Synthesis, characterization and biological evaluation of platinum(II) complexes with a chiral N-monosubstituted 1,2-cyclohexyldiamine derivative

Article abstract of DOI:10.1248/cpb.59.851

Eight platinum(II) compounds with a new chiral ligand, 2-(((1R,2R)-2- aminocyclohexylamino)methyl)phenol (HL), were designed, prepared and spectrally characterized. All compounds showed better aqueous solubility than cisplatin and oxaliplatin. In vitro cy

Full text of DOI:10.1248/cpb.59.851

July 2011
Regular Article
Chem. Pharm. Bull. 59(7) 851—854 (2011)
851
Synthesis, Characterization and Biological Evaluation of Platinum(II)
Complexes with a Chiral N-Monosubstituted 1,2-Cyclohexyldiamine
Derivative
b
,a,b
a,b
Chuanzhu GAO, Shaohua GOU,* and Gang XU
a
b
Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, Southeast University; and Pharmaceutical
Research Center, School of Chemistry and Chemical Engineering, Southeast University; Nanjing 211189, China.
Received January 4, 2011; accepted March 27, 2011; published online May 6, 2011
Eight platinum(II) compounds with a new chiral ligand, 2-(((1R,2R)-2-aminocyclohexylamino)methyl)phe-
nol (HL), were designed, prepared and spectrally characterized. All compounds showed better aqueous solubility
than cisplatin and oxaliplatin. In vitro cytotoxicity of these compounds against human HepG-2, MCF-7, A549
and HCT-116 cell lines was evaluated. Results indicated that all compounds showed cytotoxicity against A549
ꢀ
ꢀ
and HepG-2 cell lines. Particularly, compounds B1 and B8, which have CF SO3 and (CH ) COCH COO as
3
3 3
2
leaving groups, respectively, exhibited better cytotoxicitiy than that of carboplatin in these two cell lines.
Key words 1R,2R-cyclohexyldiamine derivative; platinum(II) complex; cytotoxicity
Cisplatin is one of the most frequently used chemothera- mononuclear platinum complexes (B1—B8) have been ob-
peutics in the treatment of malignant tumors, nevertheless, tained. Herein reported are these platinum complexes and
the clinical application is greatly limited by two factors: in- their in vitro cytotoxicity against four human cancer cell
1—5)
tolerable side effects and intrinsic/acquired resistance.
So lines.
far, tremendous efforts have been devoted to developing new
platinum compounds with improved pharmacological proper-
ties and broader range of antitumor activity. This leads to the ical company, mono-tert-butoxycarbonyl (Boc) protecting DACH was used
Experimental
Materials and Instruments K PtCl was purchased from a local chem-
2
4
21)
clinical development of cisplatin analogues such as carbo- as the starting material and prepared according to the procedure reported.
All reagents were of high purity and used without any further purification.
Elemental analysis for C, H and N was performed with a Perkin-Elmer
platin and oxaliplatin which have been widely used for treat-
6—9)
ing ovarian cancers and colorectal tumors, respectively.
Oxaliplatin is the first platinum-based drug owning a chi-
1400C instrument, while Pt was determined according to the method in EP5.
Electrospray ionization-mass spectra (ESI-MS) spectra were carried out in
ral moiety, 1R,2R-diaminocyclohexane (DACH), as a carrier Finnigan MAT SSQ 710 (120—1000 amu) apparatus and IR spectra were
group, and now a preferred drug in treating advanced col- scanned by a Nicolet IR200 spectrophotometer in the range of 4000—
ꢀ
1
1
4
00 cm in KBr pellet. H-NMR spectra were recorded on a Bruker DRX-
orectal carcinoma (ACRC). Although oxaliplatin has sup-
planted cisplatin as the largest selling platinum therapeutic,
its dose-limiting toxicity in the clinical practice is still insuf-
ferable. It has been reported that approximately 90% of pa-
tients treated with oxaliplatin suffered from acute neurotoxic-
ity, while 10—15% of patients suffered from cumulative sen-
5
00 spectrometer at 500 MHz in D O using tetramethylsilane (TMS) as an
2
internal reference. Specific rotations were tested on a Shenguang WZZ-2B
instrument.
Synthesis. Ligand HL: 2-(((1R,2R)-2-Aminocyclohexylamino)methyl)-
phenol Fifty millimole mono-Boc protecting DACH and 60 mmol salicyl-
aldehyde were dissolved in 100 ml of toluene and refluxed for 5 h. After con-
centrating the solution, white solids were obtained, which was dissolved in
10,11)
sory.
Like other clinically available platinum anticancer
200 ml of methanol and 100 mmol NaBH was added in portions. The mix-
4
drugs, oxaliplatin can not offer any substantial clinical ad-
ture was refluxed for 3 h, EtOAc was used to extract the product into the or-
ganic phase which was washed with water twice. The organic solution was
mixed with excess HCl/EtOAc (5 mol/l), leading to the formation of HL hy-
12—14)
vantages over the existing cisplatin, either.
Considering the advantages of oxaliplatin in treating
ACRC and its drawbacks, we have been devoting to studying
new platinum compounds with chiral ligands in recent years.
drochloride, which was finally neutralized by aqueous Na CO3 solution
2
(1 mol/l) to give free HL 4.3 g. Yield, 40%. Found (Calcd for C H N O), C
13 20 2
ꢀ1
7
1.08 (70.91), H 9.23 (9.09), N 12.58 (12.73). IR (KBr, cm ): 3418—3274
Since 1R,2R-diaminocyclohexane plays an important role in (m, nN–H), 2928, 2852 (m, nC–H), 1596 (m, nAr), 750 (m, gArH). ESI-MS m/z:
15,16)
ꢁ
1
the molecular skeleton of oxaliplatin,
we have designed [MꢁH] ꢂ221 (100%). H-NMR (CDCl
3
, ppm) d: 1.06—2.38 (m, 8H,
4
CH of DACH), 2.79—3.05 (m, 2H, 2CH of DACH), 3.79—4.02 (m, 2H,
and prepared a number of 1R,2R-diaminocyclohexane based
compounds, whose structures remain the chiral unit of
DACH. Among those compounds, 2-(((1R,2R)-2-aminocy-
2
1
5
C H –CH ), 6.78—7.13 (m, 4H, C H ). [a] ꢁ95.0 (cꢂ1.0, MeOH).
6
4
2
6
4
D
Intermediate [PtLI] Twelve millimole K PtCl was added into a stir-
2
4
ring aqueous solution containing 80 mmol KI in 100 ml water. The blending
clohexylamino)methyl)phenol (HL) as a tridentate ligand has solution was stirred at 25 °C for 30 min under a nitrogen atmosphere to get a
PtI . Then a mixing aqueous solution of 12 mmol HL
been prepared. A methylphenolic group was introduced to black solution of K
2
4
and 12 mmol NaOH in 30 ml water was added dropwisely under stirring in
the dark at 25 °C. After 6 h, the dark yellow precipitate was filtered, washed
sequentially with water, ethanol and ether, and finally dried in vacuum. Data
for [PtLI]: 6.2 g, Yield: 95%, dark yellow solid. Found (Calcd for
the DACH skeleton for two expectations. One is that the li-
gand can offer three coordination sites to bind a platinum
atom that leaves an empty position to allow bridging ligands
17)
to form dinuclear platinum(II) complexes. The other is that C H IN OPt), C 28.56 (28.83), H 3.65 (3.51), N 5.26 (5.18), Pt 35.87
1
3
19
2
ꢀ
1
(
36.04). IR (KBr, cm ): 3418—3180 (m, n ), 2933, 2859 (m, nC–H), 1594
N–H
ꢁ ꢁ
the aromatic ring in the ligand might yield steric hindrance
18)
(m, n ), 748 (m, g ). ESI-MS m/z: [MꢁH] ꢂ542 (60%), [MꢁNa] ꢂ564
Ar ArH
1
like a-picoline in ZD0473 that shows no cross resistance
with classical platinum-based drugs such as cisplatin and
carboplatin. With HL as a carrier ligand and some
(
4
4
100%). H-NMR (DMSO, ppm) d: 1.06—2.74 (m, 10H of DACH), 3.88—
.09 (m, 2H, C H –CH ), 5.83—6.54(m, 3H, NH and NH), 6.72—7.09 (m,
6
4
2
2
15
D
H, C H ). [a] ꢁ96.9 (cꢂ1.0, MeOH).
6
4
19,20)
monoacidic anions
as leaving groups, eight novel
Compound B1 Two millimole [PtLI] was first suspended in 100 ml pure
∗
To whom correspondence should be addressed. e-mail: sgou@seu.edu.cn
© 2011 Pharmaceutical Society of Japan

8
52
Vol. 59, No. 7
ꢀ
ꢀ
ꢀ
1
water, and next a solution of 2 mmol AgNO in 20 ml pure water was added.
ESI-MS m/z: [MꢁCH (CH ) OCH COO ] ꢂ676 (100%). H-NMR (D O,
3 2 3 2 2
3
After stirring under a nitrogen atmosphere in the dark for 12 h at 40 °C, the
deposit was filtered off. Filtrate was blended with 2 mmol CF SO Na and
ppm) d: 0.84—2.73 (m, 17H, 10H of DACH and 7H of CH CH CH ),
3 2 2
3.34—3.49 (m, 4H of CH OCH COO), 3.80—4.04 (m, 2H, C H –CH ),
3
3
2
2
6
4
2
stirred at 60 °C for 24 h. The solution was concentrated and cooled to 0 °C.
White solid was collected, washed with a small amount of chilled water and
ethanol, and then dried at 60 °C in vacuum. Yield 21%, Found (Calcd for
6.48—7.07 (m, 4H, C H ).
Compound B8 Yield 36%, Found (Calcd for C H N O Pt), C 41.52
(41.83), H 5.66 (5.50), N 5.06 (5.14), Pt 35.68 (35.79). IR (KBr, cm ):
6 4
1
9
30
2
4
ꢀ
1
C H F N O SPt), C 29.61 (29.83), H 3.53 (3.37), N 5.10 (4.97), Pt 34.81 3437—3111 (m, nN–H), 2936, 2862 (m, n ), 1597 (s, nCꢂO), 751 (m, gArH).
1
4
19
3
2
4
C–H
ꢀ
1
ꢀ
ꢀ
ꢀ
1
(
(
34.64). IR (KBr, cm ): 3433—3107 (m, nN–H), 2936, 2864 (m, nC–H), 1566
ESI-MS m/z: [Mꢁ(CH ) COCH COO ] ꢂ676 (100%). H-NMR (D O,
3
3
2
2
ꢀ
1
m, nAr), 758 (m, gArH). ESI-MS m/z: [MꢀH] ꢂ62 (50%). H-NMR (D O, ppm) d: 0.92—2.72 (m, 19H, 10H of DACH and 9H of 3CH )), 3.35—3.74
2
3
ppm) d: 1.13—2.64 (m, 10H of DACH), 3.87—4.23 (m, 2H, C H –CH ), (m, 2H of COCH COO), 3.80—4.09 (m, 2H, C H –CH ), 6.25—7.02 (m,
6
4
2
2
6
4
2
6
.66—7.15 (m, 4H, C H ).
4H, C H ).
6
4
6 4
The procedures for preparing compounds B2—B8 were similar to B1.
Compound B2 Yield 27%, Found (Calcd for C H ClN O Pt), C 35.20 zolium bromide (MTT) assay was carried out as described by Mosmann.
In Vitro Cytotoxicity 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetra-
22)
1
5
21
2
3
ꢀ
1
(
3
35.46), H 4.27 (4.14), N 5.39 (5.52), Pt 38.29 (38.43). IR (KBr, cm ): Tumor cells were plated onto 96-well sterile plates in 100 ml of medium at a
3
3
427—3104 (m, nN–H)ꢀ, 2937, 2861 (m, nC–H), 1596 (s, nCꢂO), 755 (m, gArH). density of 4ꢃ10 —8ꢃ10 cells per well and incubated for 24 h at 37 °C in a
1
ESI-MS m/z: [MꢀH] ꢂ507 (100%). H-NMR (D O, ppm) d: 1.12—2.60 5% CO containing incubator. Compounds B1—B8, oxaliplatin and carbo-
2
2
(
m, 10H of DACH), 3.84—3.97 (m, 2H, ClCH COO), 4.18—4.28 (m, 2H,
C H –CH ), 6.63—7.14 (m, 4H, C H ).
Compound B3 Yield 19%, Found (Calcd for C H N O Pt), C 37.90
platin were added in final concentrations ranging from 0 to 100 mM. After
2
48 h, 50 ml MTT in phosphate buffered saline (PBS) (5 mg/ml) was added to
each well and the plates were incubated for 3 h at 37 °C. Removing the liq-
uid and adding dimethyl sulfoxide (DMSO) (100 ml) to dissolve the MTT
formazan. The optical density (OD) for each well was measured on a mi-
croplate reader at a wavelength of 490 nm. All cytotoxicity tests were carried
out 3 times parallelly, IC50 values were got from curves constructed by plot-
ting cell survival (%) versus compound concentration (in mM).
6
4
2
6
4
1
5
22
2
3
ꢀ
1
(
3
38.05), H 4.79 (4.65), N 5.76 (5.92), Pt 41.38 (41.23). IR (KBr, cm ):
413—3102 (m, n ), 2936, 2861 (m, nC–H), 1596 (s, nCꢂO), 751 (m, gArH).
N–H
ꢀ
ꢀ
1
ESI-MS m/z: [MꢀH] ꢂ472 (100%). H-NMR (D O, ppm) d: 1.12—2.60
2
(
6
m, 13H, 10H of DACH and 3H of CH ), 3.83—4.27 (m, 2H, C H –CH ),
3
6
4
2
.24—7.15 (m, 4H, C H ).
6 4
Compound B4 Yield 31%, Found (Calcd for C H N O Pt), C 38.03
1
6
24
2
4
ꢀ
1
(
3
38.17), H 4.90 (4.77), N 5.82 (5.57), Pt 38.93 (38.77). IR (KBr, cm ):
418—3111 (m, n ), 2936, 2862 (m, n ), 1597 (s, nCꢂO), 750 (m, gArH).
Result and Discussion
For the synthesis of the ligand (HL), it is hard to directly
N–H
C–H
ꢀ
ꢀ
ꢀ
1
ESI-MS m/z: [MꢁCH OCH COO ] ꢂ592 (100%). H-NMR (D O, ppm)
3
2
2
d: 1.06—2.74 (m, 10H of DACH), 3.19—3.43 (m, 5H of CH OCH COO), get a N-monsubstituted derivative due to the equivalent reac-
3
2
3
.76—4.04 (m, 2H, C H –CH ), 6.30—7.07 (m, 4H, C H ).
tivity of the two amino groups in DACH. Thus, mono-Boc
protecting DACH was used as the starting material, and the
ligand was synthesized via several synthetic steps.
When preparing the targeted platinum compounds, we first
6
4
2
6
4
Compound B5 Yield 33%, Found (Calcd for C H N O Pt), C 39.21
21)
1
7
26
2
4
ꢀ
1
(
39.46), H 5.20 (5.03), N 5.58 (5.42), Pt 37.49 (37.74). IR (KBr, cm ):
432—3112 (m, nN–H), 2934, 2863 (m, n ), 1597 (s, nCꢂO), 749 (m, gArH).
3
C–H
ꢀ
ꢀ
ꢀ
1
ESI-MS m/z: [MꢁCH CH OCH COO ] ꢂ620 (100%). H-NMR (D O,
3
2
2
2
ppm) d: 0.84—2.74 (m, 13H, 10H of DACH and 3H of CH ), 3.19—3.49 synthesized the intermediate [PtLI] by adopting a similar
3
2
3)
(
4
m, 4H of CH OCH COO), 3.67—4.09 (m, 2H, C H –CH ), 6.25—7.07 (m, method described literaturally.
And then AgNO3 was
2
2
6
4
2
H, C H ).
6 4
used to remove the iodide anions of [PtLI] to form
[PtL(H O)]NO , which was in situ reacted with sodium salts
of the corresponding acids, respectively, to give compounds
Compound B6 Yield 23%, Found (Calcd for C H N O Pt), C 40.52
1
8
28
2
4
ꢀ
1
2
3
(
3
40.68), H 5.11 (5.27), N 5.42 (5.27), Pt 36.88 (36.72). IR (KBr, cm ):
428—3114 (m, n ), 2934, 2863 (m, nC–H), 1598 (s, nCꢂO), 748 (m, gArH).
N–H
ꢀ
ꢀ
1
ESI-MS m/z: [MꢀH] ꢂ530 (100%). H-NMR (D O, ppm) d: 1.01—2.72 B1 to B8 (Chart 1) .
2
1
(
m, 16H, 10H of DACH and 6H of 2CH )), 3.19—3.66 (m, 3H of
3
All platinum complexes were characterized by IR, H-
CHOCH COO), 3.76—4.08 (m, 2H, C H –CH ), 6.29—7.07 (m, 4H, C H ).
Compound B7 Yield 34%, Found (Calcd for C H N O Pt), C 41.56
41.83), H 5.33 (5.50), N 5.21 (5.14), Pt 35.91 (35.79). IR (KBr, cm ):
419—3110 (m, nN–H), 2935, 2863 (m, nC–H), 1596 (s, nCꢂO), 751 (m, gArH).
2
6
4
2
6
4
NMR, ESI-MS spectra and microanalyses. The elemental
analysis results are in good agreement with the calculated
values. The IR spectra of these complexes are similar, Pt–N
1
9
30
2
4
ꢀ
1
(
3
Chart 1. Synthetic Chart for Platinum(II) Compounds B1—B8

July 2011
853
coordination bonds were confirmed by the examination of B6 and B7 also showed better antitumor activity than carbo-
nNH /nNH shifting to lower frequencies comparing with platin against HepG-2. Further studies indicated that when
2
their free amino groups. On the other hand, the shifts of the alkoxyacetates were selected as leaving groups in these com-
ꢀ
1
CꢂO absorption from free carboxylic acids near 1700 cm
pounds against A549 cell lines,the longer the carbon chain
ꢀ
1
to a band near 1597—1596 cm proved that carboxylate an- was, the better the antitumor activity was. The activity order
24)
ꢀ
ꢀ
ions were coordinated to Pt(II) ions in each case (B2—B8).
was B4 (CH OCH COO )ꢄB5 (CH CH OCH COO )ꢄB6
3 2 3 2 2
ꢀ ꢀ
1
The H-NMR spectra of the complexes are consistent with ((CH ) CHOCH COO )ꢄB7 (CH (CH ) OCH COO )ꢄB8
their corresponding protons both in the chemical shifts and ((CH ) COCH COO ). It is observed that compounds B4 to
3
2
2
3
2 3
2
ꢀ
3
3
2
the number of hydrogens. All prepared complexes showed a B8 have diminished their hydrophily but increased their
ꢀ
ꢀ
peak of [MꢁZ] or [MꢀH] in their negative ESI mass lipotropy with the increase of the carbon chain in alkoxy-
spectra, which are consistent with expected molecular for- acetate. Thus, B8 was assumed to be easier to enter the tu-
2
5—29)
mula weights. The mass spectra of the compounds exhibited mor cells and inhibit proliferation.
It is noted that
1
94
three typical molecular ion peaks due to the isotopes of Pt compounds B7 and B8 have the same carbon numbers,
1
95
196
(
33%), Pt (34%) and Pt (25%).
but B8 with a branched carbon chain showed better activity
Poor aqueous solubility is a problem for some platinum than B7 with a linear carbon chain. All complexes exhibit-
anticancer drugs, such as cisplatin. Hence the aqueous solu- ed analogous optical rotations to that of oxaliplatin, this
bility of our Pt compounds was measured at 25 °C (Table 1). may be one of reasons that they are of activity against HepG-
Compared with cisplatin (1 mg/ml) and oxaliplatin 2 and A549 cell lines.
(8 mg/ml), all prepared platinum compounds have rather
When against MCF-7 and HCT-116, only compound B1
good aqueous solubility ranging from 12.8 to 26.2 mg/ml. In exhibited close activity to positive controls. Despite of being
addition, the optical rotations of all complexes were tested. less cytotoxicity than that of oxaliplatin against HCT-116,
All compounds exhibited analogous optical rotations our compounds were assumed to have no cross resistance
(
ꢁ35.2°—ꢁ67.9°) to that of oxaliplatin (ꢁ76.1°).
with classical platinum-based drugs due to the unique coor-
The in vitro cytotoxicity of these platinum compounds was dination mode of the deprotonated ligand with the metal
evaluated by MTT colorimetric assay using HepG-2 human atom. But further work needs to be done to support our as-
hepatocellular carcinoma cell, MCF-7 human breast cancer sumption in future.
cell, A549 human lung cancer cell and HCT-116 human
We have ever reported a number of Pt(II) complexes with
19)
colorectal cancer cell, with carboplatin and oxaliplatin as several alkoxyacetates as leaving groups. Among them,
positive controls. As we can see from Table 2, all platinum compounds 1a, 2a and 3a with DACH as a carrier ligand
compounds showed activity against HepG-2 and A549 cell showed better activity than those of cisplatin, carboplatin and
lines. Among them, compounds B1 and B8 gave lower IC50 oxaliplatin against a few of human tumor cell lines including
values than carboplatin in these two cell lines. Compounds A549. Although compounds B1 and B8 showed better activ-
ity than carboplatin, they did not surpass those of compounds
2
a and 3a when treated with A549 cell line. As expected, HL
Table 1. Aqueous Solubility and Optical Rotation of Complexes B1—B8
has offered three donor atoms to bind a platinum atom
strongly by forming three chelating rings. The methyl phenol
group was assumed not to function as a leaving group but
offer steric resistance to hinder the Pt-DACH species to bind
with glutathione, however, this group has appreared to de-
crease the antitumor activity of the Pt-DACH species of our
compounds in comparison to that of oxaliplatin. While in
compounds 1a, 2a and 3a, the Pt-DACH species with more
empty space after the leaving of two alkoxyacetate anions
could interact with DNA, leading to high cytotoxicity of
these compounds.
1
5
Aqueous solubility
[a]
D
Complex
(mg/ml, 25 °C)
(cꢂ1.0, H O)
2
B1
B2
B3
B4
B5
B6
B7
B8
12.8
23.8
20.5
26.2
21.3
18.9
13.6
15.1
ꢁ60.8°
ꢁ48.8°
ꢁ67.9°
ꢁ39.7°
ꢁ40.8°
ꢁ35.2°
ꢁ42.3°
ꢁ41.8°
Conclusion
Table 2. Cytotoxicity of Compounds B1—B8 against Four Tumor Cell
Lines
We prepared a new compound of HL derived from 1R,2R-
diaminocyclohexane. Using HL as a carrier ligand, we have
designed and synthesized eight novel Pt(II) complexes with a
number of caroxylate anions as leaving groups. All com-
pounds showed better aqueous solubility than cisplatin and
oxaliplatin. In vitro cytotoxicity tests showed that these com-
pounds had certain antitumor activity against A549 and
HepG-2 cell lines. Among them, compounds B1 and B8
showed better antitumor activity than carboplatin against
these two cell lines. Besides, compound B1 also exhibited
close activity to positive controls against HCT-116 and MCF-
ꢀ
1
IC /(mmol·l
)
5
0
Compd.
HepG-2
MCF-7
A549
HCT-116
B1
B2
B3
B4
B5
B6
B7
B8
4.8
31.3
47.4
27.9
13.1
8.3
9.6
7.1
9.7
18.1
ꢅ100
66.5
ꢅ100
ꢅ100
ꢅ100
53.2
27.6
15.3
Not tested
5.4
36.0
22.5
50.1
36.9
6.9
ꢅ100
ꢅ100
ꢅ100
ꢅ100
59.2
38.1
13.6
Not tested
4.3
25.5
16.8
8.3
7
cell lines. Consequently, the prepared platinum com-
Carboplatin
Oxaliplatin
11.2
Not tested
pounds, especially B1, may be deserved for further investiga-
tion as a leading compound.
Not tested

8
54
Acknowledgements This work is supported by the National Natural
Vol. 59, No. 7
14) McKeage M. J., Expert Opin. Investig. Drugs, 14, 1033—1046 (2005).
15) Tyagi P., Gahlot P., Kakkar R., Polyhedron, 27, 3567—3574 (2008).
16) Sanofi-Synthélabo L., Drugs Future, 25, 644—645 (2000).
17) Gao C. Z., Gou S. H., Fang L., Zhao J., Bioorg. Med. Chem. Lett., 21,
1763—1766 (2011).
Science Foundation of China (Project 20971022) and the Six Top Talents
Funding of Jiangsu Province (Project 2008046) as well as the New Drug
Creation Project of the National Science and Technology Major Foundation
of China (project 2010ZX09401-401) to S. H. Gou.
1
8) Banerjee S., Sengupta P. S., Mukherjee A. K., Chem. Phys. Lett., 1—3,
References
108—115 (2010).
1)
Trimmer E. E., Essigmann J. M., Essays Biochem., 34, 191—211 19) Cui K., Wang L. H., Zhu H. B., Gou S. H., Liu Y., Bioorg. Med. Chem.
1999).
Lett., 16, 2937—2942 (2006).
(
2)
3)
4)
Loehrer P. J., Einhorn L. H., Ann. Intern. Med., 100, 704—713 (1984).
Krakoff I. H., Cancer Treat. Rep., 63, 1523—1525 (1979).
20) Liu X., Gou S. H., Shen H., Zhu H. B., Zheng H. G., Chin. J. Inorg.
Chem., 4, 1—8 (2009).
Loehrer P. J., Williams S. D., Einhorn L. H., J. Natl. Cancer Inst., 80, 21) Lee D. W., Ha H. J., Lee W. K., Synth. Commun., 37, 737—742 (2007).
1
373—1376 (1988).
22) Mosmann T., J. Immunol. Methods, 65, 55—63 (1983).
23) Dhara S. C., Indian J. Chem., 8, 148—153 (1970).
24) Khokhar A. R., Krakoff I. H., Hacker M. P., Inorg. Chim. Acta, 108,
63—66 (1985).
25) Calvert A. H., Harland S. J., Newell D. R., Siddik Z. H., Jones A. C.,
McElwain T. J., Raju S., Wiltshaw E., Smith I. E., Baker J. M., Peck-
ham M. J., Harrap K. R., Cancer Chemother. Pharmacol., 9, 140—147
(1982).
5
6
7
)
)
)
Hambley T. W., Coord. Chem. Rev., 166, 181—223 (1997).
Wong D., Lippard S. J., Nat. Rev. Drug Discov., 4, 307—320 (2005).
“Platinum Coordination Complexes in Cancer Chemotherapy,” ed. by
Hacker M. P., Douple E. B., Krakoff I. H., Martinus, Boston, 1984.
Frey U., Ranford J. D., Sadler P. J., Inorg. Chem., 32, 1333—1340
8
)
)
(1993).
9
Doi Y., Okada T., Matsumoto H., Ichihara M., Ishida T., Kiwada H.,
Cancer Sci., 101, 2470—2475 (2010).
0) Sood P., Thurmond K. B. 2nd, Jacob J. E., Waller L. K., Silva G. O.,
26) Carter S. K., Canetta R., Rozencweig M., Cancer Treat. Rev., 12
(Suppl. A), 145—152 (1985).
1
Stewart D. R., Nowotnik D. P., Bioconjug. Chem., 17, 1270—1279
27) Canetta R., Rozencweig M., Carter S. K., Cancer Treat. Rev., 12
(Suppl. A), 125—136 (1985).
28) MacLean D. S., Khokhar A. R., Perez-Soler R., Cancer Biother.
Radio., 15, 253—259 (2000).
(
2006).
1) Gamelin E., Gamelin L., Bossi L., Quasthoff S., Semin. Oncol., 29
Suppl 15), 21—33 (2002).
1
1
1
(
2) Jakupec M. A., Galanski M., Keppler B. K., Rev. Physiol. Biochem.
Pharmacol., 146, 1—54 (2003).
3) Momekov G., Bakalova A., Karaivanova M., Curr. Med. Chem., 12,
29) Kishimoto S., Miyazawa K., Terakawa Y., Ashikari H., Ohtani A.,
Fukushima S., Takeuchi Y., Jpn. J. Cancer Res., 91, 1326—1332
(2000).
2
177—2191 (2005).