Article
analytically pure compounds. The ligands and complexes synthesized
were dried in a vacuum and stored in a desiccator in the dark.
Syntheses. Synthesis of 4-(2-(Pyridin-2-ylmethyleneamino)-
ethyl)phenol (L1). To a stirred solution of tyramine monohydro-
chloride (0.2 g, 1.15 mmol) in MeOH, LiOH (0.04 g, 1.15 mmol) was
added. The mixture was allowed to stir for 1 h and placed under ice.
Pyridine-2-carbaldehyde (0.123 g, 1.15 mmol) was added dropwise to
the above solution over a period of 15 min. The resulting solution was
allowed to stir at room temperature for 12 h. The solvent was
evaporated under reduced pressure, and the obtained crude product
was washed two times with petroleum ether, yielding a yellowish-white
1
solid. Yield: 85%. H NMR (500 MHz, DMSO-d ): δ 9.17 (s, 1H,
6
−
OH), 8.61 (d, 1H, J = 4.45 Hz, Py-H), 8.22 (s, 1H, −CHN), 7.94
d, 1H, J = 7.85 Hz, Py-H), 7.88 (t, 1H, J = 7.62 Hz, Py-H), 7.46 (t, 1H, J
6.1 Hz, Py-H), 7.03 (d, 2H, J = 8.3 Hz, Ar−H), 6.66 (d, 2H, J = 8.3
Hz, Ar−H), 3.82 (t, 2H, J = 7.17 Hz, −CH ), 2.83 (t, 2H, J = 7.27 Hz,
(
=
1
3
−
CH ) (Supporting Information, Figure S1). C NMR (125 MHz,
2
DMSO-d , 25 °C): δ 161.9, 155.9, 154.2, 149.4, 137.0, 129.6, 125.1,
6
120.5, 115.5, 115.2, 62.3, 35.9 (Supporting Information, Figure S2).
Synthesis of 2-(((4-Hydroxyphenethyl)imino)methyl)phenol (L2).
To a stirred solution of tyramine monohydrochloride (0.2 g, 1.15
mmol) in MeOH, LiOH (0.04 g, 1.15 mmol) was added. The mixture
was allowed to stir for 1 h. Salicylaldehyde (0.140 g, 1.15 mmol) was
added dropwise to the above solution and allowed to stir at rt for 12 h.
The solvent was evaporated under reduced pressure, and the obtained
Figure 1. Representation of RuIII (NKP-1339 and NAMI-A),
II
organometallic half-sandwich Ru (RM-175, RAPTA-C, and RAPTA-
II
T), and polypyridyl Ru (TLD1433) anticancer agents, along with the
II
p-cymene based Ru complexes studied in this work.
crude was washed repeatedly with petroleum ether, yielding a bright
1
yellow solid. Yield: 83%. H NMR (500 MHz, DMSO-d ): δ 13.53 (s,
6
II
Co complexes of similar ligands have displayed electrochemical
1H, Sal−OH), 9.24 (s, 1H, Ar−OH), 8.45 (s, 1H, −CHN), 7.38 (d,
1H, J = 9.3 Hz, Sal-H), 7.32 (t, 1H, J = 10.1 Hz, Sal-H), 7.03 (d, 2H, J =
10.35 Hz, Ar−H), 6.87 (t, 2H, J = 9.15 Hz, Sal-H), 6.68 (d, 2H, J = 10.4
61
hydrogen evolution at pH < 4. Hence, the ligands used are
known for their activity against various proteins depending on
the metal ions used. The work presented here involves Ru (p-
II
Hz, Ar−H), 3.79 (t, 2H, J = 8.62 Hz, −CH ), 2.84 (t, 2H, J = 8.72 Hz,
1
3
−
CH ) (Supporting Information, Figure S3). C NMR (125 MHz,
cymene) complexes (1−4) of tyramine based Schiff bases with
pyridine-2-carbaldehyde and salicylaldehyde (L1, L2) leading to
variation in the coordination from N,N to N,O. In addition the
kinetic stability was also altered with variation of the halide (X =
Cl, I) and the aldehyde. All the four complexes were well
characterized by various analytical techniques like FT-IR, UV−
visible spectroscopy, H NMR, C NMR, and ESI-HRMS. The
structures of 1 and 2 were confirmed by single crystal X-ray
diffraction. Bulk purity was confirmed by elemental analysis.
Activities of 1−4 were probed in vitro against a panel of three
different carcinoma cell lines (MDA-MB-231, triple-negative
breast adenocarcinoma; Hep G2, hepatocellular carcinoma; and
MIA PaCa-2, pancreas ductal adenocarcinoma). The stability of
the complexes in solution varied based on the ligands used, and
it also influenced their cytotoxicity.
2
DMSO-d , 25 °C): δ 165.8, 161.0, 155.7, 154.4, 132.3, 131.6, 129.6,
6
129.2, 118.6, 118.3, 116.6, 115.2, 60.0, 35.9 (Supporting Information,
II
6
[(L1)Ru (η -p-cym)(Cl)](PF ) (1). To a solution of L1 (0.1 g, 0.44
6
mmol), dissolved in 10 mL of methanol, a 10 mL methanolic solution of
II
6
[
Ru (η -p-cymene)Cl ] (0.130 g, 0.22 mmol) was added under stirring
2 2
1
13
conditions. The whole reaction mixture was allowed to reflux for 4 h,
followed by the addition of NH PF (0.087 g, 0.53 mmol), dissolved in
4
6
ca. 5 mL of methanol. The solvent was evaporated under reduced
pressure, extracted with dichloromethane, and re-evaporated. The
resulting orange colored crude product was washed with chilled diethyl
ether multiple times. The pure product was isolated as a yellow powder,
which was soluble in methanol, ethanol, acetonitrile, and DMSO. Yield:
0
.179 g (64%). Anal. Calcd for C H ClF N OPRu: C,44.90; H, 4.40;
24 28 6 2
1
N, 4.36. Found: C, 44.67; H, 4.31; N, 4.41. H NMR (500 MHz,
DMSO-d ): δ 9.53 (d, 1H, J = 4.32 Hz, Py-H), 8.67 (s, 1H, −CHN),
6
8
2
.25 (t, 1H, J = 6.12 Hz, Py-H), 8.14 (d, 1H, J = 6.04 Hz, Py-H), 7.82 (t,
H, J = 5.24 Hz, Py-H), 7.19 (d, 2H, J = 6.68 Hz, Ar−H), 6.74 (d, 2H, J
EXPERIMENTAL SECTION
■
Materials and Methods. All chemicals and solvents were
purchased from commercial sources. Solvents were distilled and dried
prior to use by standard procedures. Pyridine 2-carbaldehyde,
salicylaldehyde, and reduced L-glutathione were purchased from
Sigma-Aldrich and used without any further purification. Tyramine
monohydrochloride was purchased from Spectrochem, India.
Ruthenium(III) trichloride was purchased from Precious Metals
= 6.68 Hz, Ar−H), 6.29 (d, 1H, J = 5.04 Hz, p-cym-H), 6.21 (d, 1H, J =
4.88 Hz, p-cym-H), 5.97 (d, 1H, J = 4.88 Hz, p-cym-H), 5.92 (d, 1H, J =
62
5.04 Hz, p-cym-H), 4.65 (m, 1H, −CH
(m, 1H, −CH ), 2.93 (m, 1H, −CH ), 2.62 (m, 1H, p-cym-CH), 2.18
(s, 3H, p-cym-CH ), 1.03 (d, 3H, J = 5.52 Hz, iPr-CH ), 0.94 (d, 3H, J =
5.52 Hz, iPr-CH ) (Supporting Information, Figure S5). C NMR
(125 MHz, DMSO-d , 25 °C): δ 167.3, 156.0, 155.8, 154.4, 139.8,
), 4.54 (m, 1H, −CH
), 3.21
2
2
2
2
3
1
3
3
6
II
6
Online, Australia. [Ru (η -p-cymene)Cl ] was prepared using a
130.0, 128.6, 128.2, 127.8, 115.2, 104.5, 103.2, 87.3, 84.9, 84.7, 84.3,
67.4, 34.6, 30.4, 22.0, 21.4, 18.3 (Supporting Information, Figure S6).
2
2
63
literature protocol. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide] (USB), along with supplements and assay kits,
were purchased from Gibco and used as received. UV−visible
measurements were done using an Agilent Cary 300 UV−vis
spectrophotometer. FT-IR spectra were recorded using a PerkinElmer
−
1
FT-IR (KBr pellets, cm ): 3541, 2970, 1613, 1515, 1261, 1202, 836,
3
−1
−1
553. UV−vis [CH
OH, λmax, nm (ε/dm mol cm )]: 271 (6600),
3
350 (2530), 406 (1820). ESI-HRMS (methanol) m/z (calcd):
+
497.0928 (497.0744) [C24H28ClN ORu ].
2
1
II
6
SPECTRUM RX I spectrometer in KBr pellets. H and proton
[(L1)Ru (η -p-cym)(I)](I) (2). To a solution of L1 (0.08 g, 0.35
decoupled 13C NMR spectra were measured using either a JEOL ECS
mmol), dissolved in 10 mL of methanol under stirring conditions,
II
6
4
00 MHz or Bruker Avance III 500 MHz spectrometer at room
temperature. The chemical shifts are reported in parts per million
ppm). Electro-spray ionization mass spectra were recorded using a
Bruker maXis impact mass spectrometer by positive mode of
electrospray ionization. The synthetic yields reported are of isolated
[Ru (η -p-cymene)I ] (0.173 g, 0.17 mmol) dissolved in 10 mL of
2 2
methanol was added. The whole reaction mixture was allowed to reflux
for 5 h. The solvent was evaporated under reduced pressure, extracted
with dichloromethane, and re-evaporated. The resulting deep orange
crude was washed with chilled diethyl ether for purification. The pure
(
B
Inorg. Chem. XXXX, XXX, XXX−XXX
Acharya, Sourav
