.0 Hz, 1H; aro-
matic), 7.79 (d, J=8.4 Hz, 2H; aromatic), 6.78 ppm (dd, J=3.5,
1.7 Hz, 1H; aromatic); 13C NMR (125 MHz, [D6]DMSO): d=179.5 (C=
S), 157.9 (C=O), 149.0, 145.1, 142.1, 126.8, 125.1, 123.5, 119.3, 113.2
(aromatic), 126.3, 126.3, 126.2, 126.2 ppm (CF3); 19F NMR (471 MHz,
[D6]DMSO): d=60.7 ppm; UV/Vis (CHCl3): lmax (e)=285 (20094),
310 nm (8333 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3240 (m, n(thioamide
NÀH)), 3027 (m, n(amide NÀH)), 1672 (s, n(C=O)), 1230 cmÀ1 (s,
n(C=S)); elemental analysis calcd (%) for C13H9F3N2O2S (314.0336): C
49.68, H 2.89, N 8.91, S 10.20; found: C 49.81, H 2.74, N 8.99, S
10.32.
+
H+]+; found: 481.0538; elemental analysis calcd (%) for
C22H24Cl2N2O2RuS: C 47.83, H 4.38, N 5.07, S 5.80; found: C 47.98, H
4.51, N 5.21, S 5.61.
[Dichloro(p-cymene){N-(benzylcarbamothioyl)furan-2-carbox-
amide}ruthenium(II)] (C2)
L2 (52 mg, 0.2 mmol) and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol)
were used. Yield: 72%; m.p. 1968C; orange; 1H NMR (500 MHz,
CDCl3): d=11.23 (s, 1H; OC-NH), 10.86 (s, 1H; SC-NH), 7.93 (d, J=
3.4 Hz, 1H; aromatic), 7.60 (s, 1H; aromatic), 7.41–7.32 (m, 5H; aro-
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matic), 6.51–6.48 (m, 1H; aromatic), 5.47 (d, J=5.7 Hz, 2H; aromat-
ic-H of p-cymene), 5.30 (d, J=5.7 Hz, 2H; aromatic-H of p-cymene),
4.86 (d, J=5.0 Hz, 2H; CH2), 3.06–2.96 (m, 1H; CH(CH3)2 of p-
cymene), 2.29 (s, 3H; C-CH3 of p-cymene), 1.34 ppm (d, J=6.9 Hz,
6H; CH(CH3)2 of p-cymene); 13C NMR (125 MHz, CDCl3): d=179.2
(C=S), 158.7 (C=O), 147.8, 144.6, 134.9, 129.0, 128.3, 127.8, 121.5,
112.6 (aromatic), 103.5, 100.0, 84.2, 82.6 (aromatic-C of p-cymene),
49.5 (CH2), 30.4, 22.2, 18.4 ppm (aliphatic-C of p-cymene); UV/Vis
[Dichloro(p-cymene){N-(mesitylcarbamothioyl)furan-2-car-
boxamide}ruthenium(II)] (C5)
L5 (57 mg, 0.2 mmol) and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol)
were used. Yield: 76%; m.p. 1978C; orange; 1H NMR (500 MHz,
[D6]DMSO): d=11.60 (s, 1H; OC-NH), 11.30 (s, 1H; SC-NH), 8.07 (d,
J=1.5 Hz, 1H; aromatic), 7.86 (d, J=3.6 Hz, 1H; aromatic), 6.93 (s,
2H; aromatic), 6.77 (dd, J=3.6, 1.7 Hz, 1H; aromatic), 5.82 (d, J=
6.3 Hz, 2H; aromatic-H of p-cymene), 5.78 (d, J=6.3 Hz, 2H; aro-
matic-H of p-cymene), 2.90–2.76 (m, 1H; CH(CH3)2 of p-cymene),
2.25 (s, 3H; C-CH3 of p-cymene), 2.14 (s, 6H; o-CH3), 2.09 ppm (s,
3H; p-CH3), 1.20 ppm (d, J=6.9 Hz, 6H; CH(CH3)2 of p-cymene);
13C NMR (125 MHz, [D6]DMSO): d=180.4 (C=S), 157.9 (C=O), 148.8,
145.2, 137.0, 135.1, 134.1, 129.3, 118.9, 113.1 (aromatic), 106.8,
100.5, 86.8, 85.9 (aromatic-C of p-cymene), 30.4, 21.9, 18.2 (aliphat-
ic-C of p-cymene), 21.0, 18.3 ppm (o,p-CH3); UV/Vis (CHCl3): lmax
(e)=285 (15823), 346 (7685), 433 nm (1062 dm3 molÀ1 cmÀ1); FTIR
(KBr): n=3226 (m, n(thioamide NÀH)), 3115 (m, n(amide NÀH)),
1671 (s, n(C=O)), 1184 cmÀ1 (s, n(C=S)); MS (ESI): m/z calcd for
(CHCl3):
lmax
(e)=282
(16383),
323
(4874),
429 nm
(1062 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3244 (m, n(thioamide NÀH)),
3179 (m, n(amide NÀH)), 1679 (s, n(C=O)), 1202 cmÀ1 (s, n(C=S));
MS (ESI): m/z calcd for [C23H25N2O2RuS]+: 495.0680 [MÀ2H+
À2ClÀ+H+]+; found: 495.0656; elemental analysis calcd (%) for
C23H26Cl2N2O2RuS: C 48.76, H 4.63, N 4.95, S 5.66; found: C 48.59, H
4.80, N 4.81, S 5.73.
[Dichloro(p-cymene){N-(phenethylcarbamothioyl)furan-2-car-
boxamide}ruthenium(II)] (C3)
[C25H29N2O2RuS]+:
523.1011; elemental analysis calcd (%) for C25H30Cl2N2O2RuS: C
50.50, H 5.09, N 4.71, S 5.39; found: C 50.67, H 5.24, N 4.54, S 5.51.
523.0993
[MÀ2H+À2ClÀ+H+]+;
found:
L3 (54 mg, 0.2 mmol) and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol)
were used. Yield: 71%; m.p. 1848C; orange; 1H NMR (500 MHz,
CDCl3): d=10.97 (s, 1H; OC-NH), 10.74 (s, 1H; SC-NH), 7.92 (d, J=
3.2 Hz, 1H; aromatic), 7.60 (s, 1H; aromatic), 7.36 (t, J=7.3 Hz, 2H;
aromatic), 7.26 (d, J=7.6 Hz, 3H; aromatic), 6.49 (dd, J=2.7, 1.1 Hz,
1H; aromatic), 5.46 (d, J=4.2 Hz, 2H; aromatic-H of p-cymene),
5.29 (d, J=3.6 Hz, 2H; aromatic-H of p-cymene), 3.92 (dd, J=12.6,
7.6 Hz, 2H; HN-CH2CH2), 3.03 (t, J=7.4 Hz, 2H; HN-CH2CH2), 2.29 (s,
3H; C-CH3 of p-cymene), 1.77–1.53 (m, 1H; CH(CH3)2 of p-cymene),
1.35 ppm (d, J=6.4 Hz, 6H; CH(CH3)2 of p-cymene); 13C NMR
(125 MHz, CDCl3): d=179.0 (C=S), 158.6 (C=O), 147.7, 144.6, 137.4,
128.9, 128.7, 127.0, 121.4, 112.6 (aromatic), 103.4, 99.9, 84.2, 82.6
(aromatic-C of p-cymene), 46.9, 34.4 (CH2CH2), 30.4, 22.2, 18.3 ppm
(aliphatic-C of p-cymene); UV/Vis (CHCl3): lmax (e)=282 (21313),
326 (6332), 428 nm (1351 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3218 (m,
n(thioamide NÀH)), 3169 (m, n(amide NÀH)), 1668 (s, n(C=O)),
1197 cmÀ1 (s, n(C=S)); MS (ESI): m/z calcd for [C24H27N2O2RuS]+:
509.0836 [MÀ2H+À2ClÀ+H+]+; found: 509.0740; elemental analy-
sis calcd (%) for C24H28Cl2N2O2RuS: C 49.52, H 4.95, N 4.77, S 5.46;
found: C 49.66, H 4.83, N 4.92, S 5.60.
[Dichloro(p-cymene){N-({4-(trifluoromethyl)phenyl}carbamo-
thioyl)furan-2-carboxamide}ruthenium(II)] (C6)
L6 (62 mg, 0.2 mmol) and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol)
were used. Yield: 79%; m.p. 1818C; orange; 1H NMR (500 MHz,
[D6]DMSO): d=12.50 (s, 1H; OC-NH), 11.46 (s, 1H; SC-NH), 8.10 (s,
1H; aromatic), 7.95 (d, J=8.3 Hz, 2H; aromatic), 7.88 (d, J=3.5 Hz,
1H; aromatic), 7.79 (d, J=8.3 Hz, 2H; aromatic), 6.78 (dd, J=3.9,
1.8 Hz, 1H; aromatic), 5.82 (d, J=6.2 Hz, 2H; aromatic-H of p-
cymene), 5.78 (d, J=6.1 Hz, 2H; aromatic-H of p-cymene), 2.89–
2.78 (m, 1H; CH(CH3)2 of p-cymene), 2.09 (s, 3H; C-CH3 of p-
cymene), 1.20 ppm (d, J=6.9 Hz, 6H; CH(CH3)2 of p-cymene);
13C NMR (125 MHz, [D6]DMSO): d=179.5 (C=S), 157.9 (C=O), 149.0,
145.1, 142.1, 126.8, 125.1, 123.4, 119.3, 113.1 (aromatic), 126.3,
126.2, 126.2, 126.2 (CF3), 106.8, 100.5, 86.8, 85.9 (aromatic-C of p-
cymene), 30.4, 21.9, 18.3 ppm (aliphatic-C of p-cymene); 19F NMR
(471 MHz, [D6]DMSO): d=60.7 ppm; UV/Vis (CHCl3): lmax (e)=291
(15780), 359 (3561), 428 nm (849 dm3 molÀ1 cmÀ1); FTIR (KBr): n=
3149 (m, n(thioamide NÀH)), 3031 (m, n(amide NÀH)), 1678 (s, n(C=
O)), 1172 cmÀ1 (s, n(C=S)); MS (ESI): m/z calcd for
[C23H22F3N2O2RuS]+: 549.0397 [MÀ2H+À2ClÀ+H+]+; found:
549.0314; elemental analysis calcd (%) for C23H23Cl2F3N2O2RuS: C
44.52, H 3.74, N 4.51, S 5.17; found: C 44.69, H 3.90, N 4.37, S 5.34.
[Dichloro(p-cymene)(N-{(2,6-diethylphenyl)carbamothioyl}-
furan-2-carboxamide)ruthenium(II)] (C4)
L4 (60 mg, 0.2 mmol) and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol)
were used. Yield: 72%; m.p. 2108C; orange; 1H NMR (500 MHz,
CDCl3): d=12.08 (s, 1H; OC-NH), 11.17 (s, 1H; SC-NH), 8.05 (d, J=
4.2 Hz, 1H; aromatic), 7.65 (s, 1H; aromatic), 7.36 (t, J=8.1 Hz, 1H;
aromatic), 7.21 (d, J=8.3 Hz, 2H; aromatic), 6.54 (dd, J=3.8, 1.5 Hz,
1H; aromatic), 5.32 (d, J=6.5 Hz, 2H; aromatic-H of p-cymene),
5.21 (d, J=6.5 Hz, 2H; aromatic-H of p-cymene), 2.89–2.79 (m, 1H;
CH(CH3)2 of p-cymene), 2.67–2.58 (m, 4H; CH2CH3), 2.21 (s, 3H; C-
CH3 of p-cymene), 1.25–1.19 ppm (m, 12H; CH(CH3)2 of p-cymene,
CH2CH3); 13C NMR (125 MHz, CDCl3): d=181.5 (C=S), 159.0 (C=O),
147.9, 144.7, 141.3, 133.32, 129.1, 126.6, 121.9, 112.7 (aromatic),
103.0, 99.8, 83.8, 82.8 (aromatic-C of p-cymene), 24.7, 14.3
(CH2CH3), 30.2, 22.0, 18.2 ppm (aliphatic-C of p-cymene); UV/Vis
[Dichloro(p-cymene){N-({3,5-bis(trifluoromethyl)phenyl}car-
bamothioyl)furan-2-carboxamide}ruthenium(II)] (C7)
L7 (76 mg, 0.2 mmol) and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol)
were used. Yield: 77%; m.p. 1858C; orange; 1H NMR (500 MHz,
[D6]DMSO): d=12.51 (s, 1H; OC-NH), 11.64 (s, 1H; SC-NH), 8.43 (s,
2H; aromatic), 8.11 (d, J=0.9 Hz, 1H; aromatic), 8.01 (s, 1H; aro-
matic), 7.90 (d, J=3.5 Hz, 1H; aromatic), 6.79 (dd, J=3.6, 1.6 Hz,
1H; aromatic), 5.83 (d, J=6.2 Hz, 2H; aromatic-H of p-cymene),
5.79 (d, J=6.2 Hz, 2H; aromatic-H of p-cymene), 2.89–2.79 (m, 1H;
CH(CH3)2 of p-cymene), 2.09 (s, 3H; C-CH3 of p-cymene), 1.20 ppm
(d, J=6.9 Hz, 6H; CH(CH3)2 of p-cymene); 13C NMR (125 MHz,
[D6]DMSO): d=180.4 (C=S), 157.7 (C=O), 149.2, 145.0, 140.6, 130.9,
130.6, 124.6, 119.4, 113.2 (aromatic), 120.0, 119.9 (CF3), 106.8, 100.5,
86.8, 85.9 (aromatic-C of p-cymene), 30.4, 21.9, 18.3 ppm (aliphatic-
C of p-cymene); 19F NMR (471 MHz, [D6]DMSO): d= 61.4 ppm; UV/
Vis (CHCl3): lmax (e)=292 (19260), 364 (4260), 429 nm
(CHCl3):
lmax
(e)=283
(17553),
342
(4645),
428 nm
(1099 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3215 (m, n(thioamide NÀH)),
3129 (m, n(amide NÀH)), 1664 (s, n(C=O)), 1168 cmÀ1 (s, n(C=S)); MS
(ESI): m/z calcd for [C26H31N2O2RuS]+: 537.1149 [MÀ2H+À2ClÀ+H+
]+; found: 537.1052; elemental analysis calcd (%) for
C26H32Cl2N2O2RuS: C 51.31, H 5.30, N 4.60, S 5.27; found: C 51.45, H
5.18, N 4.72, S 5.45.
Chem. Eur. J. 2021, 27, 7418 –7433
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Chemistry—A European Journal
(985 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3228 (m, n(thioamide NÀH)),
3118 (m, n(amide NÀH)), 1683 (s, n(C=O)), 1180 cmÀ1 (s, n(C=S)); MS
(ESI): m/z calcd for [C24H21F6N2O2RuS]+: 617.0271 [MÀ2H+
À2ClÀ+H+]+; found: 617.0297; elemental analysis calcd (%) for
C24H22Cl2F6N2O2RuS: C 41.87, H 3.22, N 4.07, S 4.66; found: C 41.68,
H 3.41, N 4.20, S 4.85.
H+]+; found: 453.0150; elemental analysis calcd (%) for
C20H20Cl2N2O2RuS: C 45.81, H 3.84, N 5.34, S 6.11; found: C 45.69, H
3.97, N 5.23, S 6.26.
[Dichloro(benzene)(N-{(2,6-diethylphenyl)carbamothioyl}fu-
ran-2-carboxamide)ruthenium(II)] (C11)
[Dichloro(benzene){N-(phenylcarbamothioyl)furan-2-carbox-
amide}ruthenium(II)] (C8)
L4 (60 mg, 0.2 mmol) and [RuCl2(benzene)]2 (50 mg, 0.1 mmol)
were used. Yield: 73%; m.p. 2208C; orange; 1H NMR (500 MHz,
CDCl3): d=12.13 (s, 1H; OC-NH), 11.12 (s, 1H; SC-NH), 7.98 (d, J=
3.4 Hz, 1H; aromatic), 7.66 (s, 1H; aromatic), 7.37 (t, J=7.5 Hz, 1H;
aromatic), 7.22 (d, J=7.6 Hz, 2H; aromatic), 6.54 (dd, J=3.6, 1.3 Hz,
1H; aromatic), 5.62 (s, 6H; aromatic-H of benzene), 2.66–2.59 (m,
4H; CH2CH3), 1.22 ppm (t, J=7.5 Hz, 6H; CH2CH3); 13C NMR
(125 MHz, CDCl3): d=181.1 (C=S), 159.0 (C=O), 148.1, 144.6, 141.2,
133.0, 129.3, 126.7, 122.0, 112.8 (aromatic), 85.3 (aromatic-C of ben-
zene), 24.8, 14.4 ppm (CH2CH3); UV/Vis (CHCl3): lmax (e)=284
(18996), 322 (5501), 428 nm (1003 dm3 molÀ1 cmÀ1); FTIR (KBr): n=
3204 (m, n(thioamide NÀH)), 3136 (m, n(amide NÀH)), 1671 (s, n(C=
O)), 1166 cmÀ1 (s, n(C=S)); MS (ESI): m/z calcd for [C22H23N2O2RuS]+:
481.0524 [MÀ2H+À2ClÀ+H+]+; found: 481.0395; elemental analy-
sis calcd (%) for C22H24Cl2N2O2RuS: C 47.83, H 4.38, N 5.07, S 5.80;
found: C 47.99, H 4.21, N 5.19, S 5.61.
L1 (49 mg, 0.2 mmol) and [RuCl2(benzene)]2 (50 mg, 0.1 mmol)
were used. Yield: 74%; m.p. 2508C; orange; 1H NMR (500 MHz,
[D6]DMSO): d=12.34 (s, 1H; OC-NH), 11.27 (s, 1H; SC-NH), 8.07 (d,
J=1.0 Hz, 1H; aromatic), 7.85 (d, J=3.6 Hz, 1H; aromatic), 7.65 (d,
J=8.9 Hz, 2H; aromatic), 7.41 (t, J=8.1 Hz, 2H; aromatic), 7.26 (t,
J=7.6 Hz, 1H; aromatic), 6.75 (dd, J=3.8, 1.8 Hz, 1H; aromatic),
5.96 ppm (s, 6H; aromatic-H of benzene); 13C NMR (125 MHz,
[D6]DMSO): d=179.1 (C=S), 158.0 (C=O), 148.9, 145.1, 138.4, 129.1,
126.8, 124.8, 119.1, 113.1 (aromatic), 88.1 ppm (aromatic-C of ben-
zene); UV/Vis (CHCl3): lmax (e)=289 (25888), 362 (6380), 424 nm
(1500 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3229 (m, n(thioamide NÀH)),
3159 (m, n(amide NÀH)), 1672 (s, n(C=O)), 1182 cmÀ1 (s, n(C=S)); MS
(ESI): m/z calcd for [C18H15N2O2RuS]+: 424.9898 [M À 2H+ À 2ClÀ
+
H+]+; found: 424.9902; elemental analysis calcd (%) for
C18H16Cl2N2O2RuS: C 43.56, H 3.25, N 5.64, S 6.46; found: C 43.71, H
3.04, N 5.42, S 6.64.
[Dichloro(benzene){N-(mesitylcarbamothioyl)furan-2-carbox-
amide}ruthenium(II)] (C12)
[Dichloro(benzene){N-(benzylcarbamothioyl)furan-2-carbox-
L5 (57 mg, 0.2 mmol) and [RuCl2(benzene)]2 (50 mg, 0.1 mmol)
were used. Yield: 76%; m.p. 2488C; orange; 1H NMR (500 MHz,
[D6]DMSO): d=11.60 (s, 1H; OC-NH), 11.33 (s, 1H; SC-NH), 8.08 (s,
1H; aromatic), 7.87 (d, J=3.8 Hz, 1H; aromatic), 6.93 (s, 2H; aro-
matic), 6.77 (dd, J=3.6, 1.6 Hz, 1H; aromatic), 5.97 (s, 6H; aromat-
ic-H of benzene), 2.25 (s, 3H; p-CH3), 2.1 ppm (s, 6H; o-CH3);
13C NMR (125 MHz, [D6]DMSO): d=180.4 (C=S), 157.9 (C=O), 148.8,
145.2, 137.0, 135.1, 134.1, 128.9, 118.9, 113.1 (aromatic), 88.1 (aro-
matic-C of benzene), 21.0, 18.2 ppm (o,p-CH3); UV/Vis (CHCl3): lmax
(e)=283 (21285), 326 (6666), 424 nm (1095 dm3 molÀ1 cmÀ1); FTIR
(KBr): n=3227 (m, n(thioamide NÀH)), 3143 (m, n(amide NÀH)),
1676 (s, n(C=O)), 1185 cmÀ1 (s, n(C=S)); MS (ESI): m/z calcd for
amide}ruthenium(II)] (C9)
L2 (52 mg, 0.2 mmol) and [RuCl2(benzene)]2 (50 mg, 0.1 mmol)
were used. Yield: 70%; m.p. 2428C; orange; 1H NMR (500 MHz,
CDCl3): d=11.06 (s, 1H; OC-NH), 10.93 (s, 1H; SC-NH), 7.97 (d, J=
1.6 Hz, 1H; aromatic), 7.73 (d, J=3.5 Hz, 1H; aromatic), 7.30 (s, 2H;
aromatic), 7.29 (d, J=3.3 Hz, 2H; aromatic), 7.22 (dt, J=8.2, 4.1 Hz,
1H; aromatic-H), 6.66 (dd, J=3.4, 1.5 Hz, 1H; aromatic), 5.90 (s, 6H;
aromatic-H of benzene), 4.79 ppm (d, J=5.7 Hz, 2H; CH2); 13C NMR
(125 MHz, CDCl3): d=185.3 (C=S), 162.6 (C=O), 149.9, 142.1, 133.5,
132.6, 132.4, 123.4, 123.3, 117.6 (aromatic), 92.8 (aromatic-C of ben-
zene), 53.5 ppm (CH2); UV/Vis (CHCl3): lmax (e)=284 (18403), 321
(6525), 425 nm (985 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3222 (m,
n(thioamide NÀH)), 3131 (m, n(amide NÀH)), 1675 (s, n(C=O)),
1201 cmÀ1 (s, n(C=S)); MS (ESI): m/z calcd for [C19H17N2O2RuS]+:
439.0054 [MÀ2H+À2ClÀ+H+]+; found: 439.0264; elemental analy-
sis calcd (%) for C19H18Cl2N2O2RuS: C 44.71, H 3.55, N 5.49, S 6.28;
found: C 44.53, H 3.70, N 5.65, S 6.10.
[C21H21N2O2RuS]+:
467.0367
[MÀ2H+À2ClÀ+H+]+;
found:
467.0283; elemental analysis calcd (%) for C21H22Cl2N2O2RuS: C
46.84, H 4.12, N 5.20, S 5.95; found: C 46.67, H 4.29, N 5.35, S 5.72.
[Dichloro(benzene){N-({4-(trifluoromethyl)phenyl}carbamo-
thioyl)furan-2-carboxamide}ruthenium(II)] (C13)
[Dichloro(benzene){N-(phenethylcarbamothioyl)furan-2-car-
L6 (62 mg, 0.2 mmol) and [RuCl2(benzene)]2 (50 mg, 0.1 mmol)
were used. Yield: 77%; m.p. 2418C; orange; 1H NMR (500 MHz,
[D6]DMSO): d=12.50 (s, 1H; OC-NH), 11.46 (s, 1H; SC-NH), 8.10 (s,
1H; aromatic), 7.95 (d, J=8.3 Hz, 2H; aromatic), 7.88 (d, J=3.5 Hz,
1H; aromatic), 7.79 (d, J=8.4 Hz, 2H; aromatic), 6.78 (dd, J=3.6,
1.7 Hz, 1H; aromatic), 5.98 ppm (s, 6H; aromatic-H of benzene);
13C NMR (125 MHz, [D6]DMSO): d=179.5 (C=S), 157.9 (C=O), 149.0,
145.1, 142.1, 128.7, 126.2, 126.2, 126.2, 126.2 (CF3), 125.1, 123.4,
119.3, 113.1 (aromatic), 88.1 ppm (aromatic-C of benzene); 19F NMR
(471 MHz, [D6]DMSO): d=60.5 ppm; UV/Vis (CHCl3): lmax (e)=292
(15326), 344 (4477), 426 nm (882 dm3 molÀ1 cmÀ1); FTIR (KBr): n=
3149 (m, n(thioamide NÀH)), 3031 (m, n(amide NÀH)), 1678 (s, n(C=
O)), 1172 cmÀ1 (s, n(C=S)); MS (ESI): m/z calcd for
[C19H14F3N2O2RuS]+: 492.9771 [MÀ2H+À2ClÀ+H+]+; found:
492.9701; elemental analysis calcd (%) for C19H15Cl2F3N2O2RuS: C
40.44, H 2.68, N 4.96, S 5.68; found: C 40.62, H 2.51, N 4.77, S 5.85.
boxamide}ruthenium(II)] (C10)
L3 (54 mg, 0.2 mmol) and [RuCl2(benzene)]2 (50 mg, 0.1 mmol)
were used. Yield: 71%; m.p. 2388C; orange; 1H NMR (500 MHz,
CDCl3): d=10.99 (s, 1H; OC-NH), 10.67 (s, 1H; SC-NH), 7.86 (d, J=
4.2 Hz, 1H; aromatic), 7.62 (s, 1H; aromatic), 7.36 (dd, J=8.8,
5.7 Hz, 2H; aromatic), 7.30–7.24 (m, 4H; aromatic), 6.50 (dd, J=3.9,
1.3 Hz, 1H; aromatic), 5.73 (s, 6H; aromatic-H of benzene), 3.94
(dd, J=12.6, 6.9 Hz, 2H; HN-CH2CH2), 3.03 ppm (t, J=7.1 Hz, 2H;
HN-CH2CH2); 13C NMR (125 MHz, CDCl3): d=178.8 (C=S), 158.5 (C=
O), 147.8, 144.5, 137.3, 128.9, 128.7, 127.1, 121.4, 112.7 (aromatic),
85.5 (aromatic-C of benzene), 47.0, 34.4 ppm (CH2CH2); UV/Vis
(CHCl3):
lmax
(e)=284
(15191),
322
(6510),
430 nm
(936 dm3 molÀ1 cmÀ1); FTIR (KBr): n=3229 (m, n(thioamide NÀH)),
3184 (m, n(amide NÀH)), 1675 (s, n(C=O)), 1194 cmÀ1 (s, n(C=S)); MS
(ESI): m/z calcd for [C20H19N2O2RuS]+: 453.0211 [M À 2H+ À 2ClÀ
+
Chem. Eur. J. 2021, 27, 7418 –7433
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doi.org/10.1002/chem.202004954
Chemistry—A European Journal
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S.S. thanks the Department of Science and Technology, Ministry
of Science and Technology, Government of India, for a doctoral
fellowship under the DST-INSPIRE (IF160449) programme. R.K.
gratefully acknowledges SERB (EMR/2016/003215) for financial
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Keywords: antitumor agents · apoptosis · biological activity ·
ligand effects · ruthenium arene
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Manuscript received: November 14, 2020
Revised manuscript received: December 21, 2020
Accepted manuscript online: January 6, 2021
Version of record online: March 12, 2021
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