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

Article abstract of DOI:10.1016/j.ejmech.2010.11.025

A series of novel cisplatin-type platinum 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 these compounds were tested against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines by the MTT test. Some compounds exhibited better cytotoxic activity than cisplatin. The structure-activity relationship has been revealed.

Full text of DOI:10.1016/j.ejmech.2010.11.025

European Journal of Medicinal Chemistry 46 (2011) 356e363
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and cytotoxicity of cis-dichloroplatinum (II) complexes of (1S,3S)-
1,2,3,4-tetrahydroisoquinolines
*
Geng Xu, Zheng Yan, Nan Wang, Zhanzhu Liu
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine (Ministry of Education), Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College, No. 1, Xiannongtan Street, Beijing 100050, People’s Republic of 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 cisplatin-type platinum complexes with (1S,3S)-1,2,3,4-tetrahydroisoquinolines as the
Received 30 September 2010
Received in revised form
9 November 2010
Accepted 15 November 2010
Available online 24 November 2010
ligands were synthesized as potential anticancer agents in several steps starting from commercially
available L-DOPA. The cytotoxicities of these compounds were tested against HCT-8, BEL-7402, A2780,
MCF-7, Hela, A549 and BGC-823 cell lines by the MTT test. Some compounds exhibited better cytotoxic
activity than cisplatin. The structureeactivity relationship has been revealed.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
cis-Dichloroplatinum (II) complexes
Tetrahydroisoquinolines
Synthesis
Antitumor activity
1. Introduction
DNA by attaching it to a suitable carrier ligand. The examples
include the attachment of a Pt moiety to bioactive carrier ligands
Platinum (II) complexes [1e3] are widely used in cancer
chemotherapy. Up to now, the most important platinum-based
drugs are cisplatin (1), carboplatin (2), oxaliplatin (3), nedaplatin (4),
lobaplatin (5), and heptaplatin (6) (Fig. 1). The first three platinum
(II) complexes are used worldwide while the last three are used
mainly in Asian countries. 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,
bladder cancers, etc. Despite its wide application as a chemothera-
peutic 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 analogues with broader spectra of
activity, improved clinical efficacy, and reduced toxicity [3].
More recently, efforts have been directed at the design of non-
classical Pt complexes to overcome the side effects of cisplatin [3],
such as orally active platinum (IV) complexes [4], sterically
hindered platinum (II) complexes [5], trans-platinum complexes
[6], multinuclear platinum complexes [7], complexes with biolog-
ically active carrier ligands [8] etc. The complexes with biologically
active carrier ligands are to target the Pt coordination moiety to
such as DNA intercalators, doxorubicin, estrogen analogues, amino
acids and sugars [1d,3d,8]. Overall, studies of Pt compounds with
biologically active carrier groups have yielded interesting results,
and there is still potential for varying the biological activity of these
compounds through altering the structure of the carrier group [3d].
1,2,3,4-Tetrahydroisosoquinoline scaffold existed in both natural
products and synthetic molecules that possess various bioactivities
[9]. A series of cisplatinum complexes with 1-(2-aminophenyl)-
1,2,3,4-tetrahydroisoquinolines have been reported [8e,10]. Several
of these new complexes showed better in vitro cytotoxicity against
some human tumor cell lines than cisplatin. In this paper, we
designed and synthesized a series of novel cisplatin analogues
(compound 8aer) with (1S,3S)-1,2,3,4-tetrahydroisoquinolines as
the ligands, in which an aniline group is covalently connected with
a tetrahydroisoquinoline unit at the C-3 position. All complexes
were evaluated for their in vitro cytotoxicity against a panel of
human tumor cell lines from solid tumors including HCT-8, BEL-
7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines.
2. Chemistry
In order to investigate the influence of different substituents at
the C-4 position of phenyl group of the 1,2,3,4-tetrahy-
droisoquinoline ring (R1) and the C-4 position of aniline ring (R2), we
have designed and synthesized a series of novel cisplatin-type
* Corresponding author. Tel.: þ86 10 63165253; fax: þ86 10 63017757.
E-mail address: liuzhanzhu@imm.ac.cn (Z. Liu).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.11.025

G. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 356e363
357
HO
HO
COOCH3
O
O
HO
HO
COOCH3
NH2
a
O
O
O
NH2
H3N
H3N
Cl
Cl
H3N
H3N
NH
Pt
Pt
Pt
O
O
NH2
8
O
O
3
2
1
9a: R1=H
9b: R1=Cl
R1
b
9c: R1=OMe
NH2
Pt
O
NH2
Pt
O
O
H3N
O
O
O
O
O
O
COOCH3
O
COOCH3
NH2
Pt
NH2
O
H3N
c
N
NH
5
6
4
Boc
O
11a: R1=H
11b: R1=Cl
11c: R1=OMe
10a: R1=H
10b: R1=Cl
10c: R1=OMe
Fig. 1. Structures of the known platinum (II) complexes used in clinics.
R1
d
R1
platinum complexes with (1S,3S)-1,2,3,4-tetrahydroisoquinolines
as the ligands (7aer). Synthesis of the new derivatives (7aer) was
R2
carried out by a stereoselective route starting from
(Scheme 1). -DOPA was esterified by SOCl2 and CH3OH to the cor-
responding ester 8. The synthesis of 9 was accomplished via an
asymmetric PicteteSpengler reaction from -DOPA methyl ester and
L-DOPA
O
CHO
e
O
O
N
H
L
N
N
Boc
O
Boc
L
aromatic aldehydes under acidic conditions. The major product with
cis configuration was obtained via 1,3-diastereoselective induction
[11]. Treatment of compound 9 with HCOOH/Ac2O/HCOONa at rt
afforded the N-protected product. Methylation of the N-protected
product with Me2SO4/K2CO3 in acetone under refluxing produced
the corresponding O-methylated product. Then the O-methylated
product was refluxed in HCl/CH3OH to cleave the formyl group and
product 10 was afforded [12]. Compound 10 was converted to the N-
Boc amino ester 11 in almost quantitative yield by treatment with
Boc2O in the presence of triethylamine. The N-Boc esters 11 were
reduced with DIBAL-H in dichloromethane at ꢀ78 ꢁC to give the
amino aldehydes 12, which was then coupled with various para- or
meta-substituted aryl amines through reductive amination. Subse-
quently, removal of Boc in the presence of trifluoroacetic acid and
dimethyl sulfide led to compound 14. The platinum (II) complexes
(7aer) were prepared by treatment of the tetrahydroisoquinoline
ligands with potassium tetrachloroplatinate in a mixture of dime-
thylformamide and water at 60 ꢁC.
12a: R1=H
12b: R1=Cl
13a-r
12c: R1=OMe
R1
R1
f
R2
R2
O
O
O
O
N
H
N
g
H
NH
NH
Pt
Cl
Cl
7a-r
14a-r
R1
R1
Scheme 1. Reagents and conditions: (a) (1) SOCl2, CH3OH, rt, 72 h (2) para-substituted
aromatic aldehyde, CH3COOH, CH3COONa, rt, 20 h (b) (1) HCOOH, HCOONa, (CH3CO)2O,
rt, 4 h, then 1 N HCl, CH3OH, rt, 24 h (2) K2CO3, Me2SO4, Acetone, reflux 10 h (3)
HCleCH3OH, reflux 3 h (c) Boc2O, TEA, CH2Cl2, rt, 16 h (d) DIBAL-H, toluene, ꢀ78 ꢁC,
1 h. (e) para- or meta-substituted aniline, CH3OH, rt, 30 min, then NaBH3CN, rt, 2 h (f)
Me2S, TFA, CH2Cl2, rt, 30 min (g) K2PtCl4, DMF, H2O, 60 ꢁC, 24 h.
3. Cytotoxicity
The cytotoxicities of the cis-dichloroplatinum complexes of tet-
rahydroisoquinoline were tested against HCT-8, BEL-7402, A2780,
MCF-7, Hela, A549 and BGC-823 cell lines by the MTT method. The
results are summarized in Table 1. Cisplatin was used as control
substance. From the screening results, it is evident that all of these
compounds exhibited good activity against the tested cell lines
except A549. MCF-7 was the most sensitive cell line to all the plat-
inum complexes. Most of these compounds are more active against
MCF-7 cell line than cisplatin except 7c. On the other hand, all of the
compounds are less active against A549 cell line than cisplatin. Also,
they are less active against Hela cell line than cisplatin except 7l.
Furthermore, they are less active against BGC-823 cell line than
cisplatin except 7i. Compounds 7gel with chloro-substituent at the
C-4 position of phenyl (C-1 position of tetrahydroisoquinoline) are
more active than the other compounds.
activity (7gel). (b) Compounds with electron-donating group
(R2 ¼ MeO) or strong electron-withdrawing groups at the C-4
position of the aniline ring would decrease the antitumor activity
(7c, 7e, 7o and 7q). (c) Compounds with R2 ¼ 3-CF3 (7f, 7l, 7r) and
compounds with R2 ¼ 4-Cl (7d, 7j, 7p) showed stronger cytotoxic
activity against most cell lines than the compounds in the three
sub-groups with the same substituent R1 (R1 ¼ H, Cl, OMe).
It could be seen from Table 1 that the antitumor activities of this
series of platinum complexes increase in the sequence: H < 4-
MeO < 4-Cl (R1). According to the research of Kuo, the “trans effect”
theory can explain why compounds 7jel are more active than the
other compounds [8e,13]. The inductive effect of chloro-group at
the 4-position of phenyl group of tetrahydroisoquinoline ring (C-1)
makes the amino group in the tetrahydroisoquinoline ring more
acidic and the PteN bond was less stable than the other compounds
(Fig. 2A). However, it is hard to explain why compounds 7mer
(R1 ¼ 4-MeO) are more active than compounds 7aef (R1 ¼ H). It
seems that the “trans effect” theory is not the only factor influ-
encing the antitumor activities.
4. Results and discussion
Based on the comparison of the IC50 values of these compounds,
the structureeactivity relationship can be summarized as follows:
(a) The existence of chloro-substituent at the C-4 position of phenyl
group of the 1,2,3,4-tetrahydroisoquinoline ring would improve the
The substituent R2 on the aniline ring has much influence on the
biological activity. The compounds containing electron-donating
group on the aniline ring are less active than others, probably due

358
G. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 356e363
Table 1
Cytotoxicity of compounds 7aer against human tumor cells (IC50 ꢂ SD,
m
M).a
Compound
Compound descriptors
Human tumor cells
HCT-8
BEL-7402
A2780
MCF-7
Hela
A549
BGC-823
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
R1 ¼ H, R2 ¼ H
5.51 ꢂ 0.16
8.92 ꢂ 0.57
7.84 ꢂ 0.17
3.92 ꢂ 0.75
3.43 ꢂ 0.67
2.95 ꢂ 0.14
2.14 ꢂ 0.83
2.21 ꢂ 0.45
2.32 ꢂ 0.32
1.81 ꢂ 0.23
3.64 ꢂ 0.13
2.19 ꢂ 0.57
3.12 ꢂ 0.85
8.78 ꢂ 0.48
4.65 ꢂ 0.33
2.88 ꢂ 0.72
6.03 ꢂ 0.35
3.14 ꢂ 0.49
2.92 ꢂ 0.33
4.78 ꢂ 0.65
4.62 ꢂ 0.43
12.17 ꢂ 0.57
3.52 ꢂ 0.81
8.59 ꢂ 0.19
4.02 ꢂ 0.73
2.41 ꢂ 0.15
3.32 ꢂ 0.23
2.17 ꢂ 0.74
2.23 ꢂ 0.35
8.21 ꢂ 0.43
1.92 ꢂ 0.37
3.91 ꢂ 0.58
5.03 ꢂ 0.43
3.17 ꢂ 0.74
3.23 ꢂ 0.32
5.71 ꢂ 0.65
3.23 ꢂ 0.31
2.51 ꢂ 0.02
8.21 ꢂ 0.31
3.52 ꢂ 0.41
25.42 ꢂ 2.05
8.90 ꢂ 0.18
7.61 ꢂ 0.23
5.20 ꢂ 0.38
1.92 ꢂ 0.05
3.41 ꢂ 0.75
2.74 ꢂ 0.33
2.21 ꢂ 0.09
2.88 ꢂ 0.12
1.91 ꢂ 0.43
3.01 ꢂ 0.38
8.72 ꢂ 0.33
3.42 ꢂ 0.25
2.91 ꢂ 0.48
8.72 ꢂ 0.91
2.54 ꢂ 0.31
2.72 ꢂ 0.58
3.02bꢂ0.57
4.61 ꢂ 0.34
17.45 ꢂ 2.47
3.82 ꢂ 0.07
4.05 ꢂ 0.73
3.02 ꢂ 0.55
1.23 ꢂ 0.17
1.92 ꢂ 0.45
1.27 ꢂ 0.38
2.01 ꢂ 0.95
2.33 ꢂ 0.87
1.01 ꢂ 0.65
1.53 ꢂ 0.49
2.72 ꢂ 0.37
3.01 ꢂ 0.78
2.23 ꢂ 0.55
2.51 ꢂ 0.03
1.32 ꢂ 0.60
5.31 ꢂ 0.08
8.92 ꢂ 0.77
4.79 ꢂ 0.32
6.43 ꢂ 0.77
4.93 ꢂ 0.31
4.72 ꢂ 0.54
2.83 ꢂ 0.71
2.41 ꢂ 0.08
2.23 ꢂ 0.33
2.24 ꢂ 0.39
2.71 ꢂ 0.77
2.83 ꢂ 0.65
0.91 ꢂ 0.47
4.73 ꢂ 0.52
2.41 ꢂ 0.36
2.43 ꢂ 0.89
3.01 ꢂ 0.57
2.92 ꢂ 0.78
3.23 ꢂ 0.85
1.43 ꢂ 0.15
5.24 ꢂ 0.32
5.11 ꢂ 0.81
36.24 ꢂ 0.36
22.15 ꢂ 2.55
33.90 ꢂ 3.17
4.82 ꢂ 0.28
8.14 ꢂ 0.55
9.21 ꢂ 0.17
8.63 ꢂ 0.32
5.52 ꢂ 0.25
8.78 ꢂ 0.30
14.22 ꢂ 1.51
24.01 ꢂ 2.32
18.34 ꢂ 3.38
49.45 ꢂ 5.55
5.82 ꢂ 0.73
44.38 ꢂ 2.75
7.03 ꢂ 0.28
1.42 ꢂ 0.03
2.93 ꢂ 0.38
2.52 ꢂ 0.24
8.71 ꢂ 0.91
4.15 ꢂ 0.73
4.02 ꢂ 0.29
3.24 ꢂ 0.57
0.93 ꢂ 0.13
1.92 ꢂ 0.58
0.63 ꢂ 0.03
1.72 ꢂ 0.06
2.13 ꢂ 0.35
19.92 ꢂ 3.58
2.21 ꢂ 0.08
2.74 ꢂ 0.43
1.62 ꢂ 0.83
2.24 ꢂ 0.74
3.72 ꢂ 0.90
1.13 ꢂ 0.48
0.83 ꢂ 0.05
R1 ¼ H, R2 ¼ 4-Me
R1 ¼ H, R2 ¼ 4-OMe
R1 ¼ H, R2 ¼ 4-Cl
R1 ¼ H, R2 ¼ 4-COOCH3
R1 ¼ H, R2 ¼ 3-CF3
R1 ¼ Cl, R2 ¼ H
R1 ¼ Cl, R2 ¼ 4-Me
R1 ¼ Cl, R2 ¼ 4-OMe
R1 ¼ Cl, R2 ¼ 4-Cl
R1 ¼ Cl, R2 ¼ 4-COOCH3
R1 ¼ Cl, R2 ¼ 3-CF3
R1 ¼ OMe, R2 ¼ H
R1 ¼ OMe, R2 ¼ 4-Me
R1 ¼ OMe, R2 ¼ 4-OMe
R1 ¼ OMe, R2 ¼ 4-Cl
R1 ¼ OMe, R2 ¼ 4-COOCH3
R1 ¼ OMe, R2 ¼ 3-CF3
Cisplatin
Control
a
Mean value ꢂ SD (standard deviation from three experiments).
Boldface: IC50 ꢃ the control.
b
to its lower trans effect. The electron-donating group on the aniline
ring makes the amino group in the aniline more basic, so the PteN
bond is stronger than the other compounds (Fig. 2B and C). On the
contrary, the strong electron-withdrawing group (COOCH3) at the
C-4 position of the aniline ring (compounds 7e, 7k and 7q) lowered
the antitumor activity.
6. Experimental
6.1. General
Melting points were measured on a Yanaco Micro Melting Point
Apparatus and are uncorrected. 1H NMR spectra were recorded on
a Varian 300 MHz spectrometer at 24 ꢁC in the indicated solvent
and are reported in ppm relative to tetramethylsilane and refer-
enced internally to the residually protonated solvent. 13C NMR
spectra were recorded at Mercury 75 MHz spectrometer at 24 ꢁC in
the solvent indicated and are reported in ppm relative to tetra-
methylsilane and referenced internally to the residually protonated
solvent. HRMS were carried out by Agilent LC/MSD TOF. Optical
rotations were measured on a PerkinElmer Polarimeter 341LC using
10 cm cells and the sodium D line (589 nm) at 15 ꢁC and concen-
tration indicated. Diethyl ether and tetrahydrofuran were dried and
distilled over sodium under nitrogen. Toluene, methylene chloride
and hexane were distilled with P2O5. Other solvents used were
purified and dried by standard procedures. The synthesis of
5. Conclusion
In conclusion, we have synthesized a series of new platinum
complexes with chiral 1,2,3,4-tetrahydroisoquinolines as the
ligands. The cytotoxicities of the series of complexes were screened
against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823cell
lines by the MTT test. Some compounds exhibited better cytotoxic
activity than cisplatin. The structureeactivity relationship has been
analyzed, and this study wouldbe helpful in designing new platinum
anticancer drugs.
R2
compound 10 starting from commercially available L-DOPA was
performed according to previously described procedures [12].
O
N
H
NH2
+
O
¦Ä
Pt
Cl
6.2. General procedure for the syntheses of 11aec
Cl
N
Pt
Cl
To a DCM (150 mL) solution of 10 (14.7 mmol) at rt was added
TEA (10 mL) and Boc2O (29.4 mmol). After stirring the mixture at
room temperature for 16 h, the solution was washed with aqueous
1 M HCl, saturated NaHCO3 and brine. The organic layer was
separated, dried over MgSO4 and the solvent was evaporated in
vacuo. The residue was purified by a column chromatography on
silica (3:1, v/v, EtOAc-petroleum ether) to afford pure product 11.
Cl
-
¦Ä
A
+
O
¦Ä
Cl
-
¦Ä
+
¦Ä
O
O
O
O
N
H
-
N
¦Ä
H2
NH2
NH2
6.3. General procedure for the syntheses of 12aec
Pt
Cl
Pt
Cl
Cl
Cl
Diisobutylaluminum hydride (1 M solution in toluene, 34.3 mL,
5 equiv) was added to a cooled (ꢀ78 ꢁC) solution of the ester 11
(6.87 mmol) in toluene (100 mL). After 1.5 h at ꢀ78 ꢁC, methanol
(2 mL) was added and the mixture was poured into a stirred solution
of Rochelle salt (20 mL of saturated aqueous solution diluted with
120 mL of H2O at 0 ꢁC). The mixture was filtered through Celite, and
the aqueous phase was extracted with EtOAc. The combined organic
R1
R1
B
C
Fig. 2. Trans influence of amino group in both tetrahydroisoquinoline and aniline ring.
(A: the trans influence of R1; B and C: the trans influence of R2).

G. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 356e363
359
extracts were dried over anhydrous sodium sulfate. The dried
solution was filtered and the filtrate was concentrated. The residue
was purified bycolumn chromatography (100:1, v/v, CHCl3eCH3OH)
AreH). ESI-MS: 409 (m/z þ 1); HRMS (ESI) calcd. for C24H26N2O2Cl
409.1677, found 409.1693.
to afford the N-protected
6.4. General procedure for the syntheses of 13aer
solution of 12 (0.468 mmol) and substituted aniline
(0.493 mmol) in MeOH (10 mL) containing 0.5 g of 4 Å molecular
sieves was stirred at rt for 0.5 h. Glacial acetic acid (0.2 mL) was added
followed by portionwise addition of NaBH3CN (63 mg) under
nitrogen. The mixturewasstirredfor2h. Afterthemixturewascooled
to 0 ꢁC, saturatedNaHCO3 (50 mL) wasslowlyadded. The mixturewas
then extracted with ethyl acetate. The ethyl acetate layer was washed
with water and brine, dried, concentrated, and column chromato-
graphed (100:1, v/v, CHCl3eCH3OH) to yield 13 as white foam.
a
-aminoaldehyde 12 as white foam.
6.5.5. Methyl 4-([(1S,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-
tetrahydro-3-isoquinolinyl]methylamino)benzoate (14e)
24
Yield: 86%. M. P.: 74e76 ꢁC, [
NMR (300 MHz, CDCl3,
a
]
¼ þ25.8 (c ¼ 0.31 CHCl3) 1H
D
d ppm): 1.77 (br, 1H, eNH), 2.81 (m, 2H,
A
CH2eAr), 3.22 (m, 1H, eCHeN), 3.40 (m, 2H, eCH2eN), 3.59 (s,
3H, CH3), 3.84 (s, 3H, CH3), 3.86 (s, 3H, CH3), 4.69 (br, 1H, eNH), 5.06
(s, 1H, AreCHeAr), 6.17 (s, 1H, AreH), 6.62 (s, 1H, AreH), 6.58 (d,
2H, J ¼ 8.7 AreH), 7.30e7.40 (m, 5H, AreH). 7.85 (d, 2H, J ¼ 8.7,
AreH) ESI-MS: 433 (m/z þ 1); HRMS (ESI) calcd. for C26H29N2O4
433.2127, found 433.2142.
6.5.6. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
isoquinolinyl]methyl-N-[4-(trifluoromethyl)phenyl]amine (14f)
24
Yield: 71%. M. P.: 135e137 ꢁC, [
a
]
¼ þ13.7 (c ¼ 0.30 CHCl3) 1H
D
6.5. General procedure for the syntheses of 14aer
NMR (300 MHz, CDCl3, d ppm): 1.71 (br, 1H, eNH), 2.81 (m,
2H, CH2eAr), 3.18 (m, 1H, eCHeN), 3.38 (m, 2H, eCH2eN), 3.59 (s,
3H, CH3), 3.86 (s, 3H, CH3), 4.39 (br, 1H, eNH), 5.06 (s, 1H,
AreCHeAr), 6.17 (s, 1H, AreH), 6.63 (s, 1H, AreH), 6.77 (d, 1H,
J ¼ 8.1 AreH), 6.82 (s, 1H, AreH), 6.92 (d, 1H, J ¼ 8.1, AreH), 7.23 (d,
1H, J ¼ 8.1 AreH), 7.30e7.40 (m, 5H, AreH). ESI-MS: 443 (m/z þ 1);
HRMS (ESI) calcd. for C25H26N2O2F3 443.1946, found 443.1959.
A solution of 13 (200 mg) in 2 mL of 1:1 TFA/CH2Cl2 was added
Me2S (35
mL) and stirred at room temperature for 0.5 h. The
solvents were removed in vacuo, and the oily residue was dissolved
in ethyl acetate. The organic solution was washed by saturated
aqueous solution of NaHCO3, dried, concentrated, and recrystal-
lized with methyl alcohol to yield 14 as white foam.
6.5.7. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
6.5.1. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
tetrahydro-3-isoquinolinyl]methyl-N-phenylamine (14g)
24
isoquinolinyl]methyl-N-phenylamine (14a)
Yield: 74%. M. P.: 164e166 ꢁC, [
a]
¼ þ54.5 (c ¼ 0.31 CHCl3) 1H
D
24
Yield: 79%. M. P.: 96e98 ꢁC, [
a
]
¼ þ27.2 (c ¼ 0.36 CHCl3) 1H
NMR (300 MHz, CDCl3, d ppm): 1.88 (br, 1H, eNH), 2.62 (m,
D
NMR (300 MHz, CDCl3,
d
ppm): 1.77 (br, 1H, eNH), 2.79 (m, 2H,
2H, CH2eAr), 3.05 (m, 1H, eCHeN), 3.21 (m, 2H, eCH2eN), 3.44 (s,
3H, CH3), 3.70 (s, 3H, CH3), 3.88 (br, 1H, eNH), 4.86 (s, 1H,
AreCHeAr), 5.95 (s,1H, AreH), 6.50 (s,1H, AreH), 6.47 (d, 2H, J ¼ 3.9
AreH), 6.55 (t, 1H, J ¼ 6.9, AreH), 7.02 (t, 2H, J ¼ 7.5 AreH), 7.11 (d,
2H, J ¼ 8.1, AreH), 7.15 (d, 2H, J ¼ 8.7, AreH) ESI-MS: 409 (m/z þ 1);
HRMS (ESI) calcd. for C24H26N2O2Cl 409.1677, found 409.1693.
CH2eAr), 3.19 (dd, 1H, J ¼ 8.7, 13.5, eCHeN), 3.36 (m, 2H, eCH2eN),
3.59 (s, 3H, CH3), 3.86 (s, 3H, CH3), 4.10 (br, 1H, eNH), 5.04 (s, 1H,
AreCHeAr), 6.16 (s, 1H, AreH), 6.60e6.68 (m, 3H, AreH), 6.71
(t, 1H, J ¼ 7.8 AreH), 7.17 (t, 3H, J ¼ 7.2, AreH), 7.30e7.40 (m, 5H,
AreH). ESI-MS: 375 (m/z þ 1); HRMS (ESI) calcd. for C24H27N2O2
375.2072, found 375.2079.
6.5.8. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
6.5.2. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
tetrahydro-3-isoquinolinyl]methyl-N-(4-methylphenyl)amine (14h)
24
isoquinolinyl]methyl-N-(4-methylphenyl)amine (14b)
Yield: 86%. M. P.: 142e144 ꢁC, [
a]
¼ þ54.6 (c ¼ 0.56 CHCl3) 1H
D
24
Yield: 47%. M. P.: 89e91 ꢁC, [
a
]
¼ þ26.4 (c ¼ 0.26 CHCl3) 1H
NMR (300 MHz, CDCl3, d ppm): 2.23 (s, 3H, CH3), 2.76 (m, 2H,
D
NMR (300 MHz, CDCl3,
d
ppm): 2.23 (s, 3H, CH3), 2.79 (m, 2H,
CH2eAr), 3.16 (dd, 1H, J ¼ 12.9, 9.3 eCHeN), 3.34 (m, 2H, eCH2eN),
3.61 (s, 3H, CH3), 3.86 (s, 3H, CH3), 5.01 (s, 1H, AreCHeAr), 6.11 (s,
1H, AreH), 6.62 (s, 1H, AreH), 6.58 (d, 2H, J ¼ 8.4, AreH), 6.99 (d,
2H, J ¼ 8.1, AreH), 7.26 (d, 2H, J ¼ 6.0 AreH), 7.31 (d, 2H, J ¼ 9.0,
AreH). ESI-MS: 423 (m/z þ 1); HRMS (ESI) calcd. for C25H28N2O2Cl
423.1839, found 423.1857.
CH2eAr), 3.17 (dd, 1H, J ¼ 8.7, 13.5, eCHeN), 3.35 (m, 2H, eCH2eN),
3.58 (s, 3H, CH3), 3.86 (s, 3H, CH3), 5.04 (s, 1H, AreCHeAr), 6.15
(s, 1H, AreH), 6.62 (s, 1H, AreH), 6.56 (d, 2H, J ¼ 8.4, AreH), 6.99 (d,
2H, J ¼ 8.4, AreH), 7.30e7.40 (m, 5H, AreH). ESI-MS: 389 (m/z þ 1);
HRMS (ESI) calcd. for C25H29N2O2 389.2229, found 389.2247.
6.5.3. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
6.5.9. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
isoquinolinyl]methyl-N-(4-methoxyphenyl)amine (14c)
tetrahydro-3-isoquinolinyl]methyl-N-(4-methoxyphenyl)amine (14i)
24
24
Yield: 74%. M. P.: 68e70 ꢁC, [
a
]
D
¼ þ18.6 (c ¼ 0.14 CHCl3) 1H
Yield: 80%. M. P.: 125e127 ꢁC, [
a]
D
¼ þ49.8 (c ¼ 0.42 CHCl3) 1H
NMR (300 MHz, CDCl3,
d
ppm): 2.78 (m, 2H, CH2eAr), 3.14 (dd, 1H,
NMR (300 MHz, CDCl3, d ppm): 1.99 (br, 1H, eNH), 2.77 (m, 2H,
J ¼ 8.4, 12.3, eCHeN), 3.31 (m, 2H, eCH2eN), 3.59 (s, 3H, CH3), 3.74
(s, 3H, CH3), 3.86 (s, 3H, CH3), 5.05 (s, 1H, AreCHeAr), 6.16 (s, 1H,
AreH), 6.62 (s, 1H, AreH), 6.61 (d, 2H, J ¼ 8.4, AreH), 6.78 (d, 2H,
J ¼ 9.0, AreH), 7.30e7.40 (m, 5H, AreH). ESI-MS: 405 (m/zþ1);
HRMS (ESI) calcd. for C25H29N2O3 405.2178, found 405.2192.
CH2eAr), 3.15 (dd, 1H, J ¼ 9.9, 12.0, eCHeN), 3.32 (d, 2H, J ¼ 9.6,
eCH2eN), 3.61 (s, 3H, CH3), 3.75 (s, 3H, CH3), 3.86 (s, 3H, CH3), 5.02 (s,
1H, AreCHeAr), 6.12 (s, 1H, AreH), 6.63 (s, 1H, AreH), 6.61 (d, 2H,
J ¼ 6.0 AreH), 6.78 (d, 2H, J ¼ 7.8, AreH), 7.17 (t, 2H, J ¼ 7.5 AreH), 7.29
(d, 2H, J ¼ 8.1, AreH), 7.31 (d, 2H, J ¼ 8.7, AreH) ESI-MS: 439 (m/z þ 1);
HRMS (ESI) calcd. for C25H28N2O3Cl 439.1788, found 439.1802.
6.5.4. N-(4-Chlorophenyl)-N-[(1S,3S)-6,7-dimethoxy-1-phenyl-
1,2,3,4-tetrahydro-3-isoquinolinyl]methylamine (14d)
6.5.10. N-(4-Chlorophenyl)-N-[(1S,3S)-1-(4-chlorophenyl)-6,7-
¼ þ18.1 (c ¼ 0.16 CHCl3) 1H
dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinyl]methylamine (14j)
24
Yield: 66%. M. P.: 82e84 ꢁC, [
a]
D
24
NMR (300 MHz, CDCl3,
d
ppm): 1.68 (br, 1H, eNH), 2.77 (m,
Yield: 74%. M. P.: 140e142 ꢁC, [
a
]
D
¼ þ49.6 (c ¼ 0.46 CHCl3) 1H
2H, CH2eAr), 3.14 (dd, 1H, J ¼ 9.0, 12.9, eCHeN), 3.34 (m, 2H,
eCH2eN), 3.59 (s, 3H, CH3), 3.86 (s, 3H, CH3), 4.16 (br, 1H, eNH),
5.04 (s, 1H, AreCHeAr), 6.16 (s, 1H, AreH), 6.62 (s, 1H, AreH), 6.56
(d, 2H, J ¼ 8.7, AreH), 7.11 (d, 2H, J ¼ 8.7, AreH), 7.30e7.40 (m, 5H,
NMR (300 MHz, CDCl3, d ppm): 1.80 (br, 1H, -NH), 2.76 (m, 2H,
CH2eAr), 3.14 (m, 1H, eCHeN), 3.33 (m, 2H, eCH2eN), 3.61 (s, 3H,
CH3), 3.86 (s, 3H, CH3), 4.10 (br, 1H, eNH), 5.02 (s, 1H, AreCHeAr),
6.12 (s, 1H, AreH), 6.62 (s, 1H, AreH), 6.56 (d, 2H, J ¼ 8.7, AreH), 7.11

360
G. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 356e363
(d, 2H, J ¼ 8.1, AreH), 7.26 (d, 2H, J ¼ 5.4 AreH), 7.32 (d, 2H, J ¼ 8.4,
AreH). ESI-MS: 443 (m/z þ 1); HRMS (ESI) calcd. for C24H25N2O2Cl2
443.1293, found 443.1303.
eCHeN), 3.32 (m, 2H, eCH2eN), 3.60 (s, 3H, CH3), 3.80 (s, 3H, CH3),
3.86 (s, 3H, CH3), 4.15 (br, 1H, eNH), 5.00 (s, 1H, AreCHeAr), 6.18 (s,
1H, AreH), 6.61 (s,1H, AreH), 6.57 (d, 2H, J ¼ 8.4, AreH), 6.87 (d, 2H,
J ¼ 7.8, AreH), 7.11 (d, 2H, J ¼ 8.4, AreH), 7.24 (d, 2H, J ¼ 9.6, AreH).
6.5.11. Methyl 4-([(1S,3S)-1-(4-chlorophenyl)-6,7-dimethoxy-
13C NMR (CDCl3,
d ppm): 159.09, 147.70, 147.22, 146.90, 136.63,
1,2,3,4-tetrahydro-3-isoquinolinyl]methylamino)benzoate (14k)
131.07, 129.96, 129.04, 126.75, 122.05, 114.00, 113.95, 111.40, 110.76,
62.35, 55.89, 55.27, 53.40, 46.84, 33.65. ESI-MS: 439 (m/z þ 1); HRMS
(ESI) calcd. for C25H28N2O3Cl 439.1783, found 439.1794.
24
Yield: 77%. M. P.: 89e91 ꢁC, [
a]
¼ þ61.7 (c ¼ 0.29 CHCl3) 1H
D
NMR (300 MHz, CDCl3, d ppm): 2.77 (m, 2H, CH2eAr), 3.23 (dd, 1H,
J ¼ 12.3, 6.6 eCHeN), 3.40 (m, 2H, eCH2eN), 3.61 (s, 3H, CH3), 3.84
(s, 3H, CH3), 3.86 (s, 3H, CH3), 4.60 (br, 1H, eNH), 5.03 (s, 1H,
AreCHeAr), 6.12 (s, 1H, AreH), 6.61 (s, 1H, AreH), 6.60 (d, 2H,
J ¼ 10.8, AreH), 7.26 (d, 2H, J ¼ 5.4, AreH), 7.32 (d, 2H, J ¼ 8.4 AreH),
7.86 (d, 2H, J ¼ 8.4 AreH). ESI-MS: 467 (m/z þ 1); HRMS (ESI) calcd.
for C26H28N2O4Cl 467.1738, found 467.1754.
6.5.17. Methyl 4-([(1S,3S)-6,7-dimethoxy-1-(4-methoxyphenyl)-
1,2,3,4-tetrahydro-3-isoquinolinyl]methylamino)benzoate (14q)
24
Yield: 87%. M. P.: 75e77 ꢁC, [
a
]
¼ þ50.0 (c ¼ 0.11 CHCl3) 1H
D
NMR (300 MHz, CDCl3,
d
ppm): 2.78 (dd, 2H, J ¼ 3.6, 16.8, CH2eAr),
3.21 (m, 1H, eCHeN), 3.39 (m, 2H, eCH2eN), 3.61 (s, 3H, CH3), 3.81
(s, 3H, CH3), 3.85 (s, 3H, CH3), 3.86 (s, 3H, CH3), 4.66 (br, 1H, eNH),
5.01 (s, 1H, AreCHeAr), 6.19 (s, 1H, AreH), 6.61 (s, 1H, AreH), 6.59
(d, 2H, J ¼ 9.0, AreH), 6.87 (d, 2H, J ¼ 8.7, AreH), 7.23 (d, 2H, J ¼ 8.7,
AreH), 7.86 (d, 2H, J ¼ 8.7 AreH). ESI-MS: 463 (m/z þ 1); HRMS
(ESI) calcd. for C27H31N2O5 463.2232, found 463.2239.
6.5.12. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-[4-(trifluoromethyl)phenyl]
amine (14l)
24
Yield: 64%. M. P.: 129e131 ꢁC, [
a]
¼ þ35.2 (c ¼ 0.56 CHCl3) 1H
D
NMR (300 MHz, CDCl3,
d ppm): 2.79 (m, 2H, CH2eAr), 3.19 (m, 1H,
eCHeN), 3.38 (m, 2H, eCH2eN), 3.62 (s, 3H, CH3), 3.87 (s, 3H, CH3),
4.33 (br, 1H, eNH), 5.04 (s, 1H, AreCHeAr), 6.14 (s, 1H, AreH), 6.63
(s, 1H, AreH), 6.78 (d, 2H, J ¼ 7.8, AreH), 6.84 (s, 1H, AreH), 6.94 (d,
2H, J ¼ 7.2, AreH), 7.25 (d, 2H, J ¼ 10.2, AreH), 7.29 (s, 1H, AreH),
7.33 (d, 2H, J ¼ 8.4, AreH), ESI-MS: 477 (m/z þ 1); HRMS (ESI) calcd.
for C25H25N2O2F3Cl 477.1557, found 477.1559.
6.5.18. N-[(1S,3S)-6,7-Dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-[4-(trifluoromethyl)phenyl]
amine (14r)
24
Yield: 63%. M. P.: 101e103 ꢁC, [
a]
¼ þ18.7 (c ¼ 0.53 CHCl3) 1H
D
NMR (300 MHz, CDCl3,
d ppm): 2.78 (m, 2H, CH2eAr), 3.18 (m, 1H,
eCHeN), 3.36 (m, 2H, eCH2eN), 3.61 (s, 3H, CH3), 3.81 (s, 3H, CH3),
3.87 (s, 3H, CH3), 4.39 (br, 1H, eNH), 5.01 (s, 1H, AreCHeAr), 6.19 (s,
1H, AreH), 6.62 (s, 1H, AreH), 6.77 (d, 2H, J ¼ 8.1, AreH), 6.83 (s, 1H,
AreH), 6.88 (d, 2H, J ¼ 8.4, AreH), 6.92 (d, 1H, J ¼ 8.1, AreH),
7.20e7.30 (m, 3H, AreH). ESI-MS: 473 (m/z þ 1); HRMS (ESI) calcd.
for C26H28N2O3F3 473.2052, found 473.2061.
6.5.13. N-[(1S,3S)-6,7-Dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-phenylamine (14m)
24
Yield: 53%. M. P.: 143e145 ꢁC, [
NMR (300 MHz, CDCl3,
a]
¼ þ32.0 (c ¼ 0.35 CHCl3) 1H
D
d ppm): 1.79 (br, 1H, eNH), 2.77 (m, 2H,
CH2eAr), 3.18 (m, 1H, eCHeN), 3.36 (m, 2H, eCH2eN), 3.60 (s, 3H,
CH3), 3.80 (s, 3H, CH3), 3.86 (s, 3H, CH3), 4.09 (br, 1H, eNH), 4.99 (s,
1H, AreCHeAr), 6.18 (s, 1H, AreH), 6.68 (s, 1H, AreH), 6.62 (d, 2H,
J ¼ 4.5 AreH), 6.70 (t, 1H, J ¼ 7.5, AreH), 6.87 (d, 2H, J ¼ 8.1, AreH),
7.17 (t, 2H, J ¼ 7.5 AreH), 7.24 (d, 2H, J ¼ 8.7, AreH) ESI-MS: 405 (m/
z þ 1); HRMS (ESI) calcd. for C25H29N2O3 405.2178, found 405.2193.
6.6. General procedure for the syntheses 7aer
To a solution of 14 (0.20 mmol) in DMF (1 mL) at 23 ꢁC was added
potassium tetrachloroplatinate (II) (0.22 mmol) dissolved in
a mixture of DMF/H2O (2 mL:1.6 mL). The resulting mixture was
stirred in the dark for 24 h at 60 ꢁC. Then, a drop of dimethylsulfoxide
was added to destroy the excessive K2PtCl4 and the stirring was
continued for 1 h. The solvent was evaporated and the residue was
stirred vigorously in a saturated aqueous potassium chloride solu-
tion (5 mL) for 15 min. The resulting suspensionwas filtered, washed
with water (100 mL). The product was further purified by TLC (5:1, v/
v, EtOAc/n-hexane) to give the title compound as a yellow solid
which was finally crystallized from acetoneeether.
6.5.14. N-[(1S,3S)-6,7-Dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-(4-methylphenyl)amine (14n)
24
Yield: 35%. M. P.: 155e157 ꢁC, [
NMR (300 MHz, DMSO-d6,
a
]
¼ þ4.8 (c ¼ 0.21 CH3OH) 1H
D
d ppm): 2.20, (s, 3H, CH3), 3.06, (m, 2H,
CH2eAr), 3.28 (m, 1H, eCHeN), 3.45 (s, 3H, CH3), 3.51 (m, 1H,
eCH2eN), 3.69 (m, 1H, eCH2eN), 3.76 (s, 3H, CH3), 3.80 (s, 3H, CH3),
3.80, (br, 1H, eNH), 5.66 (s, 1H, AreCHeAr), 6.07 (s, 1H, AreH), 6.83
(s, 1H, AreH), 6.80e6.90 (m, 2H, AreH), 7.00e7.10 (m, 4H, AreH),
7.46 (d, 2H, J ¼ 8.7, AreH). ESI-MS: 419 (m/z þ 1); HRMS (ESI) calcd.
for C26H31N2O3 419.2329, found 419.2325.
6.6.1. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
isoquinolinyl]methyl-N-phenylamine dichloroplatinate(II) (7a)
24
Yield: 41%. M. P.: 218e220 ꢁC, [
a]
¼ ꢀ43.3 (c ¼ 0.15 CHCl3) 1H
D
6.5.15. N-[(1S,3S)-6,7-Dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
NMR (300 MHz, CDCl3,
d
ppm): 2.26 (dd, 1H, J ¼ 12.0, 24.0, CHeAr),
tetrahydro-3-isoquinolinyl]methyl-N-(4-methoxyphenyl)amine (14o)
2.61 (m, 2H, AreCHeCHeN), 3.22 (dd, 1H, J ¼ 9.0, 16.2 eCHeN),
3.82 (s, 3H, CH3), 3.91 (s, 3H, CH3), 4.61 (m, 1H, eCHeN), 5.92 (s, 1H,
AreCHeAr), 6.14 (br, 1H, eNH), 6.70 (s, 1H, AreH), 6.76 (s, 1H,
AreH), 6.93 (d, 2H, J ¼ 6.3, AreH), 7.21 (m, 3H, AreH), 7.51 (m, 3H,
AreH), 8.16 (br, 1H, eNH), 8.39 (d, 2H, J ¼ 6.9, AreH). ESI-MS: 604
(m/z ꢀ 35.5); HRMS (ESI) calcd. for C24H26N2O2ClPt 652604.1331,
found 604.1359.
24
Yield: 30%. M. P.: 163e165 ꢁC, [
NMR (300 MHz, DMSO-d6,
a
]
D
¼ ꢀ2.9 (c ¼ 0.17 CH3OH) 1H
d ppm): 3.00 (m, 2H, CH2eAr), 3.33 (m,
1H, eCHeN), 3.46 (s, 3H, CH3), 3.64 (m,1H, eCH2eN), 3.73e3.77 (m,
1H, eCH2eN), 3.73 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.80 (s, 3H, CH3),
3.97, (br, 1H, eNH), 5.69 (s, 1H, AreCHeAr), 6.09 (s, 1H, AreH), 6.83
(s, 1H, AreH), 6.97 (d, 2H, J ¼ 9.0, AreH), 7.03 (d, 2H, J ¼ 8.7, AreH),
7.25 (d, 2H, J ¼ 6.6, AreH), 7.45 (d, 2H, J ¼ 8.7 AreH). ESI-MS: 435 (m/
z þ 1); HRMS (ESI) calcd. for C26H31N2O4 435.2283, found 435.2278.
6.6.2. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
isoquinolinyl]methyl-N-(4-methylphenyl)amine dichloroplatinate
6.5.16. N-(4-Chlorophenyl)-N-[(1S,3S)-6,7-dimethoxy-1-(4-
methoxyphenyl)-1,2,3,4-tetrahydro-3-isoquinolinyl]methylamine
(II) (7b)
24
Yield: 31%. M. P.: 225e227 ꢁC, [
a]
¼ ꢀ35.2 (c ¼ 0.25 CHCl3) 1H
D
(14p)
NMR (300 MHz, CDCl3, d ppm): 2.28 (s, 3H, CH3), 2.32 (m, 1H,
24
Yield: 64%. M. P.: 127e129 ꢁC, [
a
]
¼ þ26.3 (c ¼ 0.38 CHCl3) 1H
CHeAr), 2.59 (m, 2H, AreCHeCHeN), 3.21 (dd, 1H, J ¼ 9.3, 16.2
D
NMR (300 MHz, CDCl3,
d ppm): 2.76 (m, 2H, CH2eAr), 3.13 (m, 1H,
eCHeN), 3.82 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.61 (m, 1H, eCHeN),

G. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 356e363
361
5.91 (s, 1H, AreCHeAr), 6.12 (br, 1H, eNH), 6.69 (s, 1H, AreH), 6.75
(s, 1H, AreH), 6.82 (d, 2H, J ¼ 8.1, AreH), 6.99 (d, 2H, J ¼ 7.8, AreH),
7.47e7.54 (m, 3H, AreH), 8.08 (br, 1H, eNH), 8.37 (d, 2H, J ¼ 7.2,
8.32 (d, 2H, J ¼ 7.2, AreH). ESI-MS: 638 (m/z ꢀ 35.5); HRMS (ESI)
calcd. for C24H25N2O2Cl2Pt 638.0935, found 638.0956.
AreH). ESI-MS: 618 (m/z
ꢀ
35.5); HRMS (ESI) calcd. for
6.6.8. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-(4-methylphenyl)amine
C25H28N2O2ClPt 618.1487, found 618.1492.
dichloroplatinate(II) (7h)
24
Yield: 37%. M. P.: 227e229 ꢁC, [
a
]
D
¼ ꢀ41.7 (c ¼ 0.18 CHCl3) 1H
6.6.3. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
isoquinolinyl]methyl-N-(4-methoxyphenyl)amine dichloroplatinate
NMR (300 MHz, CDCl3,
d ppm): 2.30 (s, 3H, CH3), 2.32 (m, 1H,
CHeAr), 2.54 (m, 2H, AreCHeCHeN), 3.23 (dd, 1H, J ¼ 9.3, 16.2,
eCHeN), 3.82 (s, 3H, CH3), 3.90 (s, 6H, CH3), 4.59 (m, 1H, eCHeN),
5.87 (s, 1H, AreCHeAr), 6.15 (br, 1H, eNH), 6.66 (s, 1H, AreH), 6.74
(s, 1H, AreH), 6.82 (d, 2H, J ¼ 8.1 AreH), 7.04 (d, 2H, J ¼ 7.8, AreH),
7.50 (d, 2H, J ¼ 8.4, AreH), 8.08 (br, 1H, eNH), 8.31 (d, 2H, J ¼ 8.4,
(II) (7c)
24
Yield: 45%. M. P.: 199e201 ꢁC, [
a]
¼ ꢀ46.5 (c ¼ 0.17 CHCl3) 1H
D
NMR (300 MHz, CDCl3,
d ppm): 2.19 (m, 1H, CHeAr), 2.60 (m, 2H,
AreCHeCHeN), 3.21 (dd,1H, J ¼ 8.7,15.6 eCHeN), 3.77 (s, 3H, CH3),
3.82 (s, 3H, CH3), 3.91 (s, 3H, CH3), 4.59 (m, 1H, eCHeN), 5.91 (s, 1H,
AreCHeAr), 6.10 (br,1H, eNH), 6.69 (s, 2H, AreH), 6.71 (s,1H, AreH),
6.75 (s,1H, AreH), 6.87 (d, 2H, J ¼ 8.4, AreH), 7.51 (m, 3H, AreH), 8.11
(br, 1H, eNH), 8.38 (d, 2H, J ¼ 6.6, AreH). ESI-MS: 634 (m/z ꢀ 35.5);
HRMS (ESI) calcd. for C25H28N2O3ClPt 634.1436, found 634.1437.
AreH). ESI-MS: 652 (m/z
ꢀ
35.5); HRMS (ESI) calcd. for
C25H27N2O2Cl2Pt 652.1097, found 652.1088.
6.6.9. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-(4-methoxyphenyl)amine
dichloroplatinate(II) (7i)
6.6.4. N-(4-Chlorophenyl)-N-[(1S,3S)-6,7-dimethoxy-1-phenyl-
1,2,3,4-tetrahydro-3-isoquinolinyl]methylamine dichloroplatinate
24
Yield: 39%. M. P.: 179e181 ꢁC, [
a
]
¼ ꢀ36.0 (c ¼ 0.20 CHCl3) 1H
D
NMR (300 MHz, CDCl3,
d ppm): 2.10 (m, 1H, CHeAr), 2.44 (m, 2H,
(II) (7d)
AreCHeCHeN), 3.10 (dd, 1H, J ¼ 10.2, 15.0, eCHeN), 3.66 (s, 3H,
CH3), 3.69 (s, 3H, CH3), 3.78 (s, 3H, CH3), 4.44 (m, 1H, eCHeN), 5.73
(s, 1H, AreCHeAr), 6.00 (br, 1H, eNH), 6.53 (s, 1H, AreH), 6.60 (s,
1H, AreH), 6.62 (s, 2H, AreH), 6.74 (d, 2H, J ¼ 8.1, AreH), 7.37 (d, 2H,
J ¼ 7.8, AreH), 7.96 (br,1H, eNH), 8.19 (d, 2H, J ¼ 7.2, AreH). ESI-MS:
668 (m/z ꢀ 35.5); HRMS (ESI) calcd. for C25H27N2O3Cl2Pt 668.1041,
found 668.1023.
24
Yield: 13%. M. P.: 206e208 ꢁC, [
a
]
¼ ꢀ26.0 (c ¼ 0.10 CHCl3) 1H
D
NMR (300 MHz, CDCl3,
d
ppm): 2.19 (dd, 1H, J ¼ 12.6, CHeAr), 2.62
(m, 2H, AreCHeCHeN), 3.22 (dd, 1H, J ¼ 9.3, 16.5 eCHeN), 3.81 (s,
3H, CH3), 3.91 (s, 3H, CH3), 4.57 (m, 1H, eCHeN), 5.89 (s, 1H,
AreCHeAr), 6.07 (br, 1H, eNH), 6.68 (s, 1H, AreH), 6.75 (s, 1H,
AreH), 6.85 (d, 2H, J ¼ 8.1, AreH), 7.16 (d, 3H, J ¼ 8.1, AreH), 8.23 (br,
1H, eNH), 8.35 (d, 2H, J ¼ 6.0, AreH). ESI-MS: 638 (m/z ꢀ 35.5);
HRMS (ESI) calcd. for C24H25N2O2Cl2Pt 638.0941, found 638.0952.
6.6.10. N-(4-Chlorophenyl)-N-[(1S,3S)-1-(4-chlorophenyl)-6,7-
dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinyl]methylamine
6.6.5. Methyl 4-([(1S,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-
tetrahydro-3-isoquinolinyl]methylamino)benzoate
dichloroplatinate(II) (7j)
24
Yield: 38%. M. P.: 228e230 ꢁC, [
a
]
¼ ꢀ41.9 (c ¼ 0.32 CHCl3) 1H
D
dichloroplatinate (II) (7e)
NMR (300 MHz, CDCl3,
d ppm): 2.32 (m, 1H, CHeAr), 2.56 (m, 2H,
24
Yield: 39%. M. P.: 215e217 ꢁC, [
a]
¼ ꢀ50.7 (c ¼ 0.15 CHCl3) 1H
D
AreCHeCHeN), 3.24 (dd,1H, J ¼ 9.3,15.3, eCHeN), 3.82 (s, 3H, CH3),
3.91 (s, 6H, CH3), 4.55 (m, 1H, eCHeN), 5.85 (s, 1H, AreCHeAr), 6.10
(br, 1H, eNH), 6.66 (s, 1H, AreH), 6.75 (s, 1H, AreH), 6.85 (d, 2H,
J ¼ 8.1 AreH), 7.21 (d, 2H, J ¼ 8.1, AreH), 7.50 (d, 2H, J ¼ 7.8, AreH),
8.29 (br, 1H, eNH), 8.28 (d, 2H, J ¼ 7.5, AreH). ESI-MS: 672 (m/
z ꢀ 35.5); HRMS (ESI) calcd. for C24H24N2O2Cl3Pt 672.0551, found
672.0539.
NMR (300 MHz, CDCl3,
d ppm): 2.28 (m, 1H, CHeAr), 2.64 (m, 2H,
AreCHeCHeN), 3.23 (dd,1H, J ¼ 9.0,15.6 eCHeN), 3.82 (s, 3H, CH3),
3.92 (s, 3H, CH3 ꢄ 2), 4.61 (m, 1H, eCHeN), 5.91 (s, 1H, AreCHeAr),
6.10 (br,1H, eNH), 6.69 (s,1H, AreH), 6.76 (s,1H, AreH), 6.95 (d, 2H,
J ¼ 8.1, AreH), 7.54 (m, 3H, AreH), 7.90 (d, 2H, J ¼ 8.4, AreH), 8.30 (br,
1H, eNH), 8.36 (d, 2H, J ¼ 6.0, AreH). ESI-MS: 662 (m/z ꢀ 35.5);
HRMS (ESI) calcd. for C26H28N2O4ClPt 662.1385, found 662.1375.
6.6.11. Methyl 4-([(1S,3S)-1-(4-chlorophenyl)-6,7-dimethoxy-
1,2,3,4-tetrahydro-3-isoquinolinyl]methylamino)benzoate
6.6.6. N-[(1S,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-3-
isoquinolinyl]methyl-N-[4-(trifluoromethyl)phenyl]amine
dichloroplatinate (II) (7k)
dichloroplatinate(II) (7f)
24
Yield: 49%. M. P.: 204e206 ꢁC, [
a
]
¼ ꢀ50.9 (c ¼ 0.18 CHCl3) 1H
D
24
Yield: 53%. M. P.: 194e196 ꢁC, [
a
]
D
¼ ꢀ46.5 (c ¼ 0.16 CHCl3) 1H
NMR (300 MHz, CDCl3,
d ppm): 2.33 (m, 1H, CHeAr), 2.69 (m, 2H,
NMR (300 MHz, CDCl3,
d ppm): 2.28 (m, 1H, CHeAr), 2.64 (m, 2H,
AreCHeCHeN), 3.24 (m, 1H, eCHeN), 3.83 (s, 3H, CH3), 3.93 (s, 6H,
CH3 ꢄ 2), 4.56 (m,1H, eCHeN), 5.87 (s, 1H, AreCHeAr), 6.14 (br, 1H,
eNH), 6.66 (s, 1H, AreH), 6.76 (s, 1H, AreH), 6.98 (m, 2H, AreH),
7.53 (d, 2H, J ¼ 8.1, AreH), 7.84 (br, 1H, eNH), 7.95 (d, 2H, J ¼ 7.5,
AreH), 8.30 (d, 2H, J ¼ 6.3, AreH), ESI-MS: 696 (m/z ꢀ 35.5); HRMS
(ESI) calcd. for C26H27N2O4Cl2Pt 696.0995, found 696.0981.
AreCHeCHeN), 3.23 (dd, 1H, J ¼ 9.9, 16.5 eCHeN), 3.82 (s, 3H,
CH3), 3.92 (s, 3H, CH3), 4.61 (m, 1H, eCHeN), 5.91 (s, 1H,
AreCHeAr), 6.10 (br, 1H, eNH), 6.70 (s, 1H, AreH), 6.77 (s, 1H,
AreH), 7.06 (d, 2H, J ¼ 8.1, AreH), 7.17 (s, 1H, AreH), 7.31 (m, 1H,
AreH), 7.45 (d, 1H, J ¼ 8.1, AreH), 7.31 (m, 3H, AreH), 8.30 (br, 1H,
eNH), 8.35 (d, 2H, J ¼ 6.3, AreH). ESI-MS: 672 (m/z ꢀ 35.5); HRMS
(ESI) calcd. for C25H25N2O2Cl2PtF3 672.1204, found 672.1192.
6.6.12. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-[4-(trifluoromethyl)phenyl]
6.6.7. N-[(1S,3S)-1-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-phenylamine
amine dichloroplatinate (II) (7l)
¼ ꢀ71.4 (c ¼ 0.14 CHCl3) 1H
24
Yield: 47%. M. P.: 209e211 ꢁC, [
a
]
D
dichloroplatinate(II) (7g)
NMR (300 MHz, CDCl3,
d ppm): 2.34 (m, 1H, CHeAr), 2.65 (m, 2H,
24
Yield: 49%. M. P.: 168e170 ꢁC, [
a]
¼ ꢀ36.8 (c ¼ 0.22 CHCl3) 1H
AreCHeCHeN), 3.22 (dd,1H, J ¼ 9.3,16.5, eCHeN), 3.83 (s, 3H, CH3),
3.93 (s, 3H, CH3), 4.59 (m, 1H, eCHeN), 5.87 (s, 1H, AreCHeAr), 6.16
(br, 1H, eNH), 6.68 (s, 1H, AreH), 6.78 (s, 1H, AreH), 7.06 (d, 1H,
J ¼ 7.5, AreH), 7.37 (t, 1H, AreH), 7.48e7.54 (m, 3H, AreH), 8.31 (d,
2H, J ¼ 7.5, AreH), 8.35 (br,1H, eNH). ESI-MS: 706 (m/z þ 23); HRMS
(ESI) calcd. for C25H24N2O2Cl2PtF3 706.0814, found 706.0810.
D
NMR (300 MHz, CDCl3,
d ppm): 2.29 (m, 1H, CHeAr), 2.61 (m, 2H,
AreCHeCHeN), 3.22 (m, 1H, eCHeN), 3.83 (s, 3H, CH3), 3.91 (s, 3H,
CH3), 4.59 (m, 1H, eCHeN), 5.87 (s, 1H, AreCHeAr), 6.16 (br, 1H,
eNH), 6.67 (s, 1H, AreH), 6.75 (s, 1H, AreH), 6.95 (m, 2H, AreH),
7.16e7.33(m, 3H,AreH), 7.51 (d, 2H, J ¼ 7.2, AreH), 8.19 (br,1H, eNH),

362
G. Xu et al. / European Journal of Medicinal Chemistry 46 (2011) 356e363
6.6.13. N-[(1S,3S)-6,7-Dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-phenylamine
6.6.18. N-[(1S,3S)-6,7-dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-[4-(trifluoromethyl)phenyl]
dichloroplatinate (II) (7m)
amine dichloroplatinate (II) (7r)
24
24
Yield: 43%. M. P.: 207e209 ꢁC, [
a]
¼ ꢀ60.0 (c ¼ 0.16 CHCl3) 1H
Yield: 46%. M. P.: 189e191 ꢁC, [
a
]
¼ ꢀ54.3 (c ¼ 0.18 CHCl3) 1H
D
D
NMR (300 MHz, CDCl3,
d
ppm): 2.30 (dd, 1H, J ¼ 11.7, 24.0, CHeAr),
NMR (300 MHz, CDCl3, d ppm): 2.33 (m, 1H, CHeAr), 2.65 (m, 2H,
2.59 (m, 2H, AreCHeCHeN), 3.21 (dd, 1H, J ¼ 6.3, 16.2 eCHeN),
3.82 (s, 3H, CH3), 3.89 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.59 (m, 1H,
eCHeN), 5.87 (s, 1H, AreCHeAr), 6.05 (br, 1H, eNH), 6.68 (s, 1H,
AreH), 6.74 (s, 1H, AreH), 7.00 (d, 2H, J ¼ 7.5, AreH), 7.05 (d, 2H,
J ¼ 8.7, AreH), 7.16e7.26 (m, 3H, AreH), 8.17 (br, 1H, eNH), 8.28 (d,
2H, J ¼ 8.4, AreH). ESI-MS: 634 (m/z ꢀ 35.5); HRMS (ESI) calcd. for
C25H28N2O3ClPt 634.1436, found 634.1434.
AreCHeCHeN), 3.22 (dd, 1H, J ¼ 9.3, 16.5 eCHeN), 3.82 (s, 3H,
CH3), 3.89 (s, 3H, CH3), 3.91 (s, 3H, CH3), 4.59 (m, 1H, eCHeN), 5.86
(s, 1H, AreCHeAr), 6.05 (br, 1H, eNH), 6.68 (s, 1H, AreH), 6.76 (s,
1H, AreH), 7.05 (d, 2H, J ¼ 7.8, AreH), 7.12 (d, 2H, J ¼ 7.8, AreH), 7.26
(s, 1H, AreH), 7.32 (t, 1H, J ¼ 7.8, AreH), 8.25 (d, 2H, J ¼ 8.4, AreH),
8.38 (br, 1H, eNH). ESI-MS: 722 (m/z ꢀ 35.5); HRMS (ESI) calcd. for
C26H27N2O3ClF3Pt 702.1310, found 702.1299.
6.6.14. N-[(1S,3S)-6,7-Dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-(4-methylphenyl)amine
6.7. Cell lines
dichloroplatinate (II) (7n)
The tumor cell lines panel consisted of BCT-8 (Human colon
carcinoma cell line), BEL-7402 (Human hepatoma cell line), A2780
(Human ovarian cancer cell line), MCF-7 (Human breast adeno-
carcinoma cell line), Hela (Human cervix carcinoma cell line), A549
(Human lung adenocarcinoma cell line), and BGC-823 (Human
gastric cancer cell line).
24
Yield: 49%. M. P.: 211e213 ꢁC, [
a
]
¼ ꢀ58.2 (c ¼ 0.11 CHCl3) 1H
D
NMR (300 MHz, CDCl3, d ppm): 2.29 (s, 3H, AreCH3), 2.20e2.40(m,
1H, CHeAr), 2.69 (m, 2H, AreCHeCHeN), 3.20 (m, 1H, eCHeN),
3.82 (s, 3H, CH3), 3.90 (s, 6H, CH3 ꢄ 2), 4.58 (m, 1H, eCHeN), 5.87 (s,
1H, AreCHeAr), 6.05 (br, 1H, eNH), 6.68 (s, 1H, AreH), 6.74 (s, 1H,
AreH), 6.90 (m, 2H, AreH), 7.03 (m, 4H, AreH), 8.10 (br, 1H, eNH),
8.28 (d, 2H, J ¼ 6.6, AreH). ESI-MS: 648 (m/z ꢀ 35.5); HRMS (ESI)
calcd. for C26H30N2O3ClPt 648.1587, found 648.1571.
6.8. Cytotoxicity evaluation
Human cancer cells were cultured in PRMI1640 or DMEM/F12
supplemented with 10% fetal bovine serum, containing penicillin,
streptomycin at 37 ꢁC and humidified at 5% CO2. Briefly, cells were
6.6.15. N-[(1S,3S)-6,7-Dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydro-3-isoquinolinyl]methyl-N-(4-methoxyphenyl)amine
dichloroplatinate (II) (7o)
placed in the appropriate media on 96-well plates in a 100 mL total
24
Yield: 41%. M. P.: 209e211 ꢁC, [
a]
¼ ꢀ53.8 (c ¼ 0.13 CHCl3) 1H
volume at a density of 1e2.5 ꢄ 104 cells/mL and were allowed to
adhere for 24 h before treatment with tested drugs in DMSO solution
(10ꢀ5, 10ꢀ6, 10ꢀ7 mol/L final concentration). Triplicate wells were
treated with media and agents. Cell viability was assayed after 96 h of
continuous drug exposure with a tetrazolium compound [3-(4,5-
dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfo-
D
NMR (300 MHz, CDCl3,
d
ppm): 2.23 (dd, 1H, J ¼ 9.0, CHeAr), 2.59
(m, 2H, AreCHeCHeN), 3.20 (dd, 1H, J ¼ 6.3, 16.2, eCHeN), 3.77 (s,
3H, CH3), 3.81 (s, 3H, CH3), 3.89 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.57
(m,1H, eCHeN), 5.86 (s,1H, AreCHeAr), 6.02 (br,1H, eNH), 6.67 (s,
1H, AreH), 6.74 (s,1H, AreH), 6.70 (d, 2H, J ¼ 8.7, AreH), 6.93 (d, 2H,
J ¼ 8.7, AreH), 7.04 (d, 2H, J ¼ 8.4, AreH), 8.11 (br, 1H, eNH), 8.28 (d,
2H, J ¼ 8.4, AreH). ESI-MS: 722 (m/z þ 23); HRMS (ESI) calcd. for
C26H30N2O4Cl2PtNa 722.1128, found 722.1135.
phenyl)-2H-tetrazolium salt; MTT (0.5 mg/mL, 100
mL), Ameresco
Corp] in fresh medium. After the medium was removed, 150
mL of
DMSO was added to each well. The plates were gently agitated until
the color reaction was uniform and the OD570 was determined using
microplate reader (Wellscan MK3, Labsystems Dragon). Microsoft
Excel 2003 was used for data analysis. Media-only treated cells
served as the indicator of 100% cell viability. The 50% inhibitory
concentration (IC50) was defined as the concentration that reduced
the absorbance of the untreated wells by 50% of vehicle in the MTT
assay. Assays were performed in triplicate on three independent
experiments.
6.6.16. N-(4-Chlorophenyl)-N-[(1S,3S)-6,7-dimethoxy-1-(4-
methoxyphenyl)-1,2,3,4-tetrahydro-3-isoquinolinyl]methylamine
dichloroplatinate (II) (7p)
24
Yield: 46%. M. P.: 215e217 ꢁC, [
a]
¼ ꢀ60.7 (c ¼ 0.15 CHCl3)1H
D
NMR (300 MHz, CDCl3,
d ppm): 2.23 (m, 1H, CHeAr), 2.63 (m, 2H,
AreCHeCHeN), 3.21 (m, 1H, eCHeN), 3.81 (s, 3H, CH3), 3.89 (s, 6H,
CH3 ꢄ 2), 4.55 (m,1H, eCHeN), 5.85 (s,1H, AreCHeAr), 5.98 (br,1H,
eNH), 6.66 (s, 1H, AreH), 6.74 (s, 1H, AreH), 6.70e6.80 (br, 1H,
eNH), 6.92 (d, 2H, AreH), 7.04 (d, 2H, J ¼ 6.3, AreH), 7.16, (d, 2H,
6.9. Statistical analysis
AreH), 8.23 (m, 2H, AreH). 13C NMR (CDCl3,
d ppm): 160.12, 149.29,
148.21, 144.34, 132.67, 132.52, 128.82, 128.68, 128.07, 124.34, 124.09,
113.88, 111.64, 110.28, 67.55, 61.44, 57.70, 56.01, 55.91, 55.50, 26.80.
ESI-MS: 668 (m/z ꢀ 35.5); HRMS (ESI) calcd. for C25H27N2O3Cl2Pt
668.1046, found 668.1033.
Data were collected from three separate experiments. The
results are expressed as mean ꢂ SD. The statistical differences were
analyzed using SPSS’ t-test. P value less than 0.05 was considered to
indicate statistical differences.
6.6.17. Methyl 4-([(1S,3S)-6,7-dimethoxy-1-(4-methoxyphenyl)-
1,2,3,4-tetrahydro-3-isoquinolinyl]methylamino)benzoate
Acknowledgements
dichloroplatinate (II) (7q)
24
Yield: 19%. M. P.: 227e229 ꢁC, [
a]
¼ ꢀ14.3 (c ¼ 0.23 CHCl3) 1H
This research was financially supported by the National Science
Technology Major Project “Key New Drug Creation and
Manufacturing Program” China (Number: 2009ZX09301-003-9-1).
D
&
NMR (300 MHz, CDCl3,
d ppm): 2.50 (m, 1H, CHeAr), 2.90 (m, 2H,
AreCH), 3.27 (m, 1H, eCHeN), 3.73 (s, 3H, CH3), 3.88 (s, 3H, CH3),
3.89 (s, 3H, CH3), 3.96 (s, 3H, CH3), 4.73 (m, 1H, eCHeN), 6.00 (s, 1H,
AreCHeAr), 6.34 (br, 1H, eNH), 6.43 (s, 1H, AreH), 6.63 (s, 1H,
AreH), 6.94 (d, 3H, J ¼ 7.2, AreH), 7.05 (d,1H, J ¼ 8.1, AreH), 7.40 (br,
1H, eNH), 7.71 (d, 1H, J ¼ 8.1, AreH), 7.83 (d, 1H, J ¼ 7.2 AreH). ESI-
MS: 722 (m/z ꢀ 35.5); HRMS (ESI) calcd. for C27H30N2O5ClPt
692.1491, found 692.1495.
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