Water-soluble monochloroplatinum(II) complexes with amino acid derived Schiff bases as ligands: Synthesis, characterisation and antitumour activity

Article abstract of DOI:10.3184/174751912X13270814162774

A series of water-soluble monochloroplatinum(II) complexes K[PtCl(L)] (L = amino acid derived schiff base) have been synthesised as potential anticancer agents and characterised by ¹H NMR, elemental analysis, IR spectroscopy and molar conductivity measurements. These compounds were tested for their DNA interaction ability with salmon sperm DNA and their in vitro anticancer activities have been validated against Hela and A549 cell lines by the CCK-8 assay. Whilst some complexes had better cytotoxic activities against the Hela cell line compared with cisplatin, all the complexes had little cytotoxicity against the A549 cell line compared with cisplatin.

Full text of DOI:10.3184/174751912X13270814162774

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 85
FEBRUARY, 85–89
Water-soluble monochloroplatinum(II) complexes with amino acid
derived Schiff bases as ligands: synthesis, characterisation and
antitumour activity
Li-Jun Li*, Chao Tian, Zheng Wang, Guang-Yuan Wang, Lian-Zeng Wang and Jian-Long Du
Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, P. R. China
A series of water-soluble monochloroplatinum(II) complexes K[PtCl(L)] (L = amino acid derived schiff base) have
been synthesised as potential anticancer agents and characterised by 1H NMR, elemental analysis, IR spectroscopy
and molar conductivity measurements. These compounds were tested for their DNA interaction ability with salmon
sperm DNA and their in vitro anticancer activities have been validated against Hela and A549 cell lines by the CCK-8
assay. Whilst some complexes had better cytotoxic activities against the Hela cell line compared with cisplatin, all the
complexes had little cytotoxicity against the A549 cell line compared with cisplatin.
Keywords: water-soluble monochloroplatinum(II) complexes, Schiff base, anticancer activitity, structure–activity relationship
Malignant disease is a major cause of mortality. The biological
activity of cisplatin was discovered fortuitously in 1965 during
studies of the effect of an electric current on Escherichia coli.1
cis-Diamminedichloroplatinum(II) (cisplatin) is a very effec-
tive drug against ovarian, testicular, bladder, head and neck
cancers.2–4 However, like other chemotherapeutic agents, its
clinical effectiveness is limited by intrinsic and/or acquired
drug resistance and severe side effects such as nephrotoxicity,
neurotoxicity and ototoxicity. For over 20 years following the
introduction of cisplatin, further development of Pt-based
drugs has focused primarily on Pt(II) complexes. In clinical
practice, cisplatin, carboplatin and oxaliplatin are administered
by intravenous infusion. A drug that could be effectively deliv-
ered orally is strongly desirable as it would allow substantial
flexibility in dosing and increase the potential for the use
of platinum drugs. However, an effective oral formulation of
cisplatin is not achievable at the clinical level because of its
poor water solubility and low level of bioavailability. Although
carboplatin has greater water solubility, its very low organic/
aqueous partition coefficient resulted in low absorption through
the gastrointestinal tract.5 Overcoming the adverse effects
and eventual resistance and increasing the water solubility
associated with Pt(II) compounds are the current focus in the
development of next-generation platinum anticancer drugs.
The rapid development and understanding of the chemistry
of molecular biology and amino acids have created a signifi-
cant class of compounds that are now helpful in understanding
biological functions of macromolecules like proteins. Groups
like amino acid Schiff bases are important biological entities
and their interactions with metal ions are a fertile field
of research activity. Although there are numerous reports on
transition metal complexes of Schiff bases derived from amino
acids,6–9 there is little information on the corresponding deriva-
tives of platinum(II).10,11 We have prepared a series of L-amino
acid Schiff bases coordinated to platinum(II). The interaction
between salmon sperm DNA and these water-soluble com-
plexes was investigated by UV spectroscopy and their antitu-
mour activities have also been tested on Hela and A549 cell
lines in vitro.
Results and discussion
Ligands 3a–k were synthesised from salicylaldehyde,
5-hydroxylsalicylaldehyde and 5-bromsalicylaldehyde with
the L-amino acids: Gly, Phe, Ser and Leu. The platinum(II)
complexes 4a–k have been prepared by the reaction of K2PtCl4
with the appropriate L-amino acid Schiff bases in a mixture of
CH3OH/H2O at room temperature (Scheme 1).
Comparison of the IR spectra of the free ligands with those
of their Pt(II) complexes, shows that the (CH=N)imine stretching
frequencies, found in free ligands at about 1620–1640 cm−1,
are shifted in complexes to lower wavenumbers at about 1610–
1620 cm−1. On the other hand, the (COO−)carboxyl asymmetric
stretching frequency and symmetric stretching frequency
found at about 1580–1610 cm−1 and 1370–1415 cm−1 in the
free ligands, are shifted to about 1520–1545 cm−1 and 1305–
1320 cm−1 in the complexes, respectively. In the spectra of
the metal complexes, the bands for the phenolic group (C–O)
are shifted from about 1210–1240 cm−1 to 1150–1180 cm−1,
on passing to the bound ligands. New bands appear at about
610–620 cm−1, 470–530 cm−1 and 410–420 cm−1 and are
assigned to υPt-OAr and υPt-N, and υPt-OOC respectively. The
IR spectra of 3j and 4j are shown in Fig. 1. All of these data
indicate that the nitrogen atoms of the imine groups and
Scheme 1
* Correspondent. E-mail: llj@hbu.edu.cn

86 JOURNAL OF CHEMICAL RESEARCH 2012
Fig. 1 The IR spectrum of 3j and 4j.
Fig. 2 UV spectrum of interaction between 4c and salmon
sperm DNA: (A) DNA blank; (B) c4c : cDNA = 0.3; (C) c4c : cDNA =0.5;
(D) c4c : cDNA =0.7.
oxygen atoms of the carboxyl groups and phenolic groups are
coordinated to the metal ion (Table 1).
1
Although the overall pattern of the H NMR spectra of the
complexes (4a–k) resembles very closely that of the free
ligands, the signals have been shifted to lower fields. The ele-
mental analysis data of the complexes (4a–k) are in good
agreement with the calculated values. The molar conductance
values of platinum(II) complexes in deionised water are in the
range of 1.30–1.65 S·cm2·mol−1. All complexes are therefore
formulated as 1:1 electrolytes having one non-bonded K+
counter ion.
Interaction between complexes and DNA
The interactions between DNA and the complexes were
characterised by UV spectra. There are generally three nonco-
valent binding modes between antitumour drugs with DNA:
electrostatic binding, intercalations between base pairs and
binding into the groove of DNA. In the wavelength range of
200–400 nm, the spectra of DNA with different concentrations
of complexes (4c, 4g and 4j) were determined (Figs 2–4).
There was one positive peak at 258 nm (A = 2.0754) due to the
Fig. 3 UV spectrum of interaction between 4g and salmon
sperm DNA: (A) DNA blank; (B) c4g : cDNA = 0.3; (C) c4g : cDNA =0.5;
(D) c4g : cDNA =0.7.
Table 1 Main IR absorptions of ligands and complexes (cm−1)
υ
υas
υs
υ
υ
υ
υ
(C=N) (COO−) (COO−) (phO) (Pt–OAr) (Pt–N) (Pt–OOC)
3a 1644
3b 1630
3c 1633
3d 1641
3e 1640
3f 1638
3g 1630
3h 1638
3i 1638
3j 1638
3k 1641
4a 1611
4b 1611
4c 1613
4d 1633
4e 1614
4f 1613
4g 1614
4h 1623
4i 1610
4j 1608
4k 1611
1604
1604
1609
1602
1604
1609
1591
1600
1607
1613
1605
1525
1524
1524
1516
1525
1524
1521
1544
1515
1583
1526
1384
1371
1382
1403
1375
1375
1373
1377
1378
1374
1378
1317
1311
1314
1316
1317
1315
1319
1312
1336
1308
1321
1218
1216
1233
1222
1217
1225
1214
1224
1230
1219
1223
1177
1179
1156
1174
1174
1176
1174
1174
1177
1171
1175
610
613
614
612
613
614
614
613
596
592
610
509
480
457
505
476
485
525
495
452
449
484
415
415
415
412
420
416
412
416
416
413
412
Fig. 4 UV spectrum of interaction between 4j and salmon
sperm DNA: (A) DNA blank; (B) c4j : cDNA = 0.3; (C) c4j : cDNA =0.5;
(D) c4j : cDNA =0.7.

JOURNAL OF CHEMICAL RESEARCH 2012 87
absorption of DNA. With the increased concentration of com-
plexes 4c (c4c:cDNA = 0.3, 0.5 and 0.7), the absorbance values
were increased (A = 2.2067, 2.3451 and 2.5018), and the
absorption at 258 nm shifted to low wavelength (λ = 257, 256
and 255 nm). Also (Fig. 3), there was one similar positive peak
at 258 nm (A = 1.5226). When the concentration of complexes
4g (c4g:cDNA = 0.3, 0.5 and 0.7) was increased, the absorbance
values were enhanced (A = 1.6432, 1.7812 and 1.9023);
meanwhile, the absorption at 258 nm shifted to low wavelength
(λ = 257, 256 and 255 nm). In addition, with the same increased
concentration of complexes 4j (Fig. 4), the absorbance values
were improved (A = 3.3738, 3.8276 and 4.3276); moreover,
the absorption shifted to low wavelength (λ = 256, 251 and 246
nm). This shift might be due to the complex inserting into the
DNA double helix structure and stacking with DNA base pairs
where π-electron accumulation occurred; thus the absorbance
value increased and the maximum absorption wavelength was
blue-shifted. The results confirmed that hyperchromicity
occurs after the complexes interact with DNA and the binding
mode of complexes with DNA was might for plug-in.13−15
Fig. 5 Inhibition ratio of complexes (4a–k) against Hela.
In vitro cytotoxic activity
The cytotoxic activities of 4a–k were evaluated against two
human cancer cell lines consisting of A549 and Hela, and the
results are listed in Table 2. As shown in Table 2, the com-
plexes (4a–k) exerted cytotoxic effects against the tested Hela
cell line with lower IC50 values, moreover, they had selectivity
against the Hela cell line. However, they had little cytotoxicity
against the A549 cell line compared with cisplatin. The inhibi-
tion ratio also showed a good consistency with the cytotoxic
activity (Figures 5–6). 4f, 4j and 4k exhibited better cytotoxic
activities against the Hela cell line compared with cisplain and
4e displayed a fair cytotoxic effect against Hela cell line com-
pared with cisplain. Based on comparison of the IC50 values of
these compounds, the structure–activity relationship can be
summarised as follows: (1) The existence of a bromo-substitu-
ent at the C-4 position of the phenyl group of the Schiff bases
improves the activity (4i–k). (2) Compounds with the electron-
donating group (R1 = OH) at the C-4 position of the phenyl
group have decreased antitumour activity (4d, 4g and 4h).
It can be seen from Table 2 that the antitumour activities of
this series of platinum complexes increases in the sequence:
4-OH < H < 4-Br (R1). According to the research of Kuo, the
“trans effect” theory can explain why compounds 4i–k are
more active than the other compounds.16 The inductive effect
of the bromo group at the 4-position of the phenyl group of the
amino acid derived Schiff bases makes the phenolic hydroxyl
group more acidic and the Pt-OAr bond is less stable than in
the other compounds, thereby making it easier to hydrolyze
and coordinate to DNA guanine residues. However, the
hydroxyl group at the C-4 position of the phenyl group makes
the phenolic hydroxyl group more alkaline and the Pt–OAr
bond is more stable than in the other compounds, thus making
it more difficult to coordinate to DNA guanine residues. How-
ever, it is hard to explain why compound 4h is more active than
4f in the A549 cell line; it seems that the “trans effect” theory
is not the only factor influencing the antitumour activities.
Fig. 6 Inhibition ratio of complexes (4a–k) against A549.
Experimental
All reagents and chemicals were purchased from commercial sources
and used as received. Salicylaldehyde, K2PtCl4 and p-bromophenol
were of chemical grade, L-amino acids were of analytical grade, a cell
counting kit-8 (CCK-8) was obtained from the Chinese Academy of
Sciences, salmon sperm DNA was purchased from Sigma, two differ-
ent human carcinoma cell lines: Hela (cervical carcinoma) and A549
(lung tissue carcinoma) were obtained from the Chinese Academy of
Sciences.
Elemental analyses were determined on a Elemental Vario EL III
elemental analyser. The IR spectra were recorded using KBr pellets
and a Perkin-Elmer Model-683 spectrophotometer. The 1H NMR
spectra were recorded in DMSO-d6 on a Bruker AVIII 600 NMR spec-
trometer. The interaction between DNA and complexes was measured
on an UV-3400 Toshniwal spectrophotometer. The conductivity values
were determined on a DDSJ-308A conductivity meter. The molar
conductivities of 8 × 10−4 mol L−1 solutions of the complexes 4a–4f in
deionised water (K = 1.471 µs cm−1) were measured at 18 °C.
Table 2 The cytotoxicity of complexes in vitro (IC50)
IC50 (µM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
cisplain
Hela
A549
31.37
65.08
34.43
53.15
28.73
53.66
31.81
117.05
25.65
57.80
21.93
98.78
29.15
103.61
45.46
74.74
28.08
40.79
21.05
48.16
19.14
80.80
25.23
23.02

88 JOURNAL OF CHEMICAL RESEARCH 2012
Ligand synthesis: general procedure
(COO−)as, 1497, 1403 (COO−)s, 1299, 1222 (phO), 1159, 830, 604,
515 cm−1. Anal. Calcd for C10H10NO5K: C, 45.62; H, 3.83; N, 5.32.
Found: C, 45.37; H, 3.51; N, 5.70%.
Amino acid derived Schiff bases (3a–k) were synthesised according
to a published procedure.12 A hot aqueous solution of L-amino acids
(0.01 mol) was added with magnetic stirring to a hot EtOK solution of
the substituted salicylaldehyde (0.01 mol). The mixture was then
boiled under reflux on a water bath for 2 h and the excess of solvent
was removed by rotatory evaporation. Light yellow, needle-like crys-
tals of the ligands were recrystallised from EtOH, filtered and dried
in vacuo over P2O5.
5-Hydroxylsalicylaldehyde: To a three-neck flask, equipped with a
reflux condenser, thermometer, a dinitrogen source and magnetic stir-
rer was added hydroquinone (2.0 g, 0.018 mol), sodium hydroxide
(4.0 g, 0.10 mol), distilled water (40 mL) and chloroform (8.0 mL).
The mixture was heated to reflux for 8 h. After cooling, the reaction
mixture was acidified to pH 2–3 with 2N hydrochloric acid, and
extracted with ethyl acetate. The ethyl acetate extract was vacuum
distilled to dryness, giving crude 5-hydroxylsalicylaldehyde (1.7 g).
The crude product was purified by column chromatography to give
the yellow solid product (0.41 g, 32.6%); m.p. 94–97 °C; IR: 3441,
1660, 1631, 1582, 1486, 1398, 1278, 1151, 1039, 943, 881, 801, 769,
641, 484 cm−1; 1H NMR: δ 6.812–6.974 (m, 3H, ArH), 10.199 (s, 1H,
–CHO).
Potassium2-(2,5-dihydroxybenzylideneamino)-4-methylpentanoate
(3g): Light yellow solid. 1.739 g (60.2%): 1H NMR: δ 13.508 (s, 1H,
ArOH), 8.267 (s, 1H, –CH=N–), 6.619–6.773 (m, 3H, ArH), 3.641–
3.663 (m, 1H, N–CH), 1.660–1.705 (m, 1H, CH–H), 1.560–1.606 (m,
1H, CH–H), 1.448–1.516 (m, 1H, –CH–), 0.866–0.877 (d, 3H, CH3),
0.822–0.833 (d, 3H, CH3); IR: 3252, 1630 (C=N), 1591 (COO−)as,
1460, 1373 (COO−)s, 1214 (phO), 1158, 1064, 834, 792, 458 cm−1.
Anal. Calcd for C13H16NO4K: C, 53.96; H, 5.57; N, 4.84. Found: C,
53.54; H, 5.82; N, 4.57%.
Potassium2-(2,5-dihydroxybenzylideneamino)-3-hydroxybutanoate
(3h): Light yellow solid. 2.128 g (76.8%): 1H NMR: δ 13.354 (s, 1H,
ArOH), 9.744 (s, 1H, ArOH), 8.280 (s, 1H, –CH=N–), 6.656–6.776
(m, 3H, ArH), 3.792–3.809 (m, 1H, O–CH), 3.569–3.575 (d, 1H,
N–CH), 1.016–1.026 (d, 3H, CH3); IR: 3377, 1638 (C=N), 1600
(COO−)as, 1490, 1377 (COO−)s, 1221 (phO), 1159, 808, 699 cm−1.
Anal. Calcd for C11H12NO5K: C, 47.64; H, 4.36; N, 5.05. Found:
C, 47.32; H, 4.59; N, 5.37%.
Potassium 2-(5-bromo-2-hydroxybenzylideneamino)-3-hydroxypro-
panoate (3i): Light yellow solid. 2.031 g (62.5%): 1H NMR: δ 8.299
(s, 1H, –CH=N–), 6.618–7.507 (m, 3H, ArH), 3.739–3.766 (dd,
1H, –CH–H), 3.521–3.550 (dd, 1H, –CH–H), 3.700–3.721 (t, 1H,
N–CH–); IR: 3424, 1638 (C=N), 1607 (COO−)as, 1485, 1378 (COO−)s,
1308, 1230 (phO), 1164, 1025, 826, 775, 617 cm−1. Anal. Calcd for
C10H9NO4BrK: C, 36.82; H, 2.78; N, 4.29. Found: C, 36.48; H, 2.54;
N, 4.57%.
5-Bromosalicylaldehyde: Synthesised according to a published
procedure.12 To a three-neck flask, equipped with a thermometer and
magnetic stirrer was added glacial acetic acid (8 mL), salicylaldehyde
(2.25 g, 18.40 mmol) and hydrobromic acid (6 mL). The mixture
was heated to 35 °C for 90 minutes and NaClO3 was slowly added
dropwise, a milky precipitate then appeared. The reaction mixture was
then recrystallised from ethanol and the resuling white, crystalline
solid was collected by filtration and washed with a little ethanol. The
product was dried to obtain 5-bromosalicylaldehyde (1.53 g, 42.9%);
m.p. 104–105 °C; IR: 3445, 1669, 1563, 1465, 1273, 1159, 888, 828,
Potassium 2-(5-bromo-2-hydroxybenzylideneamino)-4-methylpent-
1
anoate (3j): Light yellow solid. 2.616 g (74.5%): H NMR: δ 8.323
(s, 1H, –CH=N–), 6.585–7.479 (m, 3H, ArH), 3.706–3.728 (dd,
1H, N–CH–), 1.684–1.729 (m, 1H, –CH–H), 1.553–1.599 (m, 1H,
–CH–H), 1.481–1.527 (m, 1H, –CH–), 0.872–0.883 (d, 3H, –CH3),
0.849–0.860 (d, 3H, –CH3); IR: 3432, 1638 (C=N), 1613 (COO−)as,
1493, 1378 (COO−)s, 1219 (phO), 1062, 1018, 868, 827, 615,
560 cm−1. Anal. Calcd for C13H15NO3BrK: C, 44.32; H, 4.29; N, 3.98.
Found: C, 44.06; H, 4.57; N, 3.64%.
1
696, 533 cm−1; H NMR: δ 10.211 (s, 1H, –CHO), 6.986–7.732 (m,
3H, ArH).
Potassium 2-(2-hydroxybenzylideneamino)acetate (3a): Light
yellow solid. 1.317 g (62.2%): 1H NMR: δ 14.40 (s, 1H, ArOH), 8.285
(s, 1H, –CH=N–), 6.650-7.310 (m, 4H, ArH), 3.895 (s, 2H, –CH2–);
IR: 3411, 1644 (C=N), 1604 (COO−)as, 1510, 1384 (COO−)s, 1308,
1218 (phO), 1187, 734, 563, 523 cm−1. Anal. Calcd for C9H8NO3K: C,
49.75; H, 3.71; N, 6.45. Found: C, 49.42; H, 3.95; N, 6.71%.
Potassium 2-(2-hydroxybenzylideneamino)-3-phenylpropanoate (3b):
Light yellow solid. 2.450 g (80.3%): 1H NMR: δ 14.30 (s, 1H, ArOH),
8.09 (s, 1H, –CH=N–), 7.180–7.220 (m, 4H, ArH), 6.650–7.170
(m, 5H, ArH), 3.800–3.840 (dd, 1H, CH–H), 3.260–3.300 (dd, 1H,
CH–H), 2.900–2.950 (dd, 1H, C-H); IR: 3406, 1630 (C=N), 1605
(COO−)as, 1512, 1371 (COO−)s, 1215 (phO), 1145, 1074, 743, 700,
477 cm−1. Anal. Calcd for C16H14NO3K: C, 62.52; H, 4.59; N, 4.56.
Found: C, 62.35; H, 4.25; N, 4.80%.
Potassium 3-hydroxy-2-(2-hydroxybenzylideneamino)propanoate (3c):
Light yellow solid. 1.927 g (78.0%): 1H NMR: δ 14.20 (s, 1H, ArOH),
8.35 (s, 1H, –CH=N–), 6.69–7.35 (m, 4H, ArH), 3.681–3.702 (t, 1H,
C–H), 3.544–3.572 (dd, 1H, CH–H), 3.727–3.754 (dd, 1H, CH-H);
IR: 3175, 1633 (C=N), 1609 (COO−)as, 1493, 1382 (COO−)s, 1233
(phO), 1147, 1094, 758, 727, 672, 567 cm−1. Anal. Calcd for
C10H10NO4K: C, 48.57; H, 4.08; N, 5.66. Found: C, 48.72; H, 4.42; N,
5.31%.
Potassium 2-(2-hydroxybenzylideneamino)-4-methylpentanoate (3d):
Light yellow solid. 1.915 g (70.1%): 1H NMR: δ 14.50 (s, 1H, ArOH),
8.364 (s, 1H, –CH=N–), 6.660–7.320 (m, 4H, ArH), 3.700–3.723
(dd, 1H, N–CH–), 1.692–1.737 (m, 1H, –CH–H), 1.571–1.618
(m, 1H, –CH–H), 1.485–1.551 (m, 1H, CH3–C–H), 0.879–0.890
(d, 3H, –CH3–), 0.849–0.859 (d, 3H, –CH3-); IR: 3422, 1640 (C=N),
1604 (COO−)as, 1516, 1374 (COO−)s, 1217 (phO), 1142, 1018, 741,
578, 539 cm−1. Anal. Calcd for C13H16NO3K: C, 57.12; H, 5.90; N,
5.12. Found: C, 57.41; H, 5.47; N, 5.44%.
Potassium 3-hydroxy-2-(2-hydroxybenzylideneamino)butanoate (3e):
Light yellow solid. 1.522 g (58.3%): 1H NMR: δ 14.33 (s, 1H, ArOH),
8.37 (s, 1H, –CH=N–), 6.74–7.36 (m, 4H, ArH), 1.031–1.041 (d, 3H,
CH3), 3.815–3.852 (m, 1H, O–CH–), 3.618–3.624 (d, 1H, N–CH–);
IR: 3382, 1638 (C=N), 1609 (COO−)as, 1513, 1375 (COO−)s, 1280,
1225 (phO), 1128, 1005, 762, 697 cm−1. Anal. Calcd for C11H12NO4K:
C, 50.56; H, 4.63; N, 5.36. Found: C, 50.22; H, 4.97; N, 5.14%.
Potassium 3-hydroxy-2-(2,5-dihydroxybenzylideneamino)propanoate
(3f): Light yellow solid. 1.998 g (76.0%): 1H NMR: δ 13.220 (s, 1H,
ArOH), 9.700 (s, 1H, ArOH), 8.264 (s, 1H, –CH=N–), 6.650–6.743
(m, 3H, ArH), 3.689–3.716 (dd, 1H, CH–H), 3.519–3.546 (dd, 1H,
CH–H), 3.612–3.634 (t, 1H,C–H); IR: 3385, 1641 (C=N), 1602
Potassium 2-(5-bromo-2-hydroxybenzylideneamino)-3-hydroxybu-
tanoate (3k): Light yellow solid. 2.316 g (68.3%): 1H NMR: δ 8.437
(s, 1H, –CH=N–), 6.5745–7.618 (m, 3H, ArH), 3.937–3.955 (m, 1H,
O–CH–), 3.724–3.731 (d, 1H, N–CH–), 1.118–1.128 (d, 3H, –CH3);
IR: 3382, 1641 (C=N), 1605 (COO−)as, 1487, 1378 (COO−)s, 1223
(phO), 1125, 1008, 827, 616, 529 cm−1.Anal. Calcd for C11H11NO4BrK:
C, 38.83; H, 3.26; N, 4.12. Found: C, 38.51; H, 3.58; N, 4.46%.
Synthesis monochloroplatinum(II) complexes 4a–k; general
procedure
K2PtCl4 (20 mg, 0.0482 mmol) was added to a CH3OH/H2O
(v/v = 1/1, 4 mL) solution of amino acid derived Schiff base (3a–k)
(0.0456–492 mmol) at room temperature, the mixture was adjusted to
pH = 8–9 in the beginning, then stirred for 48 h and the pH was then
down to about 7. The solution was dried in vacuo and the resulting
solid recrystallised from CH3OH under N2 protection to yield the
monochloroplatinum(II) complexes 4a–k: 62.4–70.0%.
K[Pt(2-{2-hydroxybenzylideneamino}acetoxyl)Cl] (4a): Yield:
62.4%.Yellow solid: 1H NMR: δ 8.965 (s, 1H, –CH=N–), 7.351–7.425
(m, 2H, ArH), 6.802–6.874 (m, 2H, ArH), 3.902(s, 2H, –CH2–); IR:
3442, 1611 (C=N), 1525 (COO–)as, 1400, 1317 (COO–)s, 1177 (phO),
610 (Pt–OAr), 519 (Pt–N), 415 (Pt-OOC) cm−1. Anal. Calcd for
C9H7NO3ClKPt: C, 24.19; H, 1.58; N, 3.13. Found: C, 24.42; H, 1.34;
N, 3.41%. Λm = 1.39 S·cm2·mol−1.
K[Pt(2-{2-hydroxybenzylideneamino}-3-phenylpropionyloxy)Cl]
1
(4b): Yield: 64.75%. Yellow solid: H NMR: δ 8.772 (s, 1H, –CH=
N–), 7.312–7.354 (m, 4H, ArH), 6.676–7.200 m, 5H, ArH), 3.622–
3.658(dd, 1H, CH–H), 3.244–3.276(dd, 1H, CH–H), 2.910–2.946
(dd, 1H, C–H); IR: 3441, 1611 (C=N), 1524 (COO–)as, 1399, 1311
(COO–)s, 1179 (phO), 753, 613 (Pt–OAr), 480 (Pt–N), 415 (Pt–OOC)
cm−1. Anal. Calcd for C16H13NO3ClKPt: C, 35.79; H, 2.44; N, 2.61.
Found: C, 35.53; H, 2.68; N, 2.43%. Λm = 1.44 S·cm2·mol−1.
K[Pt(3-hydroxy-2-{2-hydroxybenzylideneamino}propionyloxy)Cl]
1
(4c): Yield: 67.42%. Yellow solid: H NMR: δ 9.135 (s, 1H, –CH=
N–), 7.202–7.471(m, 4H, ArH), 3.673–3.692 (t, 1H, C–H), 3.741–
3.758 (dd, 1H, CH–H), 3.562–3.581 (dd, 1H, CH–H); IR: 3423, 1613
(C=N), 1524 (COO–)as, 1398, 1314 (COO–)s, 1156 (phO), 758, 614
(Pt–OAr), 457 (Pt–N), 415 (Pt–OOC) cm−1. Anal. Calcd for
C10H9NO4ClKPt: C, 25.19; H, 1.90; N, 2.94. Found: C, 25.46; H, 1.58;
N, 2.64%. Λm = 1.30 S·cm2·mol−1.

JOURNAL OF CHEMICAL RESEARCH 2012 89
K[Pt(2-{2-hydroxybenzylideneamino}-4-methylpentanyloxy)Cl]
(4d): Yield: 65.47%. Yellow solid: H NMR: δ 9.142 (s, 1H, –CH=
different concentrations (ccomplex:cDNA) = 0.3, 0.5 and 0.7), and rested
for 24 h at 4 °C. The UV absorption spectra were determined at room
temperature (∆t = 1 s, n = 3.).
1
N–), 7.432–7.445 (dd, 1H, ArH), 7.330–7.356 (m, 1H, ArH), 6.815–
6.830 (d, 1H, ArH), 6.780–6.800 (t, 1H, ArH), 3.712–3.733 (dd,
1H, N–CH–), 1.685–1.722 ((m, 1H, –CH–H), 1.566–1.612 (m, 1H,
–CH–H), 1.493–1.562 (m, 1H, CH3–C–H), 0.877–0.888 (d, 3H,
–CH3), 0.845–0.855 (d, 3H, –CH3); IR: 3420, 1614 (C=N), 1525
(COO–)as, 1399, 1317 (COO–)s, 1174 (phO), 1080, 754, 613 (Pt–OAr),
476 (Pt–N), 420 (Pt–OOC) cm−1. Anal. Calcd for C13H15NO3ClKPt: C,
31.05; H, 3.01; N, 2.79. Found: C, 31.36; H, 3.43; N, 2.54%. Λm = 1.65
S·cm2·mol−1.
Cell culture
Two different human carcinoma cell lines: Hela and A549 were cul-
tured in RPMI-1640 medium supplemented with 10% fetal bovine
serum, 100 units mL−1 of penicillin and 100 µg mL−1 of streptomycin.
Cells were maintained at 37 °C in a humidified atmosphere of 5% CO2
in air.
Cytotoxicity analysis
K[Pt(3-hydroxy-2-{2-hydroxybenzylideneamino}butanyloxy)Cl]
The two cells harvested from exponential phase were seeded equiva-
lently into 96-well plates. Both cell types were allowed to adhere for
24 h at 37 °C in 5% CO2/95% air before treatments were initiated.
Then the complexes were added to the wells at concentrations of 1.0,
10, 100, and 500 µM. The number of live cells in the wells of the
control plate at the beginning of a particular experiment was deter-
mined by use of the cell counting kit, CCK-8.17 In this assay, a solu-
tion containing a water-soluble tetrazolium salt (10 µL) is added to
each well of the control plate. If a specific cell is viable, the tetrazo-
lium salt is absorbed by the cell and bioreduced to a formazan dye,
which diffuses into the medium. After 1 h, the concentration of the
formazan dye in the well, which is proportional to the number of live
cells in the well, is determined by measuring the absorbance of the
medium in the wells at 450 nm on a luminescence plate reader. In
order to obtain the concentration of the dye produced by live cells at
the start of the experiment, t = 0 h, the absorbance at 450 nm of wells
in the control plate without cells was subtracted from the absorbance
of wells in the control plate having cells. Meanwhile, the medium
above the cells in each experimental plate was replaced with drug-
containing medium at a specific concentration/condition (five wells
per concentration/condition per plate). After 2 h, the drug-containing
medium above the cells was removed, cells were washed with culture
medium without drug, fresh medium was applied, and the cells
were allowed to grow for 24 h. At the end of this period, the number
of live cells was determined by the method described above. All
measurements were done in quintuplicate.
1
(4e): Yield: 70.03%. Yellow solid: H NMR: δ 9.162 (s, 1H, –CH=
N–), 7.475–7.490 (dd, 1H, ArH), 7.396–7.428 (m, 1H, ArH), 6.845–
6.881 (t, 2H, ArH), 3.802–3.840 (m, 1H, O–CH–), 3.629–3.636 (d,
1H, N–CH–), 1.033–1.045 (d, 3H, –CH3); IR: 3432, 1613 (C=N),
1524 (COO–)as, 1399, 1315 (COO–)s, 1176 (phO), 752, 614 (Pt–OAr),
485 (Pt–N), 416 (Pt–OOC) cm−1. Anal. Calcd for C11H11NO4ClKPt: C,
26.92; H, 2.26; N, 2.85. Found: C, 26.54; H, 2.43; N, 2.66%. Λm = 1.32
S·cm2·mol−1.
K[Pt(3-hydroxy-2-{2,5-dihydroxybenzylideneamino}propionyloxy)
1
Cl] (4f): Yield: 62.85%. Yellow solid: H NMR: δ 9.742 (s, 1H,
ArOH), 9.052 (s, 1H, –CH=N–), 6.792–6.890 (m, 3H, ArH), 3.702–
3.730 (dd, 1H, CH–H), 3.530–3.558 (dd, 1H, CH–H), 3.610–3.631
(t, 1H, C–H); IR: 3431, 1633 (C=N), 1516 (COO–)as, 1452, 1398, 1316
(COO–)s, 1174 (phO), 1078, 833, 612 (Pt–OAr), 505 (Pt–N), 412
(Pt–OOC) cm−1. Anal. Calcd for C10H9NO5ClKPt: C, 24.37; H, 1.84;
N, 2.84. Found: C, 24.64; H, 1.52; N, 2.46%. Λm = 1.30 S·cm2·mol−1.
K[Pt(2-{2,5-dihydroxybenzylideneamino}-4-methylpentanyl-
oxy)Cl] (4g): Yield: 66.48%. Yellow solid: 1H NMR: δ 9.050 (s, 1H,
–CH=N–), 6.750-6.905 (m, 3H, ArH), 3.664–3.685 (m, 1H, N–CH),
1.668–1.714 (m, 1H, CH–H), 1.570–1.617 (m, 1H, CH–H), 1.442–
1.509 (m, 1H, –CH), 0.864–0.876 (d, 3H, –CH3), 0.825–0.838 (d, 3H,
–CH3); IR: 3433, 1614 (C=N), 1521 (COO–)as, 1399, 1319 (COO–)s,
1174 (phO), 832, 614 (Pt–OAr), 525 (Pt–N), 412 (Pt–OOC) cm–1.
Anal. Calcd for C13H15NO4ClKPt: C, 30.09; H, 2.91; N, 2.70. Found:
C, 30.35; H, 2.64; N, 2.51%.
K[Pt(3-hydroxy-2-{2,5-dihydroxybenzylideneamino}butanyloxy)Cl]
(4h): Yield: 62.84%. Yellow solid: 1H NMR: δ 9.802 (s, 1H, ArOH),
9.071 (s, 1H, –CH=N–), 6.801–6.928 (m, 3H, ArH), 3.582–3.590
(d, 1H, N–CH), 3.781–3.796 (m, 1H, O–CH), 1.012–1.020 (d, 3H,
–CH3); IR: 3431, 1623 (C=N), 1544 (COO–)as, 1400, 1312 (COO–)s,
1174 (phO), 1080, 831, 613 (Pt–OAr), 495 (Pt–N), 416 (Pt–OOC)
cm−1. Anal. Calcd for C11H11NO5ClKPt: C, 26.07; H, 2.19; N, 2.76.
Found: C, 26.42; H, 2.33; N, 2.47%.
K[Pt(2-{5-bromo-2-hydroxybenzylideneamino}-3-hydroxypro-
panyloxy)Cl] (4i): Yield: 68.92%. Yellow solid: 1H NMR (600 MHz,
DMSO-d6): δ 9.084 (s, 1H, –CH=N–), 6.744–7.663 (s, 1H, –CH=N–),
3.748–3.776 (dd, 1H, –CH–H), 3.722–3.745 (t, 1H, N–CH–), 3.530–
3.560 (dd, 1H, –CH–H); IR: 3427, 1610 (C=N), 1515 (COO–)as, 1459,
1336 (COO–)s, 1177 (phO), 1062, 822, 596 (Pt–OAr), 452 (Pt–N), 416
(Pt–OOC) cm−1. Anal. Calcd for C10H8NO4ClBrKPt: C, 21.61; H,
1.45; N, 2.52. Found: C, 21.42; H, 1.68; N, 2.14%.
This work was supported by the Natural Science Foundation of
Hebei Province (No. B2010000223) and Doctoral foundation
of Hebei University (No. 2009-164).
Received 3 September 2011; accepted 9 January 2012
Paper 1100871 doi: 10.3184/174751912X13270814162774
Published online: 23 February 2012
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oxy)Cl] (4j): Yield: 68.56%. Yellow solid: H NMR: δ 9.112 (s, 1H,
–CH=N–), 6.744–7.672 (m, 3H, ArH), 3.726–3.750 (dd, 1H, N–CH–),
1.688–1.734 (m, 1H, –CH–H), 1.559–1.604 (m, 1H, –CH–H), 1.476–
1.521 (m, 1H, –CH–), 0.874–0.886 (d, 3H, –CH3), 0.851–0.861
(d, 3H, –CH3); IR: 3453, 1608 (C=N), 1513 (COO–)as, 1404, 1308
(COO–)s, 1171 (phO), 1135, 825, 728, 592 (Pt–OAr), 449 (Pt–N), 413
(Pt–OOC) cm−1. Anal. Calcd for C13H14NO3ClBrKPt: C, 26.84; H,
2.43; N, 2.41. Found: C, 26.52; H, 2.74; N, 2.16%.
K[Pt(2-{5-bromo-2-hydroxybenzylideneamin})-3-hydroxybutanyl-
oxy)Cl] (4k): Yield: 62.84%. Yellow solid: 1H NMR: δ 9.214 (s, 1H,
–CH=N–), 6.725–7.774 (m, 3H, ArH), 3.937–3.955 (m, 1H, O–CH–),
3.743–3.750 (d, 1H, N–CH–), 1.124–1.135 (d, 3H, –CH3); IR: 3422,
1611 (C=N), 1526 (COO–)as, 1410, 1321 (COO–)s, 1175 (phO), 1076,
831, 610 (Pt–OAr), 484 (Pt–N), 412 (Pt–OOC) cm−1. Anal. Calcd for
C11H10NO4ClBrKPt: C, 23.19; H, 1.77; N, 2.46. Found: C, 23.43; H,
1.46; N, 2.68%.
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Determination of UV absorption spectra
A UV-3400 Toshniwal spectrophotometer was used mainly between
200–400 nm. The salmon sperm DNA (M = 208.8 g mol−1) was
dissolved in Tris-HCl (pH = 7.5) buffer solution, and rested for 24 h at
4 °C. Then complexes (4c, 4g and 4j) were added in buffer solution in

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