Synthesis and?antitumor activity of?cis-dichloroplatinum(II) complexes of?1-(2-aminophenyl)-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.ejmech.2006.03.011

Fifteen cis-dichloroplatinum complexes (5a-5o) were synthesized by treatment of 1-(2-aminophenyl)-1,2,3,4-THIQs (4a-4o) with K₂PtCl₄. The antitumor activity of these compounds was examined against four different human tumor cell lines. Their structure-activity relationships for antitumor activity are reported. All of these compounds exhibited activity against MCF-7 cell line and showed good activity against WiDr cell line except 5c and 5f. On the other hand, compounds 5j and 5o are more active than the other compounds against Hepa59T/VGH cell line. The electron-donating group at the 6-position of isoquinoline ring seems to decrease the antitumor activity and the chloro substituent at the C-4 position of the aniline ring shown the highest potency. The "trans influence" dominates the control of the stability of [1-(2-aminophenyl)-1,2,3,4-THIQ]dichloroplatinums(II).

Full text of DOI:10.1016/j.ejmech.2006.03.011

European Journal of Medicinal Chemistry 41 (2006) 940–949
http://france.elsevier.com/direct/ejmech
Original article
Synthesis and antitumor activity of cis-dichloroplatinum(II)
complexes of 1-(2-aminophenyl)-1,2,3,4-tetrahydroisoquinolines
Chen-Yuan Kuo a,b, Ming-Jung Wu c,*, Yao-Haur Kuo d,e
a Department of Biological Engineering, Yung-Ta Institute of Technology and Commerce, Pingtung, Taiwan, ROC
b Graduate Institute of Pharmaceutical Science, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
c Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
d National Research Institute of Chinese Medicine, 112 Teipei, Taiwan, ROC
e Institute of Life Science, National Taitung University, 950, Taitung, Taiwan, ROC
Received in revised form 17 March 2006; accepted 23 March 2006
Available online 27 April 2006
Abstract
Fifteen cis-dichloroplatinum complexes (5a–5o) were synthesized by treatment of 1-(2-aminophenyl)-1,2,3,4-THIQs (4a–4o) with K2PtCl4.
The antitumor activity of these compounds was examined against four different human tumor cell lines. Their structure–activity relationships for
antitumor activity are reported. All of these compounds exhibited activity against MCF-7 cell line and showed good activity against WiDr cell
line except 5c and 5f. On the other hand, compounds 5j and 5o are more active than the other compounds against Hepa59T/VGH cell line. The
electron-donating group at the 6-position of isoquinoline ring seems to decrease the antitumor activity and the chloro substituent at the C-4
position of the aniline ring shown the highest potency. The “trans influence” dominates the control of the stability of [1-(2-aminophenyl)-
1,2,3,4-THIQ]dichloroplatinums(II).
© 2006 Elsevier SAS. All rights reserved.
Keywords: Isoquinoline; Antitumor activity; Trans influence
1. Introduction
plexes is still not clear, several rules are apparent [12]. Typi-
cally, the compounds must have two cis-coordinated amine li-
gands as nonleaving groups, each carrying at least one N–H
bond in order to be cytotoxic. Apparently, trans-coordinated
amine ligands always showed inactive. The synthesis of several
new platinum(II) complexes with 1-(2-aminophenyl) isoquino-
line ligands is reported by Nussbaum et al. [13]. Two of the
new complexes, the isoquinoline backbone appears in these
compounds, were more potent against L1210 murine leukemia
cells than the well-established antitumor compound cisplati-
num. On the other hand, isoquinolines, a kind of alkaloids,
are widespread occurrence in nature and most of them exhibit
bioactivity [14,15]. Berberrubine, a protoberberine alkaloid,
presents antitumor activity in animal models [16], 6-alkyl-12-
Cisplatin (cis-diamminedichloroplatinum, cis-DDP, cis-[
PtCl2(NH3)2]) has been known since 1845 [1], but not until
1970 was its antitumor activity established [2,3]. That is used
to treat many kinds of malignancies, including ovarian [4], cer-
vical [5–7], head [4], nonsmall cell lung cancer [4] and so on.
It is a very useful antitumor agent for the treatment of testicular
and ovarian cancers [8,9], while its geometric isomer transpla-
tin (trans-DDP), trans-[PtCl2·(NH3)2], was found to be thera-
peutically inactive. Since the antitumor activity of cisplatin was
reported, various platinum complexes have been synthesized
and tested for the antitumor activity [10], however, the rela-
tionship between the ligand structure and the cytotoxicity of
the complexes is still unclear [11]. Although the relationship
between the ligand structure and the cytotoxicity of the com-
formyl-5,6-dihydroindolo[2,1-a]isoquinolines
have
been
shown to inhibit the growth of human mammary cells [17]
and 2,3-dihydroimidazo[2,1-a]isoquinolines which contain iso-
quinoline skeleton showed antitumor activity also [18]. Con-
sidering this background, we attempted to synthesize cis-di-
chloroplatinum(II) complexes of 1-(2-aminophenyl)-1,2,3,4-
* Corresponding author.
E-mail address: mijuwu@kmu.edu.tw (M.-J. Wu).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.03.011

C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
941
tetrahydroisoquinolines (APTHIQs) and evaluate their struc-
ture–activity relationships as antitumor agents.
nophenyl)-3,4-DHIQs (APDHIQ) (3a–3o) and 5,6-dihydroin-
dazolo[3,2-a]isoquinoines [21]. Treatment of APDHIQs (3a–
3o) with sodium borohydride in methanol gave 1-(2-aminophe-
nyl)-1,2,3,4-THIQs (4a–4o) in good yields.
2. Results and discussions
2.1.2. The synthesis of [1-(2-aminophenyl)-1,2,3,4-THIQ]
dichloroplatinums(II)
2.1. Chemistry
The 1-(2-aminophenyl)-1,2,3,4-THIQs and equimolar
amounts of K2PtCl4 were dissolved in 0.1 M HCl at
60–65 °C. To this stirring solution was added with 0.1 N
NaOH to neutrality at 60–65 °C. [1-(2-Aminophenyl)-1,2,3,4-
THIQ]dichloroplatinums(II) (5a–5o) were obtained in good
yields (Scheme 2).
Three different types of isoquinoline skeleton cisplatinum
complexes have been synthesized by Nussbaum et al. [13],
two 1,2,3,4-THIQ dichloroplatinums(II) which have a twisted
structure showed more potent against L1210 murine leukemia
cells than cisplatin. In order to understand the relationship
between the structure of ligands of the complexes and the bio-
logical activity further, we synthesized five series of 1-(2-ami-
nophenyl-1,2,3,4-THIQ)dichloroplatinums(II) (APTHIQDPs)
differentiated at 1-substitution level: (a) 1-(2-aminophenyl-
1,2,3,4-THIQ) dichloroplatinums(II) (APTHIQDP) (b) 5-
chloro-1-(2-aminophenyl-1,2,3,4-THIQ)dichloroplatinums(II)
(5-Cl-APTHIQDPs) (c) 5-methoxy -1-(2-aminophenyl-1,2,3,4-
THIQ)dichloroplatinums(II) (5-MeO-APTHIQDPs) (d) 5-
Methyl-1-(2-aminophenyl-1,2,3,4-THIQ) dichloroplatinums(II)
(5-Me-APTHIQD Ps) (e) 4-chloro-1-(2-aminophenyl-1,2,3,4-
THIQ) dichloroplatinums(II) (4-Cl-AP THIQDPs).
The structures of compounds (1–3) have been determined in
our previously reported [21] and compounds (4a–4o) were de-
1
termined on the basis of their H NMR, 13C NMR spectral
data, mass spectroscopic and elemental analysis. The 1H
NMR spectroscopic data of compound 4 shows the presence
of the downfield signals at δ 6.30–7.20 suggested the presence
of aromatic protons, and the singlet signal at δ 5.10 (1H) sug-
gested the C-1 position proton (CH). These compounds have a
twisted structure showed multiple signals at δ 2.60–3.43 for
both methylene (CH2) group. 13C NMR spectra indicated that
these molecules contain 12 sp2 carbons signals at δ 110–130,
imine (C=N) signal at δ 148 no more present and C-1 position
carbon signal present at δ 61. In addition, the mass spectra in-
2.1.1. Synthesis of the 1-(2-aminophenyl)-1,2,3,4-THIQs
The synthesis of 1-(2-aminophenyl)-1,2,3,4-THIQs is
shown in Scheme 1.
The corresponding acid chlorides, prepared by the reaction
of benzoic acids with thionyl chloride, were condensed with
phenylethylamines under Schotten–Baumann [19,20] condi-
tions to give the expected N-phenylethylamides (1a–1o) [21].
The N-phenylethylamides were converted into the 1-(2-nitro-
phenyl)-3,4-DHIQs (2a–2o) [21] by Bischler-Napieralski [22–
24] reaction conditions, respectively. Compounds 2a–o were
then treated with SnCl2·2H2O in ethyl acetate to give 1-(2-ami-
Scheme 2. Synthetic route for compound 5.
Scheme 1. Synthetic route for compounds 1–4. Reagents: (a) SOCl2, benzene (b) pyridine (c) POCl3, CH3CN (d) SnCl2·2H2O, EtOAc (e) NaBH4, methanol.

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C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
Table 1
dicated that the molecular weights of compounds (4a–4o) were
equal to the value of prediction, and elemental analysis showed
that the molecule formula of compounds (4a–4o) satisfied our
expectation also. The crystal structure of compound 4o is
shown in Fig. 1. Due to Cl-DMSO ligand exchange [25], the
Cytotoxicity of compounds 5a–o against human tumor cells (ED50 S.D., μg/
ml)
Compounds
Hepa59T/
VGHa
WiDrb
HeLac
MCF-7d
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
10.42 0.67 5.32 0.61
19.77 1.20 7.12 0.31
15.84 0.60 5.94 0.83
(–)
1
target products (5a–5o) showed multiple sets of signals in H
9.66 0.73
6.95 0.90
NMR and 13C NMR spectra, taken in DMSO(d6) that made
(–)e
17.39 1.07 (–)
4.88 0.63
1
8.74 0.29
13.67 0.57 7.39 0.46
(–)
12.68 0.56 8.49 0.45
6.45 0.49
11.34 0.56 4.37 0.63
14.27 0.63 6.97 0.19
assignment more difficult. The H NMR spectroscopic data
of compound 5 shows the presence of multiple sets singlet sig-
nals at δ 5.30–5.90 suggested the methine (CH) group at the 1-
position, and 13C NMR spectra indicated that C-1 position car-
bon present of multiple sets singlet signals at δ 61–62 also.
Elemental analysis confirmed the structure of the target pro-
ducts further.
14.21 0.61 (–)
(–)
14.06 0.51 2.37 0.20
11.89 0.48 4.41 0.39
19.65 0.35 4.77 0.24
4.03 0.34
1.90 0.13
2.32 0.38
1.49 0.02
1.22 0.08
4.16 0.12
4.02 0.17
2.32 0.17
15.70 0.29 9.40 0.37
1.49 0.08
4.65 0.28
7.73 0.35
3.68 0.17
3.80 0.20
1.46 0.04
1.06 0.09
2.80 0.21
1.40 0.07
3.57 0.39
4.35 0.16
3.88 0.16
3.61 0.12
4.91 0.25
3.18 0.16
4.40 0.32
5.66 0.38
4.30 0.20
4.71 0.13
3.43 0.15
4.75 0.21
5m
5n
5o
2.2. Biological activities
Cisplatin
The cytotoxicities of the series of cis-dichloroplatinum com-
plexes (5a–5o) of 1-(2-aminophenyl)-1,2,3,4-THIQs (4a–4o)
were examined with Hepa59T/VGH, WiDr, HeLa and MCF-7
cell lines. The results are summarized in Table 1.
(–): ED50 > 20 μg/ml.
a
Human liver carcinoma.
b
Human colon adenocarcinoma.
Human cervical epitheloid carcinoma.
Human breast adenocarcinoma.
c
d
As shown in Table 1, all these compounds exhibited good
activity against MCF-7 cell lines, except compound 5f. Most of
these compounds showed good activity against WiDr cell lines,
except 5c and 5f. Compounds 5j and 5o showed more active
than other compounds against Hepa59T/VGH cell lines. Com-
pounds 5j–o showed good activity against HeLa cell lines than
other compounds.
the C-4 position of aniline ring, will improve their activity. (c)
Compounds 5d–f with electron-donating group (MeO) at the
C-5 position of aniline ring seems to decrease the antitumor
activity. This finding is in contrast to the report by Steglich.
Previously, Steglich indicated that the cytotoxicity is related
to the basicity of the amine ligands. Compounds 5c, 5f and 5i
bearing two methoxy groups at 6- and 7-positions are consid-
ered to have most basic amine in the isoquinoline ligands and
show less effective in the series of complexes. We found that
the antitumor activity of these platinum complexes have some
relevant to the trans effect of these substituents since the trans
influence [26,27] controls the stability of [1-(2-aminophenyl)-
1,2,3,4-THIQ]dichloroplatinums(II). The approximate order of
trans influence (resonance) is 6,7-DiMeO < 7-MeO < H (iso-
quinoline ring) and 5-MeO < 5-Cl < 5-Me < H < 4-Cl (aniline
ring). This effect concludes why compounds 5m–o are more
active than the other compounds and compounds 5c, 5f and
5i are less active. The 6-position methoxy group makes the
amino group in the isoquinoline ring more negative and Pt–N
was broken more rapidly than other THIQ dichloroplatinums
(II) without methoxy group at the 6-position. Similarly, The
C-5 position substituted groups with nonbonding electron pair
make the amino group in the aniline ring more negative, so the
Pt–N bond was broken more rapidly than other THIQ dichlor-
oplatinums(II) (Fig. 2).
2.3. Structure–activity relationships
Concerning the relationship between structure and cytotoxi-
city of these compounds against human tumor cell lines, the
following conclusion can be made: (a) Compounds 5c, 5f, 5i
and 5l bearing an electron-donating group (MeO) at the C-6
position of isoquinoline ring seems to decrease the antitumor
activity. (b) Compounds 5m–o containing chloro substituent at
Although cisplatin is highly effective in the treatment of
many malignancies [28] but some tumors such as colorectal
and nonsmall cell lung cancers have intrinsic resistance to cis-
platin [29]. However, most of our synthesized compounds are
effective in the treatment of human colon adenocarcinoma, and
compound 5h is the most effective one. The 6-position meth-
oxy group such as 5c, 5f and 5i make less effective in the
treatment of human colon adenocarcinoma as shown in Table 1.
Similarly, compounds 5c, 5f and 5i that contain methoxy group
Fig. 1. Structure analysis of the 6,7-dimethoxy-1-(4-chloro-2-aminophenyl)-
1,2,3,4-tetrahydroisoquinoline 4o in the crystal.

C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
943
4. Experimental section
4.1. Chemistry
1
The H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively. High-resolution mass spectra were re-
corded on a double focusing magnetic sector mass spectro-
meter using EI at 70 eV. All reactions were monitor by analy-
tical TLC (silica gel 60 F254, Merck). The residues were
purified by flash chromatography (silica gel 230–400 μm,
Merck, Germany). All melting points are uncorrected.
4.2. N-Phenylethyl-2-nitrobenzamides
4.2.1. N-Phenylethyl-2-nitrobenzam ides (1a–c) [13,21,22]
(general procedure A1)
To a stirred solution of phenethylamine (30 mmol) and pyr-
idine (38 mmol) in dry benzene (80 ml) was added a solution
of 2-nitrobenzoyl chloride (27.7 mmol) in dry benzene (30 ml).
The mixture was continuously stirred at room temperature
overnight and then poured into water (200 ml). The solution
was filtered and the solid was washed with 1.0 N HCl
(80 ml), 1.0 N NaOH (80 ml), and water (80 ml). The crude
product was recrystallized from EtOAc/n-hexane to give 1a–c.
The mother layer was evaporated and the residue was recrys-
tallized from EtOAc/n-hexane. The white crystals were com-
bined.
Fig. 2. Trans influence of amino group in both isoquinolines and anilines ring.
at the 6-position are poor in against other human tumor cells in
our report. Smith et al. [30] have reported that compounds with
substituent at the 6-position of the tetrahydroquinoline ring
were promoted their ability to cause expression of a reporter
gene downstream of an ecdysone response element in a mam-
malian cell line engineered to express the ecdysone receptor
from Aedes aegypti. Cortes [20] have reported that an alkoxy
group at the C-6 position of 1-substituted-3,4-dihydro isoqui-
noline were relevant for cytotoxicity in vitro against the leuke-
mia L1210 cell line. Contrastively, in our results, compounds
containing electron-donating group at the 6-position of isoqui-
noline ring were less active than others. On the other hand,
compounds 5m–o containing chloro substituent at the C-4 po-
sition of aniline ring, were more potent than cisplatin against
MCF-7 cell lines and HeLa cell lines. This is because the low-
est trans effect and the chelating effect [31–33] make their
DNA adducts more stable than other APTHIQdichloroplati-
nums(II)-DNA adducts and cisplatin-DNA adducts. Applica-
tion of the Student’s t-test indicates that the chloro substituent
at the C-4 position and the CH3 at the C-5 position of values
are not statistically different (P = 0.6972). The CH3 at the C-5
position and the chloro substituent at the C-4 position show a
similar activity. The exact reason is not clear, it may due to the
lower trans influence and moderate electron-donating effect
make the DNA adducts of 5j–l have a similar stability as
5m–o.
4.2.2. N-Phenylethyl-2-nitrobenzamide (1d–1o) [13,21,22]
(general procedure A2)
The acids (5-methoxy-2-nitro benzoic acid, 5-methyl-2-ni-
trobenzoic acid, 5-chloro-2-nitrobenzoic acid or 4-chloro-2-ni-
trobenzoic acid) were treated with thionyl chloride in dry ben-
zene. The resulting solution was stirred at 70–75 °C for 12 h.
The excess thionyl chloride was removed under reduced pres-
sure. The resulting acid chloride was dissolved in dry benzene,
and added dropwise to a stirred solution of phenethylamine and
pyridine in dry benzene. The mixture was continuously stirred
at room temperature overnight and then poured into water
(200 ml). The solution was filtered and the solid was washed
with 1.0 N HCl (100 ml), 1.0 N NaOH (100 ml), and water
(100 ml), the crude product was recrystallized from EtOAc/n-
hexane. The mother liquid was evaporated and the residue was
recrystallized from EtOAc/n-hexane. The crystals were com-
bined.
3. Conclusion
4.3. 1-(2-Nitrophenyl)-3,4-dihydroiso quinolines (2a–2o) [13,
21,22]
We have synthesized a series of cisplatinum complexes with
THIQs. Where we found that a compound containing the
chloro substituent at the C-4 position of the aniline ring shows
a good activity. However, the compounds bearing Cl or MeO
group at the C-5 position at the aniline ring gave the weaker
activity than others. Having an electron-donating group at the
C-6 position of isoquinoline ring also reduce the antitumor ac-
tivity.
4.3.1. General procedure B
To a stirred solution of N-phenyl ethyl-2-nitrobenzamides
(12.9 mmol) in dry CH3CN (80 ml) was added POCl3
(32 mmol) dropwise, and the stirring was continued for 1 h at
room temperature. The resulting mixture was heated to reflux
and stirred for approximately 5–12 h. After removal of the sol-

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C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
vent in vacuo, CHCl3 (50 ml) and H2O (50 ml) were added,
and the aqueous phase was adjusted with aqueous 10 N NaOH
to pH 12. The organic layer was washed with saturated aqu-
eous NaHCO3 (3 × 100 ml), dried over anhydrous Na2SO4,
and the solvent was removed in vacuo. Recrystallization of
the crude product from EtOAc/n-hexane, afforded crystals
2a–2o.
4.5.3. 7-Methoxy-1-(2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4b)
The title compound was obtained as a white powders in
70% yield in a similar procedure for the preparation of 4a;
1
m.p. 100–101 °C, H NMR (400 MHz, CDCl3) δ 7.10 (1H,
ddd, J = 7.6, 7.6, 1.2 Hz, H-4′), 7.06 (1H, d, J = 8.4, H-6′),
6.97 (1H, dd, J = 7.6, 1.2 Hz, H-3′), 6.74 (1H, dd, J = 8.4,
2.8 Hz, H-6), 6.69 (1H, ddd, J = 7.6, 7.6, 1.2 Hz, H-5′), 6.64
(1H, dd, J = 8.0, 1.8 Hz, H-5′), 6.37 (1H,d, J = 2.8 Hz , H-8),
5.08 (1H, s, H-1), 3.64 (3H, s, OCH3), 3.22–3.27 (1H, m, H-
3e), 2.93–3.09 (2H, m, H-3a, H-4e), 2.71–2.77 (1H, m, H-4a);
13C NMR (100 MHz, CDCl3) δ 157.6 (C-7), 146.0 (C-NH2),
138.3 (C-1′), 131.0 (C-4a), 130.0 (C-8a), 128.5 (CH-5) 127.2
(CH-4′), 117.5 (CH-5′), 116.8 (CH-3′), 112.6 (CH-6), 111.8
(CH-8), 61.6 (C-1), 55.1 (OCH3), 42.9 (CH2N), 28.8
(CH2CH2N). EI-MS m/z (%) = EI-MS m/z (%) = 254 (100)
[M+], 253 (49) [M+ – H], 236 (50) [M+ – NH2–2H], Anal.
Calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found:
C, 75.67; H, 6.91; N, 11.15.
4.4. 1-(2-Aminophenyl)-3,4-dihydroiso quinolines (3a–3o) [13,
21,22]
4.4.1. General procedure C
The 1-(2-nitrophenyl)-3,4-dihydro- isoquinolines (4.4 mmol)
and SnCl2·2H2O (26.4 mmol) in dry EtOAc (150 ml) were
refluxed until completion of the reaction (30 h). To this mix-
ture were added with stirring H2O (20 ml) and 10 N NaOH
(5 ml), and the resulting solution was carefully poured into
saturated aqueous NaHCO3 (100 ml). After extraction with
EtOAc (3 × 50 ml), the combined organic layers were dried
over MgSO4 (3 h), and evaporated in vacuo. Pure product
was obtained by recrystallization of the crude product from
EtOAc/n-hexane.
4.5.4. 6,7-Dimethoxy-1-(2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4c)
The title compound was obtained as a yellow powders in
78% yield in a similar procedure for the preparation of 4a;
1
m.p. 144–145 °C, H NMR (400 MHz, CDCl3) δ 7.10 (1H,
4.5. 1-(2-Aminophenyl)-1,2,3,4-tetrahydroisoquinolines
ddd, J = 7.6, 1.6, 1.2 Hz, H-4′) 6.93 (1H, dd, J = 7.6, 1.2 Hz,
H-6′) 6.81 (1H, s, H-5) 6.68 (1H, ddd, J = 7.2, 1.2, 1.2 Hz, H-
5′), 6.64 (1H, dd, J = 8.0, 1.2 Hz, H-3′) 6.63 (1H,s, H-8) 6.32
(1H, s, H-1) 3.86 (3H, s, OCH3) 3.64 (3H, s, OCH3) 3.18-3.24
(1H, m, H-3e) 3.01–3.09 (1H, m, H-3a) 2.91–2.98 (1H, m, H-
4e) 2.68-2.75 (1H, m, H-4a); 13C NMR (100 MHz, CDCl3) δ
147.7 (C-7), 147.3 (C-6), 146.2 (C-NH2), 130.8 (C-1′), 139.1
(C-4a), 128.5 (C-8a), 127.3 (CH) 127.2 (CH), 117.5 (CH-8),
116.7 (CH-5), 111.5 (CH-5′), 110.0 (CH-3′), 60.6 (C-1), 55.8
(2OCH3), 42.4 (CH2N), 29.1 (CH2CH2N). EI-MS m/z (%)
= 284 (93) [M+], 283 (51) [M+ – H], 269 (55) [M+ – CH3],
268 (15) [M+ – NH2], 253 (20) [M+ – OCH3], Anal. Calcd for
C17H20N2O2: C, 71.83; H, 7.04; N, 9.86. Found: C, 71.60; H,
7.09; N, 9.82.
4.5.1. General procedure D
To a solution of 1-(2-aminophenyl)-3,4-dihydroisoquino-
lines (4.2 mmol) in methanol (80 ml) and NaBH4 (21 mmol)
was added in portions, the mixture was continuously stirred at
room temperature for approximately 2 hours. After removal of
the solvent in vacuo, CH2Cl2 (50 ml) and H2O (50 ml) were
added. The aqueous phase was extracted with CH2Cl2
(20 ml × 2), and the combined organic layers were washed
with water (30 ml × 2) and dried over anhydrous MgSO4.
The solvent was evaporated in vacuo and the crude product
was recrystallized from acetone/n-hexane.
4.5.2. 1-(2-Aminophenyl)-1,2,3,4-tetra hydroisoquinoline (4a)
4.5.5. 1-(5-Methoxy-2-aminophenyl)-1,2,3,4-
The title compound was obtained as a white powders in
75% yield from 1-(2-aminophenyl)-3,4-dihydroisoquinoline
following procedures D; m.p. 106–108 °C, 1H NMR
(400 MHz, CDCl3) δ 7.10–7.20 (4H, m, H-5,6,7,8), 7.01 (1H,
d, J = 7.6, H-6′), 6.84 (1H, J = 7.6, H-3′), 6.73 (1H, ddd,
J = 7.6, 1.2, 0.8 Hz, H-4′), 6.65 (1H, dd, J = 8.0, 0.8 Hz, H-
5′), 5.12 (1H, s, H-1), 3.26–3.32 (1H, m, H-3e), 3.04–3.14
(2H, m, H-3a, H-4e), 2.79–2.86 (1H, m, H-4a); 13C NMR
(100 MHz, CDCl3) δ 146.0 (C-NH2), 137.3 (C-1′), 135.0 (C-
4a), 131.0 (C-8a), 128.9 (CH-6) 128.4 (CH-7), 127.0 (CH-8),
126.8 (CH-5), 126.4 (CH-4′), 125.9 (CH-6′), 117.3 (CH-5′),
116.7 (CH-3′), 61.8 (C-1), 42.9 (CH2N), 29.6 (CH2CH2N).
EI-MS m/z (%) = 224 (66) [M+], 223 (53) [M+ – H], 206
(100) [M+ – NH2–2H], Anal. Calcd for C15H16N2: C, 80.32;
H, 7.19; N, 12.49. Found: C, 80.01; H, 7.22; N, 12.32.
tetrahydroisoquinoline (4d)
The title compound was obtained in 65% yield in a similar
procedure for the preparation of 4a; 1HNMR (400 MHz,
CDCl3) δ 7.14–7.18 (2H, m, H-7,8), 7.05–7.10 (1H, ddd,
J = 7.6, 7.6, 2.4 Hz, H-6), 6.85 (1H, d, J = 7.6 Hz, H-5), 6.71
(1H, dd, J = 8.8, 2.8 Hz, H-3′), 6.62 (2H, m, H-4′,6′), 5.10 (1H,
s, H-1), 3.73 (3H, s, OCH3), 3.23–3.30 (1H, m, H-3e), 3.01–
3.12 (2H, m, H-3a, H-4e), 2.78–2.85 (1H, m, H-4a); 13C NMR
(100 MHz, CDCl3) δ 151.9 (C-5′), 139.5 (C-NH2), 136.9 (C-
1′), 134.9 (C-4a), 129.0 (C-8a), 128.8 (CH-6) 126.9 (CH-7),
126.5 (CH-8), 125.9 (CH-5), 117.7 (CH-3′), 117.4 (CH-4′),
113.3 (CH-6′), 61.2 (C-1), 55.7 (OCH3), 42.6 (CH2N), 29.4
(CH2CH2N). EI-MS m/z (%) = 254 (100) [M+], 253 (47) [M+
– 1], Anal. Calcd for C16H18N2O·1/8 CHCl3: C, 71.93; H,
6.79; N, 10.04. Found: C, 71.88; H, 6.89; N, 9.94.

C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
945
4.5.6. 7-Methoxy-1-(5-methoxy-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4e)
4.5.9. 7-Methoxy-1-(5-chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4h)
The title compound was obtained as a white powders in
The title compound was obtained as a white powders in
76% yield in a similar procedure for the preparation of 4a;
m.p. 165–166 °C, H NMR (400 MHz, CDCl3) δ 7.05 (1H,
68% yield in a similar procedure for the preparation of 4a;
m.p. 96–98 °C, H NMR (400 MHz, CDCl3) δ 7.05(1H, d,
1
1
d, J = 8.4 Hz, H-3′) 7.04 (1H, dd, J = 8.4 , 2.4 Hz, H-4′) 6.92
(1H, d, J = 2.4 Hz, H-6′) 6.75 (1H, dd, J = 8.4 , 2.8 Hz, H-6)
6.55 (1H, d, J = 8.4 Hz, H-5), 6.37 (1H, d, 2.8 Hz, H-8), 5.03
(1H, s, H-1), 3.67 (3H, s, OCH3) 3.19–3.24 (1H, m, H-3e)
3.01–3.08 (1H, m, H-3a) 2.91–2.98 (1H, m, H-4e) 2.71–2.77
(1H, m, H-4a); 13C NMR (100 MHz, CDCl3) δ 157.7 (C-7),
144.7 (C-NH2), 137.4 (C-Cl), 130.4 (C-1′), 130.0 (C-4a), 128.5
(C-8a), 128.2 (CH-4′), 127.2 (CH-5), 122.0 (CH-6′), 117.8
(CH-3′), 112.8 (CH-6), 111.9 (CH-8), 61.1 (C-1), 55.2
(OCH3), 42.6 (CH2N), 28.6 (CH2CH2N). EI-MS m/z (%)
= 290 (35) [M+ + 2], 288 (100) [M+], Anal. Calcd for
C16H17N2OCl: C, 66.55; H, 5.93; N, 9.70. Found: C, 66.41;
H, 5.90; N, 9.61.
J = 8.4, H-5), 6.72 (1H, dd, J = 8.4, 2.8 Hz, H-6), 6.69 (1H,
d, J = 2.8 Hz, H-8), 6.60 (1H, d, J = 8.4, 2.8 Hz, H-4′), 6.60
(1H, d, J = 8.4 Hz, H-3′), 6.39 (1H, d, J = 2.8 Hz, H-6′), 5.09
(1H, s, H-1), 3.72 (3H, s, OCH3), 3.65 (3H, s, OCH3), 3.20–
3.40 (3H, br, NH, NH2), 3.20–3.25 (1H, m, H-3e) 3.02–3.08
(1H, m, H-3a) 2.93–2.99 (1H, m, H-4e) 2.73–2.78 (1H, m, H-
4a); 13C NMR (100 MHz, CDCl3) δ 157.7 (C-5′), 152.1 (C-7),
139.5 (C-NH2), 137.7 (C-1′), 130.0 (C-4a), 128.6 (C-8a), 127,0
(C-5), 117.9 (CH-4′) 117.3 (CH-3′), 113.4 (CH-6′), 112.8 (CH-
8), 111.9 (CH-5), 61.0 (C-1), 55.7 (OCH3), 55.1 (OCH3), 42.5
(C-3), 28.5 (C-4). EI-MS m/z (%) = 284 (100) [M+], 283 (41)
[M+ – 1], Anal. Calcd for C17H20N2O·1/4 EtOAc: C, 70.56;
H, 7.24; N, 9.14. Found: C, 71.82; H, 7.34; N, 9.18.
4.5.10. 6,7-Dimethoxy-1-(5-Chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4i)
4.5.7. 6,7-Dimethoxy-1-(5-methoxy-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4f)
The title compound was obtained as a white powders in
The title compound was obtained as a white powders in
81% yield in a similar procedure for the preparation of 4a;
75% yield in a similar procedure for the preparation of 4a;
1
m.p. 164–166 °C, H NMR (400 MHz, CDCl3) δ 7.05 (1H,
1
m.p. 98–100 °C, H NMR (400 MHz, CDCl3) δ 6.70 (1H,
dd, J = 8.4, 2.8 Hz, H-4′) 6.87 (1H, d, J = 2.4 Hz, H-6′) 6.63
(1H, s, H-5) 6.58 (1H, d, J = 8.8 Hz, H-3′), 6.31 (1H, s, H-8),
5.08 (1H, s, H-1), 3.87 (3H, s, OCH3) 3.69 (3H, s, OCH3)
3.15–3.21 (1H, m, H-3e) 3.02–3.08 (1H, m, H-3a) 2.89–2.98
(1H, m, H-4e) 2.71–2.78 (1H, m, H-4a); 13C NMR (100 MHz,
CDCl3) δ 147.9 (C-7), 147.4 (C-6), 144.7 (C-NH2), 130.3 (C-
1′), 128.5 (C-4a), 128.3 (C-8a), 127.6 (CH-5′) 127.0 (CH),
122.2 (CH), 117.9 (CH-8), 111.5 (CH-5), 109.8 (CH-3′), 59.5
(C-1), 55.9 (OCH3), 55.8 (OCH3), 41.8 (CH2N), 28.6
(CH2CH2N). EI-MS m/z (%) = 320 (32) [M+ + 2], 318 (100)
[M+], Anal. Calcd for C17H19N2O2Cl: C, 64.05; H, 6.01; N,
8.79. Found: C, 64.00; H, 5.99; N, 8.70.
dd, J = 8.4, 2.8 Hz, H-4′), 6.61 (1H, d, J = 8.4 Hz, H-3′),
6.61 (1H, s, H-5), 6.52 (1H, d, J = 2.8 Hz, H-3′), 6.33 (1H, s,
H-8), 5.10 (1H, s, H-1), 3.86 (3H, s, OCH3), 3.70 (3H, s,
OCH3) , 3.66 (3H, s, OCH3), 3.15–3.21 (1H, m, H-3e) 3.01–
3.07 (1H, m, H-3a) 2.88–2.95 (1H, m, H-4e) 2.71–2.76 (1H,
m, H-4a); 13C NMR (100 MHz, CDCl3) δ 152.1 (C-7), 147.4
(C-6), 147.3 (C-5′), 139.5 (C-NH2), 128.9 (C-1′), 128.3 (C-4a),
127.0 (C-8a), 117.8 (CH-4′) 117.2 (CH-3′), 113.3 (CH-6′),
111.5 (CH-8), 110.0 (CH-5), 59.7 (COCH3), 55.9 (OCH3),
55.8 (OCH3), 55.7 (C-NH2), 41.9 (CH2N), 28.8 (CH2CH2N).
EI-MS m/z (%) = 314 () [M+], Anal. Calcd for C18H22N2O3·1/2
EtOAc: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.10; H, 7.21;
N, 7.55.
4.5.11. 1-(5-Methyl-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4j)
4.5.8. 1-(5-Chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4g)
The title compound was obtained as white powders in 72%
yield in a similar procedure for the preparation of 4a; m.p.
1
The title compound was obtained as a white powders in
90–92 °C, H NMR (400 MHz, CDCl3) δ 7.14–7.17 (2H, m,
70% yield in a similar procedure for the preparation of 4a;
m.p 108–110 °C, H NMR (400 MHz, CDCl3) δ 7.14–7.20
H-5,8), 7.06 (1H, ddd, J = 7.6, 7.6, 2.8 Hz, H-6), 6.93 (1H,
ddd, J = 7.6, 3.2, 0.8 Hz, H-7), 6.83–6.85 (2H, m, H-4′,6′),
6.56 (1H, J = 8.0 Hz, H-3′), 5.08 (1H, s, H-1), 3.27–3.33
(1H, m, H-3e), 3.25 (2H, br, NH2), 3.04–3.14 (2H, m, H-3a,
H-4e), 2.78-2.85 (1H, m, H-4a), 2.25 (3H, s, CH3); 13C NMR
(100 MHz, CDCl3) δ 143.4 (C-NH2), 137.4 (C-5′), 134.9 (C-
1′), 131.6 (C-4a), 129.0 (C-8a), 128.9 (CH-6) 127.2 (CH-7),
126.8 (CH-8), 126.6 (CH-5), 126.4 (CH-4′), 125.9 (CH-6′),
116.9 (CH-3′), 61.8 (C-1), 43.1 (CH2N), 29.6 (CH2CH2N),
20.4 (OCH3). EI-MS m/z (%) = 238 (78) [M+], 237 (75) [M+
– H], 220 (100) [M+ – NH2–2H], Anal. Calcd for C16H18N2:
C, 80.63; H, 7.61; N, 11.75. Found: C, 80.23; H, 7.71; N,
11.63.
1
(2H, m, H-6,7), 7.05–7.10 (2H, m, H-5,8), 6.95 (1H, d,
J = 6.4 Hz, H-6′), 6.83 (1H, d, J = 8.0 Hz, H-3′), 6.56 (1H, d,
J = 8.0, Hz, H-4′), 5.07 (1H, s, H-1), 3.22–3.28 (1H, m, H-3e),
3.05–3.12 (2H, m, H-3a, H-4e), 2.78–2.85 (1H, m, H-4a); 13C
NMR (100 MHz, CDCl3) δ 144.7 (C-NH2), 136.4 (C-1′), 135.0
(C-4a), 130.5 (C-8a), 129.1 (CH-6) 128.6 (CH-7), 128.2 (CH-
8), 126.8 (CH-5), 126.7 (CH-4′), 126.0 (CH-6′), 121.9 (CH-5′),
117.8 (CH-3′), 61.1 (C-1), 42.6 (CH2N), 29.4 (CH2CH2N). EI-
MS m/z (%) = 260 (29) [M+ + 2], 258 (92) [M+], 241 (100)
[M+ – NH2–H], Anal. Calcd for C15H15N2Cl: C, 69.63; H,
5.84; N, 10.83. Found: C, 69.73; H, 5.98; N, 10.29.

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C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
4.5.12. 7-Methoxy-1-(5-methyl-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4k)
140–142 °C, 1H NMR (400 MHz, CDCl3) δ 7.06 (1H, d,
J = 8.4 Hz, H-6′) 6.87 (1H, d, J = 8.0 Hz, H-5), 6.75 (1H, dd,
J = 8.4 , 2.8 Hz, H-5′), 6.64 (1H, dd, J = 8.0, 2.0 Hz, H-6),
6.61 (1H, d, J = 2.0 Hz, H-3′), 6.35 (1H, d, 2.0 Hz , H-8),
5.04 (1H, s, H-1), 4.20–4.80 (1H, br, NH), 3.66 (3H, s,
OCH3), 3.20–3.25 (1H, m, H-3e) 3.01–3.08 (1H, m, H-3a)
2.91–2.99 (1H, m, H-4e) 2.71–2.77 (1H, m, H-4a); 13C NMR
(100 MHz, CDCl3) δ 157.6 (C-7), 147.3 (C-NH2), 137.8 (C-
Cl), 133.9 (C-1′), 131.9 (C-4a), 129.9 (C-8a), 127.1 (CH-5′),
125.3 (CH-5), 117.1 (CH-6′), 116.2 (CH-3′), 112.7 (CH-6),
111.7 (CH-8), 61.1 (C-1), 55.1 (OCH3), 42.7 (CH2N), 28.6
(CH2CH2N). EI-MS m/z (%) = 290 () [M++2], 288 () [M+],
Anal. Calcd for C16H17N2OCl: C, 66.55; H, 5.93; N, 9.70.
Found: C, 66.53; H, 5.97; N, 9.66.
The title compound was obtained as white powders in 77%
yield in a similar procedure for the preparation of 4a; m.p.
115–117 °C, 1H NMR (400 MHz, CDCl3) δ 7.05 (1H, d,
J = 8.4, H-5), 6.91 (1H, d, J = 8.0, 2.0 Hz, H-4′), 6.80 (1H,
d, J = 2.0 Hz, H-6′), 6.73 (1H, dd, J = 8.4, 2.8 Hz, H-6), 6.56
(1H, d, J = 8.4 Hz, H-3′), 6.38 (1H, d, J = 2.8 Hz, H-8), 5.09
(1H, s, H-1), 3.65 (3H, s, OCH3), 3.24–3.29 (1H, m, H-3e)
3.05–3.08 (1H, m, H-3a) 2.97–3.03 (1H, m, H-4e) 2.72–2.77
(1H, m, H-4a), 2.23 (3H, s, CH3); 13C NMR (100 MHz,
CDCl3) δ 157.6(C-7), 143.3 (C-NH2), 138.4 (C-5′), 131.5 (C-
1′), 129.8 (C-4a), 129.0 (C-8a), 127.2 (CH-5), 126.7 (CH-4′)
117.0 (CH-3′), 112.4 (CH-6), 112.1 (CH-8), 61.6 (CH-1), 55.1
(OCH3), 43.0 (C-3), 28.8 (C-4), 20.5 (CH3). EI-MS m/z (%)
= 268 (100) [M+], 267 (67) [M+ – H], Anal. Calcd for
C17H20N2O: C, 76.09; H, 7.51; N, 10.44. Found: C, 76.24;
H, 7.50; N, 10.31.
4.5.16. 6,7-Dimethoxy-1-(4-Chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4o)
The title compound was obtained as a yellow crystals in
80% yield in a similar procedure for the preparation of 4a;
1
m.p. 135–136 °C, H NMR (400 MHz, CDCl3) δ 6.83 (1H,
4.5.13. 6,7-Dimethoxy-1-(5-methyl-2-aminophenyl)-1,2,3,4-
d, J = 8.0 Hz, H-3′), 6.63 (1H, d, J = 2.0 Hz, H-5′), 6.62 (1H,
d, J = 8.0 Hz, H-4′), 6.61 (1H, s, H-5), 6.29 (1H, s, H-8), 5.02
(1H, s, H-1), 4.20–4.80 (2H, br, NH2), 3.85 (3H, s, OCH3),
3.66 (3H, s, OCH3), 3.15–3.21 (1H, m, H-3e) 3.00–3.06 (1H,
m, H-3a) 2.88–2.96 (1H, m, H-4e) 2.68–2.74 (1H, m, H-4a),
1.50–2.20 (1H, br, NH); 13C NMR (100 MHz, CDCl3) δ 147.8
(C-7), 147.8 (C-6), 147.3 (C-NH2), 133.4 (C-Cl), 131.7 (C-1′),
128.4 (C-4a), 127.1 (C-8a), 125.6 (CH-5′), 117.1 (CH-6′),
116.2 (CH-3′), 111.4 (CH-5), 109.6 (CH-8), 60.1 (C-1), 55.8
(OCH3), 55.7 (OCH3), 42.3 (CH2N), 29.0 (CH2CH2N). EI-MS
m/z (%) = 320 () [M+ + 2], 318 () [M+], Anal. Calcd for
C17H19N2O2Cl: C, 64.05; H, 6.01; N, 8.79. Found: C, 64.08;
H, 5.92; N, 8.60.
tetrahydroisoquinoline (4l)
The title compound was obtained as a yellow crystals in
80% yield in a similar procedure for the preparation of 4a;
1
m.p. 132–134 °C, H NMR (400 MHz, CDCl3) δ 6.91 (1H,
d, J = 8.0, 2.0 Hz, H-4′), 6.75 (1H, d, J = 2.0 Hz, H-6′), 6.63
(1H, s, H-5), 6.56 (1H, d, J = 8.4 Hz, H-3′), 6.34 (1H, s,
J = 2.8 Hz, H-8), 5.03 (1H, s, H-1), 3.86 (3H, s, OCH3), 3.65
(3H, s, OCH3), 3.18–3.24 (1H, m, H-3e) 3.01–3.07 (1H, m, H-
3a) 2.90–2.97 (1H, m, H-4e) 2.68–2.74 (1H, m, H-4a), 2.22
(3H, s, CH3); 13C NMR (100 MHz, CDCl3) δ 147.6(C-7),
147.2 (C-6), 143.4 (C-NH2), 131.5 (C-5′), 129.8 (C-4a),
129.0 (C-8a), 127.5 (C-1′), 127.2 (CH-6′), 126.6 (CH-4′)
116.7 (CH-3′), 111.4 (CH-5), 110.0 (CH-8), 60.5 (CH-1), 55.9
(OCH3), 55.8 (OCH3), 42.5 (C-3), 29.2 (C-4), 20.5 (CH3). EI-
MS m/z (%) = 298 (100) [M+], 297 (60) [M+ – H].
4.6. [1-(2-Aminophenyl)-1,2,3,4-tetrahydroisoquinoline]
dichloroplatinums(II)
4.5.14. 1-(4-Chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4m)
4.6.1. General procedure E
The title compound was obtained as a white powders in
The THIQs were dissolved at 60–65 °C in 0.05 M HCl
(50 ml). After addition of the equimolar amount of K2PtCl4,
the mixture was neutralized slowly with 0.1 M NaOH to pH
6. The complexes precipitated out, were washed with H2O and
with EtOH and were dried.
60% yield in a similar procedure for the preparation of 4a;
1
m.p. 108–110 °C, H NMR (400 MHz, CDCl3) δ 7.14–7.20
(2H, m, H-7,8), 7.07 (1H, ddd, J = 7.6, 7.6, 2.0 Hz, H-6),
6.88 (1H, d, J = 8.0 Hz, H-6′), 6.82 (1H, d, J = 7.6 Hz, H-5),
6.66 (1H, d, J = 8.0, 2.0 Hz, H-5′), 6.61 (1H, J = 8.0, 2.0 Hz,
H-3′), 5.09 (1H, s, H-1), 3.23-3.29 (1H, m, H-3e), 3.05–3.12
(2H, m, H-3a, H-4e), 2.78–2.85 (1H, m, H-4a); 13C NMR
(100 MHz, CDCl3) δ 147.3 (C-NH2), 136.7 (C-1′), 135.0 (C-
4a), 133.9 (C-8a), EI-MS m/z (%) = 260 () [], 258 () [M+], 241
() [M+ – NH2–H], Anal. Calcd for C15H15N2Cl·1/3 CHCl3: C,
61.69; H, 5.18; N, 9.38. Found: C, 61.21; H, 5.28; N, 9.22.
4.6.2. [1-(2-Aminophenyl)-1,2,3,4-tetrahydroisoquinoline]
dichloroplatinum(II) (5a)
The title compound was obtained as a yellowish powders in
70% yield from 4a following procedures E; m.p. 294–296 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.50–8.50 (3H, NH, NH2),
7.21–7.42 (6H, m, H-6,7,3′,4′,5′,6′), 6.97–7.13 (1H, m, H-5),
6.33–6.82 (1H, m, H-8), 5.53 5.87 5.92 5.96 (1H, 4s, H-1),
3.38–3.43 (1H, m, H-3β), 2.97–3.12 (1H, m, H-3α), 2.72–
2.78 (1H, m, H-4β), 2.45–2.54 (1H, m, H-4α); 13C NMR
(100 MHz, [D]6DMSO) δ 137.1 (C-2′), 133.0 (C-1′), 132.5
132.2 (4a), 130.8 (C-8a), 129.4 129.2 129.0 (C-8), 128.2 (C-
4.5.15. 7-Methoxy-1-(4-chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4n)
The title compound was obtained as a colorless needles in
83% yield in a similar procedure for the preparation of 4a; m.p.

C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
947
5), 127.8 (C-6), 127.5 (C-4′), 126.1 (C-6′), 125.6 (C-5′), 121.9
(C-3′), 58.4 (C-1), 44.1 (C-3), 27.6 (C-4), Anal. Calcd for
C15H16N2PtCl2·0.5H2O: C, 36.08; H, 3.43; N, 5.61. Found:
C, 36.13; H, 3.41; N, 5.55.
4.6.6. [1-(5-Methoxy-2-aminophenyl)-7-methoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5e)
The title compound was obtained as a yellowish powders in
61% yield from 4e following procedures E; m.p. 280–282 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.55–8.50 (3H, NH, NH2),
7.11–7.48 (2H, m, H-5,3′), 6.89–7.02 (3H, m, H-6,8,4′), 6.40–
6.49 (1H, m, 6′), 5.45 5.73 5.78 5.83 (1H, 4s, H-1), 3.73 3.69
3.67 (OCH3), 3.64 3.63 3.59 (OCH3), 3.32–3.43 (1H, m, H-
3β), 2.81–2.93 (1H, m, H-3α), 2.68–2.72 (1H, m, H-4β),
2.47–2.51 (1H, m, H-4α); 13C NMR (100 MHz, [D]6DMSO)
157.4 (C-7), 156.8 156.2 (C-5′), 134.4 (C-2′), 133.6 (C-1′),
130.5 (C-4a), 130.3 130.2 (8a), 125.9 125.6 125.0 (C-5),
123.1 (C-3′), 118.3 118.2 (C-4′), 114.9 114.4 114.0 (C-6),
112.9 (C-6′), 112.3 112.1 (C-8), 58.8 (C-1), 55.4 55.3 55.2
55.1 55.0 (2OCH3), 44.6 (C-3), 26.9 (C-4), Anal. Calcd for
C17H20N2O2PtCl2: C, 37.10; H, 3.66; N, 5.09. Found: C,
37.11; H, 3.73; N, 5.03.
4.6.3. [1-(2-Aminophenyl)-7-methoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5b)
The title compound was obtained as a yellowish powders in
68% yield from 4b following procedures E; m.p. 290–292 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.50–8.70 (3H, NH, NH2),
7.13–7.40 (4H, m, H-3′,4′,5′,6′), 6.90–7.01 (1H, m, H-5), 6.29–
6.50 (2H, m, H-6,8), 5.50 5.62 5.82 (1H, 3s, H-1), 3.35–3.40
(1H, m, H-3β), 2.83–2.97 (1H, m, H-3α), 2.66–2.71 (1H, m, H-
4β), 2.44–2.50 (1H, m, H-4α); 13C NMR (100 MHz, [D]
6DMSO) δ 157.6 (C-7), 134.0 (C-2′), 131.1 (C-1′), 130.7 (C-
4a), 130.4 (8a), 129.8 (C-4′), 126.2 (C-6′), 125.8 (C-3′), 125.2
(C-4′), 115.0 (C-5), 114.2 (C-6), 112.4 (C-8), 58.9 (C-1), 55.4
55.3 55.2 (OCH3), 44.6 (C-3), 27.1 (C-4), Anal. Calcd for
C16H18N2OPtCl2·0.5H2O: C, 36.31; H, 3.62; N, 5.29. Found:
C, 36.36; H, 3.68; N, 5.26.
4.6.7. [1-(5-Methoxy-2-aminophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5f)
The title compound was obtained as a yellowish powders in
75% yield from 4f following procedures E; m.p. 306–309 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.59–9.30 (3H, NH, NH2),
7.37–7.49 (1H, m, H-3′), 6.81–7.09 (3H, m, H-8,4′,6′), 6.24
6.37 6.42 6.45 (1H, 4s, 5), 5.37 5.72 5.80 5.88 (1H, 4s, H-1),
3.81 3.78 3.77 3.73 (OCH3), 3.68 3.64 (OCH3), 3.60 3.57 3.55
3.53 (OCH3), 3.31–3.42 (1H, m, H-3β), 2.84–2.94 (1H, m, H-
3α), 2.65–2.70 (1H, m, H-4β), 2.45–2.51 (1H, m, H-4α); 13C
NMR (100 MHz, [D]6DMSO) 156.9 (C-7),149.1 (C-6) 147.3
(C-5′), 133.9 (C-2′), 129.7 (C-1′), 125.2 (8a), 124.0 (C-4a),
123.1 (C-3′), 118.4 118.3 (C-4′), 112.8 (C-6′), 112.0 (C-8),
110.3 (C-5), 58.4 (C-1), 55.7 55.6 55.5 55.4 55.3 (3OCH3),
44.5 (C-3), 27.3 (C-4), Anal. Calcd for C18H22N2O3PtCl2: C,
37.25; H, 3.82; N, 4.83. Found: C, 37.05; H, 3.92; N, 4.73.
4.6.4. [1-(2-Aminophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5c)
The title compound was obtained as a yellowish powders in
67% yield from 4c following procedures E; m.p. 298–300 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.47–9.50 (3H, NH, NH2),
7.28–7.40 (1H, m, H-6′), 7.06–7.16 (1H, m, H-4′), 6.70–6.84
(2H, m, H-3′,5′), 6.25–6.56 (2H, m, H-5, 8), 5.42 5.78 5.85
5.84 (1H, 4s, H-1), 3.79 3.78 3.68 3.63 3.54 (OCH3), 3.24–
3.40 (1H, m, H-3β), 2.88-2.97 (1H, m, H-3α), 2.63–2.66 (1H,
m, H-4β), 2.43–2.50 (1H, m, H-4α); 13C NMR (100 MHz, [D]
6DMSO) δ 148.9 (C-7), 147.4 (C-6), 137.2 (C-2′), 132.3 (C-
1′), 130.9 130.5 (C-4a), 129.7 129.4 (8a), 126.1 125.7 (C-4′),
125.1 124.9 (C-6′), 124.1 (C-3′), 121.8 (C-4′), 111.8 111.3
(C-5), 110.3 (C-8), 58.2 (C-1), 55.6 55.5 55.4 (OCH3), 44.2
(C-3), 27.3 (C-4), Anal. Calcd for C17H20N2O2PtCl2·H2O: C,
35.93; H, 3.90; N, 4.93. Found: C, 36.89; H, 4.01; N, 5.01.
4.6.8. [1-(5-Chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5g)
The title compound was obtained as a yellowish powders in
65% yield from 4g following procedures E; m.p. 305–308 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.54–8.90 (3H, br, NH,
NH2), 7.22–7.56 (6H, m, H-5,6,7,8,4′,6′), 6.70–7.02 (H, m,
H-3′), 5.54 5.75 5.89 6.16 (1H, 4s, H-1), 3.30–3.43 (1H, m,
H-3β), 2.85–3.07 (1H, m, H-3α), 2.79–2.84 (1H, m, H-4β),
2.49–2.57 (1H, m, H-4α); 13C NMR (100 MHz, [D]6DMSO)
δ 146.9 (C-2′), 133.9 (C-4′), 133.5 (C-1′), 132.2 131.9 (4a),
130.5 (C-8a), 129.8 129.5 (C-8), 129.2 (C-5), 128.8 (C-6),
128.2 (C-4′), 126.7 (C-6′), 123.5 (C-5′), 122.5 (C-3′), 58.7
(C-1), 44.8 (C-3), 27.8 (C-4), Anal. Calcd for C15H15N2PtCl3
: C, 34.33; H, 2.88; N, 5.34. Found: C, 34.58; H, 2.96; N, 5.32.
4.6.5. [1-(5-Methoxy-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5d)
The title compound was obtained as a yellowish powders in
58% yield from 4d following procedures E; m.p. 280–282 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.60–8.50 (3H, NH, NH2),
7.15–7.48 (4H, m, H-5,6,7,8), 6.79–7.00 (3H, m, H-3′,4′,6′),
5.50 5.76 5.77 5.85 (1H, 4s, H-1), 3.57 3.61 (OCH3), 3.36–
3.43 (1H, m, H-3β), 2.89–3.03 (1H, m, H-3α), 2.76–2.80
(1H, m, H-4β), 2.47–2.56 (1H, m, H-4α); 13C NMR
(100 MHz, [D]6DMSO) 156.8 (C-5′), 134.6 134.1 (C-2′),
133.9 133.8 (C-1′), 133.3 (C-4a), 132.6 (8a), 129.7 129.3
129.2 129.1(C-6,7), 126.3 (C-5), 125.9 (C-8), 123.2 (C-3′),
118.4 118.3 118.2 (C-4′), 112.9 (C-6′), 58.7 (C-1), 55.4 55.3
55.2 (OCH3), 44.5 (C-3), 27.6 (C-4), Anal. Calcd for
C16H18N2OPtCl2: C, 36.93; H, 3.49; N, 5.38. Found: C,
36.63; H, 3.55; N, 5.32.
4.6.9. [1-(5-Chloro-2-aminophenyl)-7-methoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5h)
The title compound was obtained as a yellowish powders in
66% yield from 4h following procedures E; m.p. 292–294 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.56–9.00 (3H, br, NH,

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C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
NH2), 7.21–7.58 (2H, m, H-4′,6′), 6.81–7.20 (2H, m, H-3′,5),
6.20–6.52 (2H, m, 6,8), 5.52 5.77 5.87 (1H, 3s, H-1), 3.73 3.69
3.62 (OCH3), 3.29–3.42 (1H, m, H-3β), 2.81–3.01 (1H, m, H-
3α), 2.71–2.80 (1H, m, H-4β), 2.49–2.51 (1H, m, H-4α); 13C
NMR (100 MHz, [D]6DMSO) 157.8 157.4 157.3 (C-7), 146.7
(C-5′), 135.3 (C-2′), 133.2 132.8 (C-1′), 130.7 130.4 (C-4a),
130.2 130.1 (8a), 129.6 129.5 129.3 129.2 (6′), 125.9 125.6
125.0 124.8 (C-5), 122.2 (C-3′), 117.8 (C-4′), 115.0 114.3
113.9 (C-6), 112.5 112.3 112.2 (C-8), 58.7 (C-1), 55.3 55.1
55.1 (OCH3), 44.6 (C-3), 26.8 26.4 (C-4), Anal. Calcd for
C16H17N2OPtCl3·H2O: C, 33.55; H, 3.34; N, 4.89. Found: C,
33.93; H, 3.32; N, 4.88.
(1H, m, H-3α), 2.61–2.81 (1H, m, H-4β), 2.44–2.55 (1H, m,
H-4α), 2.07 2.13 2.16 2.18 (3H, 4s, CH3); 13C NMR
(100 MHz, [D]6DMSO) 157.4 157.1(C-7),135.2 134.7 (C-5′),
134.1 (C-2′), 133.7 (C-1′), 132.8 132.1 131.2 (C-4a), 130.6
130.2 130.0 129.5 (8a), 125.9 125.6 125.5 (C-5), 125.0 (C-3′),
121.9 (C-4′), 120.3 (C-6), 114.9 114.0 (C-6′), 112.3 (C-8), 58.8
(C-1), 55.3 55.2 55.1 (OCH3), 44.5 (C-3), 26.9 26.5 (C-4),
20.7 20.6 (CH3), Anal. Calcd for C17H20N2OPtCl2: C, 38.21;
H, 3.77; N, 5.24. Found: C, 38.24; H, 3.85; N, 5.22.
4.6.13. [1-(5-Methyl-2-aminophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5l)
The title compound was obtained as a yellowish powders in
70% yield from 4l following procedures E; m.p. 296–299 °C,
1H NMR (400 MHz, [D]6 DMSO) δ 7.40–8.50 (3H, NH,
NH2), 7.04–7.47 (2H, m, H- H-3′,4′), 6.90–7.00 (1H, m, H-
6′), 6.09–6.46 (2H,m, H-5,8), 5.37 5.70 (1H, 2s, H-1), 3.79
3.78 3.68 3.61 (2OCH3), 3.20–3.49 (1H, m, H-3β), 2.91–3.00
(1H, m, H-3α), 2.65–2.89 (1H, m, H-4β), 2.49–2.51 (1H, m, H-
4α), 2.07 2.13 2.16 2.23 (3H, 4s, CH3); 13C NMR (100 MHz,
[D]6DMSO) 148.9 148.6 148.4 147.3 (C-6,7), 147.0 (C-5′),
137.2 (C-2′), 134.0 (C-1′), 132.9 (8a), 131.3 (C-4a), 129.9
129.5 (C-3′), 126.2 125.3 124.2 (C-4′), 121.7 120.2 (C-6′),
111.8 112.0 (C-8), 110.5 (C-5), 58.3 57.3 (C-1), 55.7 55.6
55.5 55.4 55.3 (2OCH3), 44.3 (C-3), 27.4 27.0 (C-4), 20.7
(CH3), Anal. Calcd for C18H22N2O2PtCl2: C, 38.31; H, 3.93;
N, 4.96. Found: C, 38.21; H, 3.92; N, 4.96.
4.6.10. [1-(5-Chloro-2-aminophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5i)
The title compound was obtained as a yellowish powders in
73% yield from 4i following procedures E; m.p. 284–286 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.55–9.10 (3H, br, NH,
NH2), 7.41–7.50 (1H, m, H-6′), 6.81–7.20 (2H, m, H-3′,6′),
6.24–6.48 (2H, m, 5,8), 5.45 5.72 5.82 (1H, 3s, H-1), 3.79
3.78 3.78 3.78 3.69 3.54 (3OCH3), 3.25–3.41 (1H, m, H-3β),
2.84–3.00 (1H, m, H-3α), 2.68–2.72 (1H, m, H-4β), 2.49–2.51
(1H, m, H-4α); 13C NMR (100 MHz, [D]6DMSO) 149.1 148.6
147.6 147.4 147.1 (C-6 ,7), 146.9 (C-5′), 135.6 (C-2′), 130.4
(C-1′), 129.7 129.6 (C-4a), 129.4 129.2 (8a), 126.9 125.9
125.3 (6′), 123.7 123.2 121.7 (C-3′), 119.4 117.8 (C-4′),
112.111.6 (C-5), 110.5 110.4 (C-8), 58.2 (C-1), 55.7 55.6
55.6 55.5 55.4 (OCH3), 44.5 (C-3), 27.3 26.9 24.3 (C-4), Anal.
Calcd for C17H19N2O2PtCl3: C, 34.92; H, 3.27; N, 4.79.
Found: C, 35.13; H, 3.57; N, 4.74.
4.6.14. [1-(4-Chloro-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5m)
The title compound was obtained as a yellowish powders in
61% yield from 4m following procedures E; m.p. 290–292 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.55–8.90 (3H, br, NH,
NH2), 7.15–7.40 (5H, m, H-5,6,7,8,6′), 6.70–7.02 (1H, m, H-
4′), 6.10–6.60 (1H, m, H-3′), 5.40 5.46 5.49 (1H, 3s, H-1),
3.29–3.49 (1H, m, H-3β), 2.90–3.08 (1H, m, H-3α), 2.67–
2.76 (1H, m, H-4β), 2.49–2.51 (1H, m, H-4α); 13C NMR
(100 MHz, [D]6DMSO) δ 149.2 149.0 (C-2′), 134.4 134.2
133.8 (C-4′), 133.6 133.2 133.0 (C-1′), 132.4 132.2 (4a),
132.1 132.0 131.9 (C-8a), 129.7 129.5 129.2 (C-8), 129.0
128.8 128.4 (C-5), 128.1 128.0 (C-6), 127.8 127.6 127.0 (C-
8), 126.3 126.1 125.0 (C-6′), 120.4 119.9 (C-5′), 116.1 117.0
115.1 (C-3′), 62.9 58.7 57.2 (C-1), 44.5 43.7 (C-3), 27.8 27.4
27.0 (C-4), Anal. Calcd for C15H15N2PtCl3·1/8C2H5OH: C,
34.48; H, 3.13; N, 5.27. Found: C, 35.90; H, 3.11; N, 5.45.
4.6.11. [1-(5-Methyl-2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5j)
The title compound was obtained as a yellowish powders in
72% yield from 4j following procedures E; m.p.
292–294 °C,1H NMR (400 MHz, [D]6 DMSO) δ 7.40–8.50
(3H, NH, NH2), 7.15–7.48 (6H, m, H-5,6,7,8,4′,6′), 5.90–6.15
(1H, m, H-3′), 5.50 5.62 5.89 (1H, 3s, H-1), 3.29–3.45 (1H, m,
H-3β), 2.92–3.02 (1H, m, H-3α), 2.76–2.81 (1H, m, H-4β),
2.49–2.55 (1H, m, H-4α), 2.08 2.09 2.12 2.13 (3H, 4s, CH3);
13C NMR (100 MHz, [D]6DMSO) 134.1 (C-5′), 133.8 133.3
(C-2′), 133.0 132.8 (C-1′), 131.3 (C-4a), 130.0 (8a), 129.5
129.4 129.1 128.3 128.0(C-6,7), 127.9 (C-5), 127.7 (C-8),
126.3 126.2 (C-3′), 121.7 (C-4′), 120.4 (C-6′), 58.6 (C-1),
44.3 (C-3), 27.5 27.3 (C-4), 20.7 20.6 (CH3), Anal. Calcd for
C16H18N2PtCl2: C, 38.11; H, 3.60; N, 5.55. Found: C, 38.11;
H, 3.69; N, 5.55.
4.6.15. [1-(4-Chloro-2-aminophenyl)-7-methoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5n)
4.6.12. [1-(5-Methyl-2-aminophenyl)-7-methoxy-1,2,3,4-
tetrahydroisoquinoline] dichloroplatinum(II) (5k)
The title compound was obtained as a yellowish powders in
70% yield from 4n following procedures E; m.p. 302–305 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.30–9.00 (3H, br, NH,
NH2), 7.06–7.15 (2H, m, H-5′,6′), 6.81–7.00 (2H, m, H-3′,5),
6.20–6.60 (2H, m, 6,8), 5.46 5.56 5.84 (1H, 3s, H-1), 3.72 3.71
3.67 3.62 (OCH3), 3.30–3.40 (1H, m, H-3β), 2.85–3.02 (1H,
m, H-3α), 2.65–2.70 (1H, m, H-4β), 2.49–2.57 (1H, m, H-4α);
13C NMR (100 MHz, [D]6DMSO) 157.8 157.4 157.2 (C-7),
The title compound was obtained as a yellowish powders in
68% yield from 4k following procedures E; m.p. 286–289 °C,
1H NMR (400 MHz, [D]6 DMSO) δ 7.40–8.50 (3H, NH,
NH2), 7.15–7.48 (3H, m, H-3′, 4′,6′), 6.90–7.00 (2H, m, 5,6),
6.09–6.46 (1H,m, H-8), 5.45 5.58 5.81 5.85 (1H, 4s, H-1), 3.72
3.69 3.68 3.67 (OCH3), 3.30–3.49 (1H, m, H-3β), 2.92–3.00

C.-Y. Kuo et al. / European Journal of Medicinal Chemistry 41 (2006) 940–949
949
149.1 (C-4′), 134.2 (C-2′), 133.6 133.4 133.2 (C-1′), 133.0
References
132.3 132.2 (C-4a), 130.5 130.3 130.1 (8a), 125.9 125.5 (6′),
124.9 124.8 (C-5), 120.3 118.8 (C-3′), 115.9 115.0 (C-4′),
114.9 114.3 113.9 (C-6), 112.5 112.3 112.1 (C-8), 62.8 58.7
57.9 (C-1), 55.2 55.1 55.0 (OCH3), 44.4 (C-3), 26.9 26.5
24.0 (C-4), Anal. Calcd for C16H17N2OPtCl3: C, 34.64; H,
3.09; N, 5.05. Found: C, 34.84; H, 3.12; N, 5.05.
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4.6.16. [1-(4-Chloro-2-aminophenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline]dichloroplatinum(II) (5o)
The title compound was obtained as a yellowish powders in
75% yield from 4o following procedures E; m.p. 272–274 °C,
1H NMR (400 MHz, [D]6DMSO) δ 7.35–9.10 (3H, br, NH,
NH2), 6.81–7.20 (3H, m, H-3′,5′,6′), 6.40–6.70 (2H, m, 5,8),
5.41 5.42 5.72 5.80 (1H, 4s, H-1), 3.78 3.77 3.76 3.67 3.61
3.54 (3OCH3), 3.24–3.49 (1H, m, H-3β), 2.84–3.01 (1H, m,
H-3α), 2.61–2.65 (1H, m, H-4β), 2.49–2.57 (1H, m, H-4α);
13C NMR (100 MHz, [D]6DMSO) 149.1 148.8 148.5 148.4
147.6 (C-6, 7), 147.2 147.0 (C-4′), 134.2 (C-2′), 133.4 (C-1′),
133.2 (C-4a), 132.4 (8a), 126.2 125.8 125.7 125.2 (6′), 124.9
124.8 123.4 (C-3′), 120.2 119.0 (C-4′), 115.8 115.0 (C-5),
111.9 111.7 111.0 110.4 (C-8), 58.4 56.8 (C-1), 55.7 55.6
55.6 55.5 55.4 (OCH3), 44.3 (C-3), 27.3 26.9 24.4 (C-4), Anal.
Calcd for C17H19 N2O2PtCl3·1/8 C2H5OH: C, 35.04; H, 3.49;
N, 4.74. Found: C, 35.56; H, 3.53; N, 4.88.
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We would like to thank the Dr. Kuo, researcher of the Na-
tional Research Institute of Chinese Medicine, for helpful cy-
totoxicity assay.