Synthesis of novel heptaplatin derivatives and evaluation of their ability to inhibit proliferation of cancer cell lines

Article abstract of DOI:10.1134/S1070363216040319

A series of novel heptaplatin derivatives were synthesized and evaluated for their ability to inhibit growth of two cancer cell lines: human colon carcinoma cell line HCT-8 and human hepatocarcinoma cell line Bel-7402. Majority of the synthesized compound

Full text of DOI:10.1134/S1070363216040319

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 4, pp. 939–943. © Pleiades Publishing, Ltd., 2016.
Synthesis of Novel Heptaplatin Derivatives
and Evaluation of Their Ability to Inhibit
Proliferation of Cancer Cell Lines1
W. Xua and D. C. Wangb
a Department of Chemical Engineering, Taizhou Institute of Science and Technology, Taizhou, 225300 China
e-mail: tracy_xu1984@yeah.net
b College of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, 210009 China
e-mail: dcwang@njtech.edu.cn
Received October 26, 2015
Abstract—A series of novel heptaplatin derivatives were synthesized and evaluated for their ability to inhibit
growth of two cancer cell lines: human colon carcinoma cell line HCT-8 and human hepatocarcinoma cell line
Bel-7402. Majority of the synthesized compounds demonstrated superior activity against cancer cell lines
compared to heptaplatin. Specifically, compounds 5a and 5b (5 µg/mL) had more pronounced efficacy against
the HCT-8 cell line while 6b and 6c (0.5 µg/mL) had higher efficacy against Bel-7402 cell line.
Keywords: heptaplatin derivatives, anti-proliferative effect, structure modification, synthesis
DOI: 10.1134/S1070363216040319
INTRODUCTION
portant. The new efficient method of synthesis of the
intermediate developed in the current study used D-
diethyl tartrate and aromatic aldehydes as starting
materials and consisted of three steps. Condensation,
aminolysis of ester and reduction of acylamide
(Scheme 2).
Heptaplatin, cis-malonate[(4R,5R)-4,5-bis(amino-
methyl)-2-isopropyl-1,3-dioxolane] platinum(II), is an
anti-tumor drug recently developed by Sunkyong
Industries (see the figure). It was first launched
clinically in South Korea in 1999 to treat advanced
gastric, small-cell lung and head and neck cancers
[1–3]. Heptaplatin is characterized by low toxicity and
clinical curative effects higher than cisplatin [4–6].
EXPERIMENTAL
All reagents were of analytical grade, obtained
from commercial suppliers and used without further
purification. Melting points were measured on an X-4
digital melting-point apparatus and the collected data
were uncorrected. Elemental analysis was carried out
on a Vario EL III CHNSO analyzer. Atomic absorp-
tion for platinum was performed on a Hitachi Z-8200
Polarized Zeeman atomic absorption spectrophoto-
Using heptaplatin as the lead compound, we syn-
thesized novel compounds containing phenyl and
hetaryl groups that supported solubility in lipids, thus
promoting their penetration across cell membranes [7].
A series of heptaplatin derivatives with aromatic groups
at the C2 position of 1,3-dioxolane were designed and
synthesized for evaluation of their antitumor activity.
1
meter. H NMR spectra were measured on a Varian
The earlier developed method of modifying hepta-
platin (Scheme 1) [8, 9] involved (4R,5R)-4,5-bis(amino-
methyl)-2-isopropyl-1,3-dioxolane as the key inter-
mediate and was characterized by rigorous experi-
mental conditions, long reaction time, complex
handling, and low total yield. Therefore, development
of a facile process for the key intermediate was im-
XL-300 MHz spectrometer with TMS as the internal
O
H2
N
O
O
O
O
Pt
N
H2
O
1 The text was submitted by the authors in English.
Chemical structural formula of heptaplatin.
939

940
XU, WANG
Scheme 1. Preparation of (4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane [8, 9].
COOC2H5
O
HO
HO
COOH
COOH
O
O
HO
COOC2H5
H2SO4
LiAlH4
Me2CHCHO
OH
OH
C2H5OH
CuSO4, MeOH
O
COOC2H5
HO
COOC2H5
O
O
O
O
O
O
NH2
NH2
MsCl, Py
N3
N3
NaN3
DMF
OMs
OMs
H2, Pd/C
Scheme 2. Synthetic route of heptaplatin derivatives.
O
O
CO2Et
+ Ar-CHO
CO2Et
OEt
O
NH2
NH2
HO
HO
O
O
NH3
cyclohexane
TsOH
Ar
Ar
O
OEt
O
O
1a−1f
NH2
2a−2f
H2
N
3a−3f
O
H2
N
Cl
O
O
O
O
O
O
O
(1) AgNO3
O
K2PtCl4
LAH
Ar
Pt
Ar
Pt
Ar
O
N
Cl
ONa
N
NH2
(2)
H2
H2
O
ONa
4a−4f
5a−5f
6a−6d
O
F
F
F
(a);
(b);
O (f).
(e);
S
(c);
Ar =
(d);
standard. MS spectra were measured on a Thermo
DSQ II mass spectrometer using the electron
ionization (EI) method.
Compound 3a. White solid, yield 78.3%, mp 61–
63°C. H NMR spectrum (CDCl3), δ, ppm: 7.42–7.52
m (5H, Ar-H), 6.70 s (1H, NH2–H), 6.80 s (1H, NH2–H),
6.21 s (1H, NH2–H), 6.30 s (1H, NH2–H), 6.02 s (1H, 2-H),
4.74–4.81 m (2H, 4,5-H). MS-ESI (m/z): 237[M + H]+,
259 [M + Na]+, 490 [2M + NH4]+, 495 [2M + Na]+.
1
Synthesis of compounds 2a–2f. An aldehyde 1
(1 equiv.), D-diethyl tartrate (1.3 equiv.), p-toluene
sulphonic acid (0.1 equiv.), and cyclohexane (1 equiv.)
were mixed together and refluxed upon stirring for 4 h.
The reaction mixture was washed 3 times with water.
The organic phase was extracted 3 times by ethyl
acetate and dried with anhydrous magnesium sulfate.
The crude product was used without further purification.
Compound 3b. White solid, yield 77.2%, mp 120–
121°C. 1H NMR spectrum (CDCl3), δ, ppm: 7.63–7.57
m (2H, Ar-H), 7.40–7.47 m (2H, Ar-H), 6.78 br (2H,
NH2–H), 6.30 s (1H, 2-H), 5.99–5.90 br (2H, NH2–H),
4.76–4.84 m (2H, 4,5-H). MS-ESI (m/z): 255 [M + H]+,
277 [M + Na]+, 531 [2M + Na]+.
Synthesis of compounds 3a–3f. A mixture of com-
pound 2 and an excess of anhydrous ammonia in
absolute alcohol was stirred at room temperature for
ca. 3.5 h. Completion of the reaction was monitored by
TLC. The reaction mixture was poured into water, the
product filtered off and recrystallized from alcohol to
produce compounds 3a–3f as white or yellow solids.
Compound 3c. White solid, yield 78.1%, mp 114–
115°C. 1H NMR spectrum (CDCl3), δ, ppm: 7.54–7.50
m (2H, Ar-H), 7.14–7.09 m (2H, Ar-H), 6.72–6.70 m
(2H, NH2–H), 6.02 s (1H, 2-H), 5.71–5.66 m (1H,
NH2–H), 4.83–4.76 m (2H, 4,5-H). MS-ESI (m/z): 255
[M + H]+, 277 [M + Na]+.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 4 2016

SYNTHESIS OF NOVEL HEPTAPLATIN DERIVATIVES
941
1
Compound 3d. White solid, yield 74.3%, mp 152–
153°C. 1H NMR spectrum (CDCl3), δ, ppm: 7.44–7.11
m (4H, Ar-H), 6.74–6.70 d (2H, NH2–H), 6.04 s (1H,
2-H), 5.86–5.80 d (2H, NH2–H), 4.82–4.74 m (2H,
4,5-H). MS-ESI (m/z): 243 [M + H]+, 265 [M + Na]+.
Compound 4d. Colorless liquid, yield 62.7%. H
NMR spectrum (CDCl3), δ, ppm: 7.44–7.49 m (2H,
Ar-H), 7.03–7.10 m (2H, Ar-H), 5.92 s (1H, 2-H),
3.96–3.92 m (2H, 4,5-H), 3.01–2.85 m (4H, CH2–H),
1.62 s (4H, NH2–H). MS-ESI (m/z): 227 [M + H]+.
1
Compound 4e. Yellow liquid, yield 55.2%. H
Compound 3e. Yellow solid, yield 69.3%, mp 129–
130°C. H NMR spectrum (300 MHz, CDCl3), δ, ppm:
6.93 m (1H, thienyl-H), 6.85 m (1H, thienyl-H) 6.69 m
(1H, thienyl-H), 6.14–6.16 d (2H, NH2–H), 6.04 s (1H,
2-H), 5.80–5.86 d (2H, NH2–H), 4.74–4.82 m (2H,
4,5-H). MS-ESI (m/z): 255 [M + H]+, 277 [M + Na]+.
1
NMR spectrum (CDCl3), δ, ppm: 7.36 m (1H, thienyl-
H), 7.20 m (1H, thienyl-H) 7.01 m (1H, thienyl-H),
6.25 s (1H, 2-H), 3.94–4.02 m (2H, 4,5-H), 2.91–3.03
m (4H, CH2–H), 1.43 s (4H, NH2–H). MS-ESI (m/z):
215 [M + H]+.
1
Compound 4f. Colorless liquid, yield 76.1%. H
Compound 3f. White solid, yield 71.7%, mp 128–
129°C.1H NMR spectrum (300 MHz, CDCl3), δ, ppm:
7.51 m (1H, furyl-H), 6.86 m (1H, furyl-H), 6.76 m
(1H, furyl-H), 6.61 d (1H), 6.44 s (1H), 6.20 s (1H,
2-H), 5.70 br (2H, 4,5-H), 4.89 d (1H, NH2–H), 4.82 d
(1H, NH2–H). MS-ESI (m/z): 227 [M + H]+, 249 [M +
Na]+, 470 [2M + NH4]+, 475[2M + Na]+.
NMR spectrum (CDCl3), δ, ppm: 7.43–7.42 m (1H,
furyl-H), 6.46 m (1H, furyl-H), 6.34–6.36 m (1H,
furyl-H), 5.99 s (1H, 2-H), 3.87–4.01 m (2H, 4,5-H),
2.90–2.97 m (4H, CH2–H), 1.58 s (4H, NH2–H). MS-
ESI (m/z): 199 [M + H]+.
Synthesis of compounds 5a–5f. To a solution of
potassium chloroplatinite dissolved in 1 equiv. of H2O
was added a solution of 1 equiv. of compound 4
dissolved in 1 equiv. of H2O in the course of 30 min.
The mixture was stirred for 6–8 h. The precipitated
solid product was filtered off, washed with alcohol and
water, and dried in vacuum.
Compound 5a. White solid, yield 95.2%. 1H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.41–7.48 m
(5H, Ar-H), 5.98–6.00 s (1H, 2-H), 4.82–4.88 m (2H,
4,5-H), 2.68–3.16 m (4H, CH2–H). MS-ESI (m/z): 509
[M + Cl]–, 983 [2M + Cl]–. Found, %: C 27.84, H 3.38,
N 5.89, Pt 41.15. C11H16Cl2N2O2Pt. Calculated, %: C
27.86, H 3.40, N 5.91, Pt 41.13.
Synthesis of compounds 4a–4f. A solution of
1 equiv. of compound 3 in 3 equiv. of dry THF was
added to a suspension of 5 equiv. of LiAlH4 in
10 equiv. of THF at 0°C under inert atmosphere. The
reaction mixture was cooled down to room tem-
perature and then refluxed upon stirring for 24 h. Upon
addition of ice cold water the suspension was formed.
It was filtered through Celite, concentrated and
extracted with dichloromethane. The organic layer was
dried, filtered, concentrated and purified by column
chromatography (SiO2; dichloromethane : methanol :
triethylamine = 100 : 100 : 1) to give colorless or
yellow oils 4a–4f.
Compound 5b. White solid, yield 96.8%. 1H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.60–7.21 m
(4H, Ar-H), 6.22–6.27 s (1H, 2-H), 4.97–4.89 m (2H,
4,5-H), 3.06–2.68 m (4H, CH2–H). MS-ESI (m/z): 491
[M – H]–, 527 [M + Cl]–. Found, %: C 23.83, H 3.05, N
5.67, Pt 39.65. C11H15Cl2FN2O2Pt. Calculated, %: C
23.84, H 3.07, N 5.69, Pt 39.63.
Compound 5c. White solid, yield 93.4%. 1H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.35–7.21 m
(4H, Ar-H), 6.01 s (1H, 2-H), 4.91–4.75 m (2H, 4,5-H),
3.17–2.71 m (4H, CH2–H). MS-ESI (m/z): 512 [M +
Na]+. Found, %: C 26.81, H 3.05, N 5.66, Pt 39.67.
C11H15Cl2FN2O2Pt. Calculated, %: C 26.84, H 3.07, N
5.69, Pt 39.63.
1
Compound 4a. Colorless liquid, yield 65.1%. H
NMR spectrum (300 MHz, CDCl3) δ, ppm: 7.39–7.51
m (5H, Ar-H), 5.94 s (1H, 2-H), 3.93–3.99 m (2H, 4,5-
H), 2.89–2.99 m (4H, CH2–H), 1.44 s (4H, NH2–H).
MS-ESI (m/z): 209 [M + H]+.
1
Compound 4b. Colorless liquid, yield 66.7%. H
NMR spectrum (CDCl3), δ, ppm: 7.56–7.59 m (1H,
Ar-H), 7.34–7.36 m (1H, Ar-H), 7.16–7.19 m (1H, Ar-
H), 7.04–7.08 m (1H, Ar-H), 6.21 s (1H, 2-H), 3.96–
3.99 m (2H, 4,5-H), 2.91–3.05 m (4H, CH2–H), 1.48 s
(4H, NH2–H). MS-ESI (m/z): 227 [M + H]+.
1
Compound 4c. Colorless liquid, yield 60.2%. H
NMR spectrum (CDCl3), δ, ppm: 7.36–7.17 m (3H,
Ar-H), 7.07–7.05 m (1H, Ar-H), 5.91 s (1H, 2-H),
3.42–3.96 m (2H, 4,5-H), 2.87–3.01 m (4H, CH2–H),
1.68 s (4H, NH2–H). MS-ESI (m/z): 227 [M + H]+, 210
[M – NH2]+.
Compound 5d. White solid, yield 96.8%. 1H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.55–7.48 m
(2H, Ar-H), 7.25–7.18 m (2H, Ar-H), 5.97 s (1H, 2-H),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 4 2016

942
XU, WANG
5.05–4.72 m (2H, 4,5-H), 3.05–2.81 m (4H, CH2–H).
MS-ESI (m/z): 491 [M – H]–, 527 [M + Cl]–. Found, %:
C 26.82, H 3.05, N 5.67, Pt 39.66. C11H15Cl2FN2O2Pt.
Calculated, %: C 26.84, H 3.07, N 5.69, Pt 39.63.
5.32, Pt 37.30. C14H17FN2O6Pt. Calculated, %: C
32.13, H 3.27, N 5.35, Pt 37.27.
Compound 6d. White solid, yield 65.4%. 1H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.54–7.49 m
(2H, Ar-H), 7.25–7.19 m (2H, Ar-H), 5.99 s (1H, 2-H),
5.42–5.21 m (4H, CH2–H), 4.60–4.79 m (2H, 4,5-H),
3.02 s (2H, CH2(COO)2H), 2.71–2.92 m (4H, NH2–H).
MS-ESI (m/z): 557 [M + Cl]–, 584 [M + Ac]–. Found,
%: C 32.11, H 3.25, N 5.32, Pt 37.29. C14H17FN2O6Pt.
Calculated, %: C 32.13, H 3.27, N 5.35, Pt 37.27.
Compound 5e. Yellow solid, yield 92.7%. 1H
NMR spectrum (DMSO-d6 + D2O), δ, ppm: 7.62 m
(1H, thienyl-H), 7.24 m (1H, thienyl-H), 7.03–7.06 m
(1H, thienyl-H), 6.32 s (1H, 2-H), 4.85–4.68 m (2H,
4,5-H), 3.17–2.63 m (4H, CH2–H). MS-ESI (m/z): 479
[M – H]–, 515[M + Cl]–, 997 [2M + Cl]–. Found, %: C
22.49, H 2.91, N 5.81, Pt 40.65. C9H14Cl2N2O2PtS.
Calculated, %: C 22.51, H 2.94, N 5.83, Pt 40.62.
1
Heptaplatin. White solid, yield 69.3%. H NMR
spectrum (DMSO-d6), δ, ppm: 5.48–5.52 br.s (3H,
NH2–H), 5.29–5.32 br.s (1H, NH2–H), 4.80 d (1H,
CH–H), 4.56 m (1H, CH–H), 4.30 m (1H, CH–H),
3.26 m [2H, CH2(COO)2–H], 3.07 m (1H, CH2–H),
2.97 m (1H, CH2–H), 2.56–2.58 m (2H, CH2–H), 1.75
m (1H, CH–H), 0.87 d (6H, CH3-H). MS-ESI (m/z):
493 [M + Na]+. Found, %: C 27.79, H 4.39, N 6.10, Pt
41.22. C11H20N2O6Pt. Calculated, %: C 28.03, H 4.28,
N 5.94, Pt 41.39.
1
Compound 5f. White solid, yield 93.3%. H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.71–7.72 m
(1H, furyl-H), 6.58–6.62 m (1H, furyl-H), 6.46–6.48 m
(1H, furyl-H), 6.07–6.09 s (1H, 2-H), 4.74–4.78 m
(2H, 4,5-H), 2.63–3.17 m (4H, CH2–H). MS-ESI (m/z):
499 [M + Cl]–, 963 [2M + Cl]–. Found, %: C 23.27, H
3.02, N 6.01, Pt 42.05. C9H14Cl2N2O3Pt. Calculated,
%: C 23.29, H 3.04, N 6.03, Pt 42.02.
Synthesis of compounds 6a–6d. The mixture of
1 equiv. of compound 5, 1 equiv. of water and 1 equiv.
of AgNO3 was homogenized upon stirring, heated to
50–60°C in darkness for 24 h and cooled down to 20°C.
Addition of 1 equiv. of sodium acetate gave the
precipitated product which was filtered off and recrys-
tallized from water.
Compound 6a. White solid, yield 62.5%. 1H NMR
spectrum (DMSO-d6), δ, ppm: 7.40–7.46 m (5H, Ar-H),
5.96 s (1H, 2-H), 5.42–5.64 m (4H, CH2–H), 4.57–
4.78 m (2H, 4,5-H), 3.03(s, 2H, CH2(COO)2-H), 2.68–
2.72 m (4H, NH2–H). MS-ESI (m/z): 527 [M + Na]+.
Found, %: C 33.25, H 3.57, N 5.52, Pt 38.63.
C14H18N2O6Pt. Calculated, %: C 33.27, H 3.59, N 5.54,
Pt 38.60.
Compound 6b. White solid, yield 70.3%. 1H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.62–7.21 m
(4H, Ar-H), 6.22 s (1H, 2-H), 5.60–5.33 m (4H, CH2–H),
4.86–4.54 m (2H, 4,5-H), 3.09 s [2H, CH2(COO)2–H],
2.93–2.89 m (4H, NH2–H). MS-ESI (m/z): 522 [M –
H]–, 557 [M + Cl]–, 584 [M + Ac]–. Found, %: C 32.11,
H 3.25, N 5.33, Pt 37.30. C14H17FN2O6Pt. Calculated,
%: C 32.13, H 3.27, N 5.35, Pt 37.27.
Compound 6c. White solid, yield 63.8%. 1H NMR
spectrum (DMSO-d6 + D2O), δ, ppm: 7.22–7.47 m
(4H, Ar-H), 5.98 s (1H, 2-H), 5.44–5.62 m (4H, CH2–H),
4.61–4.74 m (2H, 4,5-H), 3.28 s [2H, CH2(COO)2–H],
3.02–2.72 m (4H, NH2–H). MS-ESI (m/z): 524 [M +
H]+, 546 [M + Na]+. Found, %: C 32.10, H 3.25, N
Evaluation of anti-proliferative activity. Adherent
tumor cells, that had a logarithmic growth phase, were
treated with trypsin and then diluted to 5,000 cells/mL
in RPM11640 with 10% calf serum. Those cells were
seeded into 96 well culture plates by dispensing
100 μL into each well and the plates were incubated at
37°C with 5% CO2 for 24 h. (1) For the experimental
groups, 10 μL of a compound in 990 μL RPM11640
with 10% calf serum were added to each well to make
final volume of 200 μL. The plates were incubated for
3 days at 37°C with 5% CO2. (2) The supernatant was
discarded, 100 μL of freshly prepared serum-free
medium containing 0.5 mg/mL MTT was added to
each well and the plates were incubated at 37°C for
4 h. The supernatant was discarded, 200 μL DMSO
was added to dissolve MTT precipitate. The solutions
were mixed thoroughly using a micro-ultrasonicator
and the optical density was measured at 544 nm.
(3) Solutions of each compound at concentrations
0.005, 0.05, 0.5, and 5 μg/mL were tested for their
ability to inhibit two cell lines. Values for each sample
were calculated as follows:
Percent inhibition of tumor cell growth
= (ODcontrol – ODexperiment)/(ODcontrol – ODblank) × 100%.
Heptaplatin was used as the positive control.
The preliminary bioassays (see table) revealed that
compounds 5a and 5b demonstrated high anti-prolix-
ferative activity against HCT-8 cell lines and most of
compounds exhibited high anti-proliferative activity
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 4 2016

SYNTHESIS OF NOVEL HEPTAPLATIN DERIVATIVES
943
In vitro anti-proliferative activity of products against HCT-8 and Bel-7402 cell lines
Inhibitory rate of the
Inhibitory rate of
the growth, %
Concentration,
Comp. Concentration,
growth, %
Comp. no.
Ar
Ar
μg/mL
no.
μg/mL
HCT-8 Bel-7402
HCT-8 Bel-7402
Heptaplatin
0.005
0.050
0.500
5.000
–8.75
2.69
–5.68
20.43
24.79
20.02
12.50
36.06
5f
0.005
0.050
0.500
5.000
Furyl
4.38
6.09
8.18
9.04
15.76
18.90
12.67
13.65
5a
5b
5c
5d
5e
0.005
0.050
0.500
5.000
C6H5
6.45
0.49
–5.52
50.28
9.50
12.04
14.75
16.94
6a
6b
6c
6d
0.005
0.050
0.500
5.000
C6H5
2.53
–3.27
–13.08
18.42
1.45
12.32
13.11
16.80
0.005
0.050
0.500
5.000
2-FC6H4 –4.64
–3.60
5.86
16.83
18.22
20.41
0.005
0.050
0.500
5.000
2-FC6H4
3-FC6H4
3.79
–0.28
–2.44
1.70
6.77
18.49
23.48
23.96
–5.44
35.50
0.005
0.050
0.500
5.000
3-FC6H4
7.65
–3.87
–6.11
0.10
8.00
19.82
23.03
25.93
0.005
0.050
0.500
5.000
9.92
–0.81
–3.44
2.69
6.97
19.80
25.87
27.73
0.005
0.050
0.500
5.000
4-FC6H4 –10.86
9.31
20.64
23.24
28.39
0.005
0.050
0.500
5.000
4-FC6H4 –41.29
7.71
15.10
18.42
18.77
9.18
7.08
3.37
8.56
0.21
2.86
0.005
0.050
0.500
5.000
Thienyl –13.19
9.17
15.71
18.91
25.28
3.04
6.67
8.05
2. Kim, D.K., Kim, H.T., Cho, Y.B., et al., Cancer
Chemother. Pharmac., 1995, vol. 35, p. 441. DOI:
10.1007/s002800050260.
3. Lee, J.W., Park, J.L., Lee, S.H., et al., Anticancer
Drugs, 2006, vol. 17, p. 377. DOI: 10.1097/
01.cad.0000205033.08838.c7.
against Bel-7402 cells. The accumulated data indicated
that fluorine substituent at various positions of the
benzene ring of heptaplatin significantly influenced
anti-proliferative activity of the products.
CONCLUSIONS
4. Hong, W.S., Kim, H.T., Kim, K.H., et al., Anticancer
Res., 1995, vol. 15, p. 51.
A series of novel heptaplatin derivatives was
synthesized by the original method. Ability of the
compounds to inhibit HCT-8 and Bel-7402 cancer cell
lines was evaluated. Compound 5a (5 μg/mL) was the
most efficient in inhibiting HCT-8 cell line growth,
while 6c (0.5 μg/mL) was the most effective against
Bel-7402 cells. Majority of the synthesized compounds
were equivalent or superior inhibitors of the two tested
cell lines compared with heptaplatin.
5. Ahu, M.J., Oh, H.S., Choi, J.H., et al., Cancer Res. and
Treatm., 2004, vol. 36, p. 182. DOI: 10.4143/
crt.2004.36.3.182.
6. Lee, W.S., Lee, G.W., Kim, H.W., et al., Cancer Res.
and Treatm., 2005, vol. 37, p. 208. DOI: 10.4143/
crt.2005.37.4.208.
7. Sbovata, S.M., Bettio, F., Mozzon, M., et al., J. Med.
Chem., 2007, vol. 50, p. 4775. DOI: 10.1021/jm070426p.
8. Kim D.K., Kim, G., Gam, J., et al., J. Med. Chem.,
1994, vol. 37, p. 1471. DOI: 10.1021/jm00036a013.
9. Kim D.K., Kim, Y., Rim, J., Kim, G., et al., J. Lab.
Comp. Radiopharm., 1994, vol. 34, p. 157. DOI:
10.1002/jlcr.2580340208.
REFERENCES
1. Rabik, C.A. and Dolan, M.E., Cancer Treat Rev, 2007,
10. Kim, D.K. and Kim, Y., CN Patent 1204650, 1990.
vol. 33, p. 9. DOI: 10.1016/j.ctrv.2006.09.006.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 4 2016