Synthesis and cytotoxicity of dinuclear platinum(II) complexes of (1S, 3S)-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.cclet.2013.02.014

A series of novel dinuclear platinum(II) complexes with (1S, 3S)-1,2,3,4-tetrahydroisoquinolines as the ligands were synthesized as potential anticancer agents in several steps starting from commercially available l-DOPA. The cytotoxicities of the series of dinuclear platinum(II) complexes of tetrahydroisoquinoline were tested against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines by the MTT test. These complexes showed selective inhibition activity against cisplatin-insensitive cell line Skov3.

Full text of DOI:10.1016/j.cclet.2013.02.014

Chinese Chemical Letters 24 (2013) 186–188
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis and cytotoxicity of dinuclear platinum(II) complexes
of (1S, 3S)-1,2,3,4-tetrahydroisoquinolines
Geng Xu a, Ju Guo a, Zheng Yan b, Nan Wang b, Zhan-Zhu Liu a,b,
*
a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical
Sciences, Beijing 100050, China
b Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical
Sciences, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel dinuclear platinum(II) complexes with (1S, 3S)-1,2,3,4-tetrahydroisoquinolines as the
Received 21 December 2012
Received in revised form 4 February 2013
Accepted 4 February 2013
ligands were synthesized as potential anticancer agents in several steps starting from commercially
available L-DOPA. The cytotoxicities of the series of dinuclear platinum(II) complexes of tetrahy-
droisoquinoline were tested against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines
by the MTT test. These complexes showed selective inhibition activity against cisplatin-insensitive cell
Keywords:
line Skov3.
Dinuclear platinum(II) complexes
Antitumor activity
Tetrahydroisoquinolines
Synthesis
ß 2013 Zhan-Zhu Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
1. Introduction
1,2,3,4-Tetrahydroisosoquinoline alkaloids are widespread
occurring natural products possessing various bioactivities [9]. A
Platinum(II) complexes [1–3] are widely used in cancer
chemotherapy. Cisplatin [2] is one of the most potent antitumor
drugs available for the therapeutic management of solid tumors,
such as germ cell tumors, ovarian, lung, head and neck, and bladder
cancers. Despite its wide application as a chemotherapeutic agent,
cisplatin exhibits two main disadvantages: intrinsic or acquired
resistance and toxicity. These side effects limit the use of cisplatin
in some cancers. So far, tremendous efforts have been devoted to
developing cisplatin analogs with broader spectra of activity,
improved clinical efficacy, and reduced toxicity [3].
More recently, to overcome the side effects of cisplatin, there
have been efforts directed at the design of non-classical Pt
complexes [3–8]. Multinuclear platinum complexes containing
two, three or four platinum centers with both cis and/or trans
configurations have been designed and polyamines are generally
utilized as linkers to connect the platinum centers. A representa-
tive trinuclear complex, BBR3464, has entered a phase II clinical
trial and exhibits activity against pancreatic, lung and melanoma
cancers [3a].
series of cisplatinum complexes with 1-(2-aminophenyl)-1,2,3,4-
tetrahydroisoquinolines have been reported [8b,10]. Several of
these new complexes showed better in vitro cytotoxicity against
several human tumor cell lines than cisplatin. In our previous
report, we designed and synthesized a novel series of cis-
dichloroplatinum(II) complexes of (1S, 3S)-1,2,3,4-tetrahydroiso-
quinolines [11]. In the present work, we report the design and
synthesis of a series of novel dinuclear (1S, 3S)-1,2,3,4-tetrahy-
droisoquinolines platinum complex 8a–e. All complexes were
evaluated for their in vitro cytotoxicity against a panel of human
tumor cell lines.
2. Experimental
Synthesis of the new derivatives (8a–e) was realized by a
stereoselective route starting from L-DOPA (Scheme 1). L-DOPA
was esterified by SOCl2 and CH3OH to the corresponding ester 1.
The synthesis of 2 was accomplished via an asymmetric Pictet-
Spengler reaction from
L-DOPA methyl ester and aromatic
aldehydes under acidic conditions. The major product with cis
configuration was obtained via 1,3-asymmetric induction [12].
Treatment of compound 2 with HCOOH/Ac2O/HCOONa at ambient
temperature afforded the N-protected product. Methylation of the
N-protected product with Me2SO4/K2CO3 in acetone under
refluxing yielded the corresponding O-methylated product. Then
* Corresponding author at: State Key Laboratory of Bioactive Substances and
Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical
College and Chinese Academy of Medical Sciences, Beijing 100050, China.
E-mail address: liuzhanzhu@imm.ac.cn (Z.-Z. Liu).
1001-8417/$ – see front matter ß 2013 Zhan-Zhu Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.02.014

G. Xu et al. / Chinese Chemical Letters 24 (2013) 186–188
187
HO
HO
CO2CH3
CH3O
CH3O
CO2CH3
HO
HO
CO2CH3
CH3O
CH3O
CO2CH3
Boc
a
b
c
NH
NH
NH2
N
1
3
4
2
h
CH3O
CH3O
CH3O
CH3O
CH3O
CONH2
NH
NH2
g
NH2
i
NH
Pt
NH
Cl
d
CH3O
Cl
10
11
9
OCH3
CH3O
CH3O
CHO
Boc
CH3O
CH3O
N
n
N
e
H
H
N
N
N
Boc
Boc
OCH3
6a-e
5
f
OCH3
OCH3
OCH3
OCH3
CH3O
CH3O
CH3O
CH3O
N
H
N
H
Pt
n
n
N
H
N
H
Pt
g
HN
HN
NH
NH
Cl
Cl
Cl
Cl
7a-e
8a-e
8a: n=6; 8b: n=7; 8c: n=8; 8d: n=9; 8e: n=12
Scheme 1. Reagents and conditions: (a) (1) SOCl2, CH3OH, rt, 72 h. (2) Benzaldehyde, CH3COOH, CH3COONa, rt, 20 h. (b) (1) HCOOH, HCOONa (CH3CO)2O, rt, 4 h, then 1 mol/L
HCl, CH3OH, rt, 24 h. (2) K2CO3, Me2SO4, acetone, reflux 10 h. (3) HCl–CH3OH, reflux 3 h. (c) Boc2O, TEA, CH2Cl2, rt, 16 h. (d) DIBAL-H, toluene, ꢀ78 8C, 1.5 h. (e) Aliphatic
diamines, CH3OH, rt, 30 min, then NaBH3CN, rt, 5 h. (f) Me2S, TFA, CH2Cl2, rt, 30 min. (g) K2PtCl4, H2O, 1 M NaOH, 60 8C, 24 h. (h) NH3-CH3OH, rt, 16 h. (i) LiAlH4, THF, rt, 13 h.
the O-methylated product was refluxed in HCl/CH3OH to cleave the
formyl group and product 3 was afforded [13]. Compound 3 was
converted to the N-Boc amino ester 4 in almost quantitative yield
by treatment with Boc2O in the presence of triethylamine. The N-
Boc esters 4 were reduced with DIBAL-H in dichloromethane at
ꢀ78 8C to give the amino aldehyde 5, which was then coupled with
various aliphatic diamines through reductive amination. Subse-
quently, removal of Boc in the presence of trifluoroacetic acid and
dimethyl sulfide led to compound 7. The structures of ligands 7a–e
were characterized through analysis of their respective data [14].
The platinum(II) complexes (8a–e) were then prepared by
treatment of the ditetrahydroisoquinoline ligands 7 with potassi-
um tetrachloroplatinate(II) under controlled-pH conditions in
water at 60 8C [15]. In order to study the difference of standard
platinum agents and dinuclear platinum complexes, mononuclear
platinum complex 11 was synthesized via three steps from
intermediate 3. These complexes were characterized by NMR
techniques, mass spectra and elemental analysis. However, due to
slow chloro-ligand-DMSO exchange, all 1H NMR spectra of the
platinum complexes 8a–e showed multiple sets of signals which
are difficult to assign. This phenomenon was also reported in the
literature [16].
3. Results and discussion
The cytotoxicities of the platinum complexes were tested
against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549, BGC-823 and
Skov3 cell lines by the MTT method. The results are summarized in
Table 1. Cisplatin and compound 11 was used as control
compounds. From the screening results, it is evident that all of
these dinuclear compounds exhibited good activity against these
cell lines, and the mononuclear compound 11 was found only
Table 1
Cytotoxicity of compounds 8a–e against human tumor cells (IC50, m
mol/L).a
Compound
Compound descriptors
Human tumor cells
HCT-8 BEL-7402
9.4
A2780
MCF-7
Hela
40.2
A549
BGC-823
Skov3
9.33
8a
n = 6
17.2
8.9
12.5
10.6
12.3
6.0
24.9
14.4
12.1
11.2
13.8
>100
5.3
35.3
39.0
37.2
11.2
17.8
94.5
1.4
10.7
14.5
20.2
17.4
30.2
>100
0.8
8b
n = 7
16.7
21.5
25.3
20.9
24.0
20.7
20.7
42.8
24.02
32.68
21.9
8c
n = 8
42.6
20.7
33.4
8d
n = 9
8e
n = 12
18.3
73.0
2.7
20.75
11
Mononuclear
Cisplatin
>100
2.9
>100
2.5
>100
1.4
>100
>100
Control
a
Inhibitory concentration (IC50, mmol/L) as obtained by the MTT assay.

188
G. Xu et al. / Chinese Chemical Letters 24 (2013) 186–188
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marginally cytotoxic and almost showed no inhibition activity at
drug concentrations of >100 mol/L. MCF-7 and A2780 were more
m
sensitive than Hela and A549 to the dinuclear platinum complexes.
It is noteworthy that these complexes showed better selectivity
against Skov3 cell than cisplatin, which did not show any dose
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response at concentrations as high as 100
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24
[14] Data of ligands 7a–e. 7a: White solid, mp > 250 8C, ½aꢁD ꢀ33.3 (c 0.81 CH3OH) 1
H
NMR (300 MHz, DMSO-d6): d 1.38 (s, 4H, C–C2H4–C), 1.71 (s, 4H, C–CH2–Cꢂ2),
2.90-3.10 (m, 6H, CH2–Arꢂ2), 3.20–3.30 (m, 2H, CH2–Nꢂ2), 3.44 (s, 6H,
–OCH3ꢂ2), 3.78 (s, 6H, –OCH3ꢂ2), 4.10 (m, 2H, CH–Arꢂ2), 5.74 (d, 2H, J = 6.6,
Ar–CH–Arꢂ2), 6.07 (s, 2H, Ar–Hꢂ2), 6.85 (s, 2H, Ar–Hꢂ2), 7.50 (s, 10H, Ar–Hꢂ2),
9.58 (br, 4H, –NHꢂ2), 10.07 (br, 2H, –NHꢂ2), 10.27 (br, 2H, –NHꢂ2). ESI-MS: 679
(m/z + 1); HRMS (ESI) Calcd. for C42H55N4O4: 679.4217, found: 679.4224. 7b:
In conclusion, we have synthesized a series of novel dinuclear
platinum(II) complexes with (1S, 3S)-1,2,3,4-tetrahydroisoquino-
lines as the ligands. The cytotoxicities of this series of complexes
were screened against HCT-8, BEL-7402, A2780, MCF-7, Hela,
A549, BGC-823 and Skov3 cell lines by the MTT test. These
complexes showed good selective inhibition activity against
cisplatin-insensitive cell line Skov3. This result is helpful in
designing new platinum anticancer drugs to circumvent acquired
resistance to cisplatin.
24
White solid, mp 190–192 8C, ½aꢁD ꢀ35.2 (c 0.31 CH3OH) 1H NMR (300 M Hz,
DMSO-d6): d 1.35 (s, 6H, C–C3H6–C), 1.70 (s, 4H, C–CH2–Cꢂ2), 2.90-3.10 (m, 6H,
CH2–Arꢂ2), 3.20–3.30 (m, 2H, CH2–Nꢂ2), 3.44 (s, 6H, –OCH3ꢂ2), 3.78 (s, 6H,
–OCH3ꢂ2), 4.10 (m, 2H, CH–Arꢂ2), 5.72 (m, 2H, Ar–CH–Arꢂ2), 6.07 (s, 2H,
Ar–Hꢂ2), 6.85 (s, 2H, Ar–Hꢂ2), 7.49 (m, 10H, Ar–Hꢂ2), 9.65 (br, 4H, –NHꢂ2),
10.17 (br, 2H, –NHꢂ2), 10.33 (br, 2H, –NHꢂ2). ESI-MS: 693 (m/z + 1); HRMS (ESI)
Calcd. for C43H57N4O4: 693.4374, found: 693.4365. 7c: White solid, mp 237–
24
239 8C, [a]D ꢀ34.7 (c 0.39 CH3OH) 1H NMR (300 MHz, DMSO-d6): d 1.32 (s, 8H,
References
C–C4H8–C), 1.68 (m, 4H, C–CH2–Cꢂ2), 2.90–3.10 (m, 4H, CH2–Arꢂ2), 3.20–3.30
(m, 8H, CH2–N–CH2ꢂ2), 3.44 (s, 6H, –OCH3ꢂ2), 3.78 (s, 6H, –OCH3ꢂ2), 4.09 (m,
2H, N–CH–Cꢂ2), 5.72 (m, 2H, Ar–CH–Arꢂ2), 6.07 (s, 2H, Ar–Hꢂ2), 6.85 (s, 2H,
Ar–Hꢂ2), 7.49 (m, 10H, Ar–Hꢂ2), 9.62 (br, 4H, –NHꢂ2), 10.10 (br, 2H, –NHꢂ2),
10.33 (br, 2H, –NHꢂ2). 13C NMR (75 MHz, DMSO-d6): d 148.64, 147.52, 136.17,
130.19, 129.47, 128.65, 124.13, 123.51, 111.41, 110.54, 60.63, 55.57, 55.46, 51.54,
48.09, 47.16, 29.19, 28.04, 25.66, 25.26. ESI-MS: 707 (m/z + 1); HRMS (ESI) Calcd.
for C44H59N4O4: 707.4536, found: 707.4553. 7d: Yellowish solid, mp 185–187 8C,
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C–C5H10–C), 1.65 (m, 4H, C–CH2–Cꢂ2), 2.90–3.10 (m, 6H, CH2–Arꢂ2), 3.20–
3.30 (m, 2H, CH2–Nꢂ2), 3.35 (s, 6H, –OCH3ꢂ2), 3.77 (s, 6H, –OCH3ꢂ2), 4.09
(m, 2H, CH–Arꢂ2), 5.71 (m, 2H, Ar–CH–Arꢂ2), 6.06 (s, 2H, Ar–Hꢂ2), 6.83 (s, 2H,
Ar–Hꢂ2), 7.48 (m, 10H, Ar–Hꢂ2), 9.63 (br, 4H, –NHꢂ2), 10.15 (br, 2H, –NHꢂ2),
10.32 (br, 2H, –NHꢂ2). ESI-MS: 721 (m/z + 1); HRMS (ESI) Calcd. for C45H61N4O4:
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24
721.4687, found: 721.4692. 7e: Yellowish solid, mp 209–211 8C, ½aꢁD ꢀ30.9
(c 0.58 CH3OH) 1H NMR (300 MHz, DMSO-d6): d 1.27 (s, 16H, C–C8H16–C), 1.66
(m, 4H, C–CH2–Cꢂ2), 2.90-3.10 (m, 6H, CH2–Arꢂ2), 3.20–3.30 (m, 2H, CH2–Nꢂ2),
3.44 (s, 6H, –OCH3ꢂ2), 3.78 (s, 6H, –OCH3ꢂ2), 4.09 (m, 2H, CH–Arꢂ2), 5.73 (m, 2H,
Ar–CH–Arꢂ2), 6.07 (s, 2H, Ar–Hꢂ2), 6.85 (s, 2H, Ar–Hꢂ2), 7.49 (m, 10H, Ar–Hꢂ2),
9.61 (br, 4H, –NHꢂ2), 10.14 (br, 2H, –NHꢂ2), 10.32 (br, 2H, –NHꢂ2). ESI-MS: 764
(m/z + 1); HRMS (ESI) Calcd. for C48H67N4O4: 763.5156, found: 763.5155.
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(1.0 mmol) and K2PtC14 (2.0 mmol) in distilled water (12 mL) was heated to
65–70 8C with stirring. The pH of the reaction solution was checked continuously
and 1 mol/L NaOH was added to keep the pH in the range 3–4. Toward the end of
the reaction, pH was adjusted to 6 with 0.1 mol/L NaOH. After the mixture was
cooled to ambient temperature, the precipitate was filtered, washed three times
with cold water, twice with ethanol, and once with diethyl ether, and dried in
vacuo (87% yield) to afford compound 8c: yellow solid, mp: 237–239 8C, Elemen-
tal analysis: Calcd. for C44H58O4N4Cl4Pt2 (%): C 42.66, H 4.72, N 4.52; Found: C
42.59, H 4.92, N 4.36. 8a: Offwhite solid, mp: 237–239 8C, Elemental analysis:
Calcd. for C42H54O4N4Cl4Pt2 (%): C 41.65, H 4.49, N 4.63; Found: C 41.79, H 4.52, N
4.61. 8b: Offwhite solid, mp: 234–236 8C, Elemental analysis: Calcd. for
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C
43H56O4N4Cl4Pt2 (%): C 42.16, H 4.61, N 4.57; Found: C 42.57, H 4.81, N 4.40.
8d: Offwhite solid, mp: 238–240 8C, Elemental analysis: Calcd. for
45H60O4N4Cl4Pt2 (%): C 43.14, H 4.83, N 4.47; Found: C 43.30, H 4.68, N 4.64.
8e: Offwhite solid, mp: 228–230 8C, Elemental analysis: Calcd. for
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