Synthesis of platinum complexes from N-benzyl-1,3-propanediamine derivatives, potential antineoplastic agents

Article abstract of DOI:10.3390/70400405

This work describes the synthesis of seven new platinum complexes having N-benzyl 1,3-propanediamine derivatives as ligands. They were prepared by the reaction of K₂[PtCl₄] with the appropriate ligand in water. These complexes are an

Full text of DOI:10.3390/70400405

Molecules 2002, 7, 405-411
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Platinum Complexes from N-Benzyl-1,3-Propane-
diamine Derivatives, Potential Antineoplastic Agents.
Mauro Vieira de Almeida1*, Ana Paula Soares Fontes1, Richard Nilton Berg1, Eloi Teixeira
César2,3, Emanoel de Castro Antunes Felício1, and José Dias de Souza Filho3.
1
Departamento de Química, Universidade Federal de Juiz de Fora, 36036-330, Juiz de Fora-MG,
Brazil.
2
Colégio de Aplicação João XXIII, Juiz de Fora-MG, Brazil.
3
Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte-MG, Brazil.
*Author to whom correspondence should be addressed; e-mail: mvieira@quimica.ufjf.br
Received: 17 August 2001; in revised form: 8 April 2002 / Accepted: 30 April 2002 / Published: 30
April 2002
Abstract: This work describes the synthesis of seven new platinum complexes having N-
benzyl 1,3-propanediamine derivatives as ligands. They were prepared by the reaction of
K2[PtCl4] with the appropriate ligand in water. These complexes are analogs of cisplatin,
and are potential antineoplastic agents.
Keywords: Platinum(II) complexes, N-benzyl 1,3-propanediamine, anticancer agents.
Introduction
The discovery of the anticancer activity of the coordination compound cis-
diaminedichloroplatinum(II) (cisplatin) [1], and its successful clinical use, represents important
progress for inorganic medicinal chemistry. Cisplatin has been approved for commercial use in the
United States since 1979 [2], being used by itself or in combination with other chemotherapeutic
agents to treat several types of cancer, such as testicular, ovarian, head and neck [3-5]. For example,
testicular carcinoma, which once had a high mortality rate, can now be cured in 85% of the cases [6].

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However, the use of the cisplatin in the clinic is limited by its narrow activity spectrum, cellular
resistance, and some serious side effects [7-9], such as nephrotoxicity, ototoxicity and neurotoxicity.
Since then, the search for new platinum anticancer drugs has continued, and in 1987 the compound cis-
diamine(1,1-cyclobutanedicarboxylate)platinum(II), carboplatin [10,11], was approved for commercial
purposes. Carboplatin has been shown to be less nephrotoxic and emetogenic than cisplatin, however,
it is also active against a limited number of tumors, and it is not effective in cell resistant lines.
Two others compounds have been approved for use in some countries. Oxaliplatin, trans-L-
(diaminocyclohexane)oxalatoplatinum(II) has been approved for the treatment of colorectal cancer in
France, and nedaplatin, cis-diamine-glycolateplatinum(II) has received approval for use in Japan.
However, they have yet to demonstrate significant advantages over cisplatin or carboplatin [12]. Thus,
it is very important to develop new platinum complexes that could effectively act in a larger number of
tumors. At the same time those complexes should present less severe side effects and they should be
active in resistant cells lines.
In this context, complexes having N-substituted ethylenediamine ligands have shown activity
against several types of tumors [13,14]. Considering the activity displayed by these complexes and
since aromatic compounds have shown the possibility of intercalation between DNA bases [15], we
have recently reported the synthesis of a series of platinum complexes with ethylenediamine
derivatives [16]. In this paper we report the preparation and characterization of analogous complexes
having N-benzyl 1,3-propanediamine derivatives as ligands. The synthesis and characterization of
these ligands have been recently reported elsewhere [17].
Results and Discussion
We have prepared the required ligands in satisfactory yields by treating 1,3-propanediamine with
the corresponding benzyl halide in ethanol at room temperature for 48 h (Scheme 1). In the preparation
of these ligands, we have observed the formation of N,N’dibenzylated compounds as well. Thus,
during the purification process of ligand a, we have also isolated the corresponding N,N’-dibenzyl 1,3-
propanediamine, compound f .
The dichloroplatinum(II) complexes 1-7 were obtained by reaction of the corresponding ligands
with potassium tetrachloroplatinate(II) in water at room temperature for 48 hours, and were isolated by
simple filtration. For these compounds, one may observe in the IR spectra absorptions corresponding
to νPt-N e νPt-Cl at 550 and 325 cm-1, respectively, in addition to the absorptions observed for the ligand.
In the 1H-NMR spectra one observes that there is a downfield shift for the signals corresponding to NH
and NH2 relative to the free ligands. The 195Pt-NMR spectra for all the complexes show only one signal
in the vicinity of δ -2240 for all the complexes. The chemical shift values are expected based on data
for similar compounds described in the literature. For instance, the 195Pt-NMR spectrum of
[Pt(DACH)Cl2] shows a signal at δ -2287 (DACH=1,2-diaminocyclohexane) [18]. The results of
elemental analysis for all complexes prepared are in agreement with the calculated values.

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407
Scheme 1
NH NH2
NH NH2
Pt
Cl
X
X
X
Cl
Cl
K2[PtCl4]
H2O; r.t
ethanol
r.t
+ NH2(CH2)3NH2
Y
Y
Y
a: X= H; Y= H
1: X= H; Y= H
b: X= Cl; Y= H
c: X= H; Y= Cl
d: X= H; Y= NO2
e: X= H; Y= OCH3
2: X= Cl; Y= H
3: X= H; Y= Cl
4: X= H; Y= NO2
5: X= H; Y= OCH3
NH NH
NH NH
Pt
Cl
Cl
K2[PtCl4]
H2O; r.t
f
6
NH NH2
NH NH2
Pt
Br
Cl
Cl
K2[PtCl4]
H2O; r.t
ethanol
r.t
+ NH2(CH2)3NH2
O2N
O2N
O2N
g
7
Conclusions
This work describes the synthesis and characterization of new platinum(II) complexes obtained
from derivatives of 1,3-propanediamine, used as ligands. All the complexes were fully characterized
and their biological properties are being investigated to determine their possible use as anticancer
agents.
Acknowledgments
To CNPq and CAPES for the fellowships. To Dr. Ana Maria Ferreira and Wendel A. Alves for
helpful suggestions.

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Experimental
General
1
IR spectra were obtained on a Bomem FT IR MB-102 spectrometer in KBr pellets. H-NMR (200
and 400 MHz), 13C-NMR (50 and 100 MHz) and 195Pt-NMR (86 MHz) spectra were recorded on
Bruker Advance DRX 200 and DRX 400 spectrometers at the Federal University of Minas Gerais,
Brazil. Elemental analyses were done at the State University of São Paulo, Brazil. All chemicals were
reagent grade and were used without further purification.
Synthesis of ligands: N-Benzylpropane-1,3-diamine (a), N-(2-chlorobenzyl)propane-1,3-diamine (b),
N-(4-chlorobenzyl)propane-1,3-diamine (c), N-(4-nitrobenzyl)propane-1,3-diamine (d), N-(4-methoxy-
benzyl)propane-1,3-diamine (e), N,N’-dibenzylpropane-1,3-diamine (f) and N-(3-nitrobenzyl)-
propane-1,3-diamine (g).
To 1,3-propanediamine (3.34 mL; 40 mmols) in ethanol (20 mL), the corresponding benzyl halide
(20 mmol) was slowly added during 8 h. The reaction mixture was stirred for 48 h at room
temperature, after which time, the complete consumption of the starting material was evidenced by
TLC (eluent: 8:2 hexane/ethyl acetate). A saturated sodium hydroxide (30 mmol) solution in ethanol
was then slowly added. The solvent was evaporated under reduced pressure, and the residue purified
on silica gel 60 G (0.2-0.5 mm), using 9:1 dichloromethane/methanol as eluent. Yields: (a) 2.65 g
(81%); (b) 2.89 g (73%); (c) 2.81 g (71%); (d) 3.26 g (78%); (e) 2.67 g (69%); (g) 4.9 g (69 %) for
compound g. The N,N’-dibenzylated compound (f) was also isolated in 10% yield in the preparation of
compound a.
Compound a: IR νmax. KBr (cm-1): 3238, 3025, 2982, 2907, 2763, 1599, 1438, 1176, 975, 745;
1H-NMR (200 MHz; TFA-d1) δ: 2.12 (m, 2H, CH2); 3.09 (m, 4H, CH2N); 4.06 (s, 2H, CH2Ph); 7.15
(m, 5H, Ph); 13C-NMR (50 MHz, TFA-d1) δ: 26.17; 40.25; 47.06; 55.60 (CH2);108.50; 114.14; 120.77;
125.41 (Ph); MS (m/z, %): 165 (100.00); 148 (1.73); 134 (1.15); 120 (1.00).
1
Compound b: IR νmax. KBr (cm-1): 3285, 3063, 2931, 1573, 1470, 1117, 1050, 751; H-NMR (200
MHz; pyridine-d5) δ: 1,88 (m, 2H, CH2); 2.77 (t, 2H, CH2NH2); 2.99 (t, 2H, CH2NH); 4,39 (s, 2H,
CH2Ph); 7,16 (m, 2H, H4, H5); 7,28; 7,59 (2d, 2H, H3, H6, J3-4= 7,6 Hz, J6-5= 7,3 Hz); 13C-NMR (50
MHz; pyridine-d5) δ: 32.31; 40.31; 47.57; 51.24 (CH2); 127.64; 128.48; 129.60; 130.36; 133.71;
138.87 (Ph); MS (m/z, %): 199 (100.00); 182 (6.36); 125 (1.00).
Compound c: IR νmáx. KBr (cm-1): 3439, 3050, 2934, 2788, 1578, 1498, 1438, 1091, 1018, 805;
1H-NMR (200 MHz; DMSO-d6) δ: 2.07 (m, 2H, CH2); 2.86 (m, 4H, CH2N); 4.07 (s, 2H, CH2Ph);
7.48; 7.61 (2d, 4H, Ph); 13C-NMR (50 MHz; DMSO-d6) δ: 23.91; 36.29; 43.87; 49.46 (CH2); 128.48;
131.89; 132.05; 133.37 (Ph); MS (m/z, %): 199 (100.00); 182 (12.71); 125 (76.88).

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Compound d: IR νmax. KBr (cm-1): 3380, 3090, 2955, 1603, 1519, 1351, 1107, 850, 740; 1H-NMR (200
MHz; D2O) δ: 2.00 (m, 2H, CH2); 3.00 (m, 4H, CH2N); 4.21 (s, 2H, CH2Ph); 7.57; 8.19 (2d, 4H, Ph);
13C-NMR (50 MHz; D2O) δ: 24.20; 36.58; 44.58; 50.47 (CH2); 124.11; 130.59; 139.59; 147.86 (Ph);
MS (m/z, %): 210 (86.12); 193 (52.60); 179 (10.40); 165 (17.34); 136(34.68).
Compound e: IR νmax. KBr (cm-1): 3244, 3007, 2934,1614, 1542, 1513, 1479, 1249, 1180, 1030, 811;
1H-NMR (200 MHz; D2O) δ: 1.45 (m, 2H, CH2); 2.39 (m, 2H, CH2NH2); 2.55 (m, 2H, CH2NH); 3.48
(s, 2H, CH2Ph); 3.59 (s, 3H, OCH3); 6.73; 7.06 (2d, 4H, Ph); 13C-NMR (50 MHz, D2O) δ: 28.74;
38.18; 45.07; 51.52 (CH2); 55.24 (OCH3); 113.96; 130.10; 130.61; 158.8 (Ph); MS (m/z, %): 195
(94.79); 178 (0.58); 164 (1.73); 150 (1.00); 136 (1.00); 121 (100.00).
Compound f: IR νmax. KBr (cm-1): 3159, 3037, 2981, 1590, 1444, 1280, 1213, 1073, 944, 913, 860,
1
775, 738, 690, 607; H-NMR (200 MHz; TFA d1) δ: 2.55 (m, 2H, CH2); 3.36 (m, 4 H, CH2NH); 4.30
(sl, 4 H, CH2Ph); 7.41 (s, 10 H, Ph); 7.81 (sl, 2H, NH); 13C-NMR (50 MHz, TFA d1) δ: 25.73; 47.34;
55.61 (CH2); 128.86; 129.78; 131.05; 133.11 (Ph); MS (m/z, %): 255 (100.00); 148 (1.00); 134 (1.00).
Compound g: IR νmax. KBr (cm-1): 3399, 3080, 2944, 1598, 1537, 1462, 1354, 1102, 939, 736;
1H-NMR (200 MHz; DMSO d6) δ: 2.01 (m, 2H, CH2); 2.96 (t, 2H, CH2NH2); 3.12 (t, 2H, CH2NH);
13
4.24 (s, 2H, CH2Ph); 7.69 (m, 1H, H5); 8.06; 8.23 (2d, 2H, H4, H6); 8.48 (s, 1H, H2); C-NMR (50
MHz; DMSO d6) δ: 23.93; 36.33; 44.14; 49.33 (CH2); 123.74; 125.14; 130.21; 134.75; 137.13; 147.73
(Ph); MS (m/z, %): 210 (100.00); 193 (43.93); 179 (1.15); 165 (7.51); 136 (26.01).
Synthesis of complexes: (N-Benzylpropane-1,3-diamine)dichloroplatinum(II) (1), [N-(2-chlorobenzyl)-
propane-1,3-diamine]dichloroplatinum(II) (2); [N-(4-chlorobenzyl)propane-1,3-diamine]dichloro-
platinum(II) (3); [N-(4-nitrobenzyl)propane-1,3-diamine]dichloroplatinum(II) (4); [N-(4-methoxy-
benzyl)propane-1,3-diamine]dichloroplatinum(II) (5); (N,N’-dibenzylpropane-1,3-diamine)dichloro-
platinum (II) (6) and [N-(3-nitrobenzyl)propane-1,3-diamine]dichloroplatinum(II) (7):
To K2[PtCl4] (0.415 g; 1 mmol) in water (5 mL), the appropriate ligand (1 mmol) dissolved in
water (5 mL) was slowly added. After stirring for 48 h at room temperature, the product was isolated
by filtration and dried. Yields: 0.22 g (52 %) for compound 1; 0.31 g (66 %) for compound 2; 0.17 g
(37 %) for compound 3; 0.14 g (67 %) for compound 4; 0.17 g (38 %) for compound 5; 0.17 g (34 %)
for compound 6 and 0.25 g (53 %) for compound 7 .
Compound 1: IR νmax. KBr (cm-1): 3207, 3135, 3031, 2946, 2879, 1598, 1456, 1048, 748, 701, 517,
1
328; H-NMR (400 MHz; DMSO-d6) δ: 1.63 (m, 2H, CH2); 2.50; 2.63 (2m, 4H, CH2NH2, CH2NH);
4.00; 4.41 (2dd, 2H, H7, H7’, J7-7’= 13 Hz, J7-NH= 3 Hz, J7’-NH= 4 Hz); 5.12; 6.00 (2sl, 3H, NH2, NH);
7.58 (m, 5H, Ph); 13C-NMR (100 MHz, DMSO-d6) δ: 23.45; 42.41; 46.74; 55.78 (CH2); 128.24;
128.62; 129.50; 130.55; 131.20 (Ph); 195Pt-NMR (86 MHz, DMSO-d6) δ: - 2254; Anal. Calcd. for
C10H16N2Cl2Pt·2HCl: C: 23.85; H: 3.57; N: 5.56; found: C: 23.35; H: 3.43; N: 5.56.

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Compound 2: IR νmax. KBr (cm-1): 3238, 3211, 3134, 3067, 2993, 2940, 1601, 1447, 1180, 1054, 1035,
1
860, 748, 551, 435, 315; H-NMR (200 MHz; DMSO-d6) δ: 1.96 (m, 2H, CH2); 2.37 (m, 2H,
CH2NH2); 2.79 (sl ,2H, CH2NH); 4.09; 4.84 (2m, 2H, H7, H7’); 5.78; 6.63 (2m, 3H, NH2, NH); 7.42;
7.44 (2d, 2H, H3, H6); 7.51; 8.22 (2t, 2H, H4, H5); 13C-NMR (50 MHz, CDCl3) δ: 22.99; 41.81;
51.20; 54.21 (CH2); 127.28; 129.57; 131.03; 132.16; 133.86; 135.19 (Ph); 195Pt-NMR (86 MHz,
DMSO-d6) δ: - 2250; Anal. Calcd. for C10H15Cl3N2Pt: C: 25.85; H: 3.25; N: 6.03; found: C: 26.26; H:
3.48; N: 5.71.
Compound 3: IR νmax. KBr (cm-1): 3244, 3207, 3135, 3030, 2934, 2879, 1596, 1575, 1492, 1180, 1092,
1013, 848, 815, 527, 493, 320; 1H-NMR (400 MHz; DMSO-d6) δ: 1.75 (m, 2H, CH2); 2.49; 2.70 (2m,
4H, CH2NH2, CH2NH); 3.92; 4.33 (2dd, 2H, H7, H7’, J7-7’= 12 Hz, J7-NH= 4 Hz, J7’-NH= 4 Hz); 5.20;
13
6.16 (2sl, 3H, NH2, NH); 7.44; 7.52 (2d, 4H, Ph); C-NMR (100 MHz, DMSO-d6) δ: 23.10; 42.39;
47.70; 55.07 (CH2); 128.13; 128.42; 131.89; 132.03 (Ph); 195Pt-NMR (86 MHz, DMSO-d6) δ: - 2248;
Anal. Calcd. for C10H15N2Cl3Pt: C: 25.85; H: 3.25; N: 6.03; found: C: 26.37; H: 3.27; N: 5.91.
Compound 4: IR νmax. KBr (cm-1): 3258, 3228, 3111, 2951, 2935, 1609, 1516, 1459, 1350, 1190, 1109,
1
848, 706, 530, 327; H-NMR (400 MHz; DMSO- d6) δ: 1.88 (m, 2H, CH2); 2.75 (sl, 2H, CH2NH2);
2.85 (t, 2H, CH2NH); 4.00; 4.46 (2m, 2H, H7, H7’); 5.17; 6.37 (2sl, 3H, NH2, NH); 8.04; 8.28 (2d, 4H,
Ph); 13C-NMR (100 MHz, DMSO-d6) δ: 23.17; 42.53; 49.05; 55.22 (CH2); 123.10; 131.69; 132.55;
147.03 (Ph); 195Pt-NMR (86 MHz, DMSO-d6) δ: - 2236; Anal. Calcd. for C10H15N3Cl2O2Pt: C: 25.27;
H: 3.18; N: 8.84; found: C: 25.05; H: 3.38; N: 8.56.
Compound 5: IR ν KBr (cm-1): 3245, 3216, 3168, 3144, 3004, 2938, 1611, 1513, 1460, 1253, 1177,
1
1030, 817, 554, 329; H-NMR (400 MHz; DMSO-d6) δ: 1.49 (m, 2H, CH2); 2.40; 2.49 (2m, 4H,
CH2NH2, CH2NH); 3.72 (s, 3H, OCH3); 3.92; 4.33 (2dd, 2H, H7’, H7’); 5.12; 5.85 (2sl, 3H, NH2,
NH); 6.88; 7.32 (2d, 4H, Ph); 13C-NMR (100 MHz, CDCl3) δ: 23.06; 42.43; 47.05; 55.14 (CH2); 55.22
(OCH3);113.58; 131.07; 131.87; 132.45; 158.86 (Ph); 195Pt-NMR (86 MHz, DMSO-d6) δ: - 2256;
Anal. Calcd. for C11H18N2Cl2OPt: C: 28.71; H: 3.94; N: 6.09; found: C: 28.77; H: 4.03; N: 5.93.
Compound 6: IR ν KBr (cm-1): 3159, 3012, 2980, 1576, 1498, 1453, 1433, 1211, 994, 748, 697, 523,
1
325, 315; H-NMR (400 MHz; DMSO-d6) δ: 2.08 (m, 2H, CH2); 3.03 (sl, 4H, CH2NH); 4.14 (sl, 4H,
CH2Ph); 7.44; 7.56 (2d, 10H, Ph); Anal. Calcd. for C17H22N2Cl2Pt·4H2O: C: 34.46; H: 5.10; N: 4.72;
found: C: 34.60; H: 4.67; N: 4.84.
Compound 7: IR ν KBr (cm-1): 3229, 3208, 3127, 3049, 2953, 1596, 1529, 1450, 1352, 1140, 1048,
1
813, 736, 702, 472, 324; H-NMR (400 MHz; DMSO-d6) δ: 1.71 (m, 2H, CH2); 2.64; 2.66 (2t, 4H,
CH2NH2, CH2NH); 3.94; 4.44 (2sl, 2H, H7, H7’); 5.15; 6.42 (2sl, 3H, NH2, NH); 7.68 (sl ,1H, H5);
13
8.08; 8.22 (2d, 2H, H4, H6, J4-5= J5-6= 6.8 Hz); 8.51 (s, 1H, H2); C-NMR (100 MHz, DMSO-d6) δ:
23.10; 42.52; 49.19; 58.13 (CH2); 122.74; 125.24; 125.26; 129.46; 137.25; 147.38 (Ph); 195Pt-NMR

Molecules 2002, 7
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(86 MHz, DMSO-d6) δ: - 2241; Anal. Calcd. for C10H15N3Cl2O2Pt ·H2O: C: 24.34; H: 3.44; found: C:
24.46; H: 2.94.
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Sample availability: Samples of ligands a-f and compounds 1, 3 and 5 are available from MDPI
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