Chelate vs monodentate amine effects. Direct comparison of bis(acetato)amminedichloro(cyclohexylamine)platinum(IV) (JM216) with its N-cyclohexyl-1,3-propanediamine analogue

Article abstract of DOI:10.1016/j.molstruc.2003.08.006

In order to investigate the chelate effects on physicochemical properties including antitumor activity, new cis,trans,cis,[Pt^IVCl ₂L₂(chpda)] complexes (L = OH, OCOCH₃; chpda = N-cyclohexyl-1,3-propanediamine) have been synthesized and characterized. The crystal structure of cis,trans,cis-[pt^IVCl₂(OCOCH ₃)₂(chpda)] (monoclinic P2₁/a, a = 7.947(1), b = 22.753(11), and c = 10.581(3) ?, β = 110.70(2)°, V = 1790(1) ?³, Z = 4, R = 0.0534) shows that the platinum(IV) center adopts a typical octahedral arrangement with two acetate groups in a trans position. The pattern and strength of the intramolecular hydrogen bonds are delicately different from those of JM216. Both in vitro and in vivo (oral) cytotoxicities on mouse leukemia L1210 cell line indicate that the activity of chpda chelate analogue is not better than that of the corresponding compound with two monodentate amines (JM216).

Full text of DOI:10.1016/j.molstruc.2003.08.006

Journal of Molecular Structure 659 (2003) 129–133
www.elsevier.com/locate/molstruc
Chelate vs monodentate amine effects. Direct comparison of
bis(acetato)amminedichloro(cyclohexylamine)platinum(IV)
(JM216) with its N-cyclohexyl-1,3-propanediamine analogueq
1
Young-A. Lee , Shin Won Kang, Jong Yul Park, Ok-Sang Jung
*
Department of Chemistry, Pusan National University, Kumjeoung-Ku, Pusan 609-735, South Korea
Received 24 June 2003; revised 23 July 2003; accepted 7 August 2003
Abstract
In order to investigate the chelate effects on physicochemical properties including antitumor activity, new cis,trans,cis,-
[PtIVCl2L2(chpda)] complexes (L ¼ OH, OCOCH3; chpda ¼ N-cyclohexyl-1,3-propanediamine) have been synthesized and
characterized. The crystal structure of cis,trans,cis-[PtIVCl2(OCOCH3)2(chpda)] (monoclinic P21=a; a ¼ 7:947ð1Þ;
3
˚
˚
b ¼ 22:753ð11Þ, and c ¼ 10:581ð3Þ A, b ¼ 110:70ð2Þ8; V ¼ 1790ð1Þ A , Z ¼ 4; R ¼ 0:0534) shows that the platinum(IV)
center adopts a typical octahedral arrangement with two acetate groups in a trans position. The pattern and strength of the
intramolecular hydrogen bonds are delicately different from those of JM216. Both in vitro and in vivo (oral) cytotoxicities on
mouse leukemia L1210 cell line indicate that the activity of chpda chelate analogue is not better than that of the corresponding
compound with two monodentate amines (JM216).
q 2003 Elsevier B.V. All rights reserved.
Keywords: Chelate effects; Antitumor activity; Crystal structure; N-Cyclohexyl-1,3-propanediamine
1. Introduction
potential oral anticancer agents [1–6]. Among
them, cis,trans,cis-[PtIVCl2(OCOCH3)2NH3(cyclo-
C6H11NH2)] (JM216) shows selective cytotoxicity
toward cisplatin-resistant human ovarian tumor cell
lines, and is currently in clinical trials [7,8]. Thus,
efforts have been directed towards modifying the
structure and pharmacokinetics of JM216 [6]. To
date, the modified platinum(IV) complexes suitable
for oral administration should be neutral, lipophilic,
water-soluble, and stable enough to exist in the
gastric environment. In particular, the asymmetric
amine ligands of the orally active compounds have
been known to have profound effects on the
formation of orientational isomers and the selectiv-
ity for DNA binding sites [9].
A desirable alternative approach to reduce side
effects and to enhance the quality of life in the
treatment of cancer patients is to develop orally
active antitumor drugs. Six-coordinate (diamine)pla-
tinum(IV) complexes have been considered as
q Supplementary data associated with this article can be found at
doi:10.1016/j.molstruc.2003.08.006 or at British Library Document
Supply Centre as Supplementary Publication No. Sup26698
*
Corresponding author. Tel.: þ82-51-510-2591; fax: þ82-51-
516-7421.
E-mail address: oksjung@pusan.ac.kr (O.-S. Jung).
Present address: Department of Chemistry, University of
1
Rochester, Rochester, NY 14627, USA.
0022-2860/03/$ - see front matter q 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2003.08.006

130
Y.-A. Lee et al. / Journal of Molecular Structure 659 (2003) 129–133
In this context, unique JM216 analogues with an
for C9H22N2O2Cl2Pt·2H2O: C, 22.00; H, 5.32; N,
5.69. Found: C, 21.50; H, 5.22; N, 5.70. IR (KBr,
cm21): n(OH), 3452.
asymmetric chelate amine sustaining a cyclohexyl
moiety have been synthesized in order to investigate
the chelate effects on antitumor activity. This article
reports delicate structural differences between cis,-
trans,cis-[PtIVCl2(OCOCH3)2(chpda)] (chpda ¼ N-
cyclohexyl-1,3-propanediamine) and JM216. The
geometry and functional groups of the present
compound are very similar to those of JM216.
2.2.2. cis,trans,cis-[PtIVCl2(OCOCH3)2(chpda)]
An aqueous suspension of cis,trans,cis-[PtCl2-
(OH)2(chpda)] (1,0 g, 2.65 mmol) was stirred with
acetic anhydride (20 ml, 156 mmol) at room tempera-
ture for 5 h. After the resultant solution was filtered
off, the filtrate was evaporated to obtain a yellow
solid. The crude product was recrystallized from a
mixture of water and acetone. The colorless crystals
were obtained in 62% yield. m.p. 132 8C (dec.). Anal.
Calcd for C13H26N2O4Cl2Pt: C, 25.60; H, 4.77; N,
4.63. Found: C, 25.50; H, 4.87; N, 4.56. IR (KBr,
cm21): n(COO)asym, 1630; n(COO)sym, 1360. 1H
NMR (Me2SO-d6, d): 9.3 (NH2), 7.2 (NH), 1.93
(OCH3), 1.90 (OCH3), 3.5 1.0 (chpda 16H).
2.3. X-ray crystallography of cis,trans,cis-
[PtIVCl2(OCOCH3)2(chpda)]
The X-ray data were collected on an Enraf–Nonius
CAD4 automatic diffractometer with graphite-mono-
2. Experimental
˚
chromated Mo Ka (l ¼ 0:71073 A) at ambient tem-
2.1. Materials and instrumentation
perature (20(2) 8C). The unit cell dimensions were
based on 25 well-centered reflections by using a least-
squares procedure. During the data collection, three
standard reflections monitored every hour did not
show any significant intensity variation. The data
were corrected for Lorentz and polarization effects,
and empirically for absorption (azimuthal c-scans of
six reflections). The structure was solved by the
Patterson method (SHELXS-97), and was refined by
full-matrix least squares techniques (SHELXL-97) [11].
All non-hydrogen atoms were refined anisotropically.
The hydrogen atoms were placed at the calculated
positions. Crystal parameters and procedural infor-
mation corresponding to data collection and a
structure refinement are given in Table 1.
Reagent grade potassium tetrachloroplatinate(II)
(Kojima) and N-cyclohexyl-1,3-propanediamine
(Aldrich) were used as received. Fresh cis-[PtIICl2(-
chpda)] was prepared by a routine procedure [10]. 1H
NMR spectra were recorded on a Varian Gemini 300
instrument. The chemical shifts are reported relative
to internal Me4Si. The infrared spectra in the 5000–
400 cm21 region were measured as potassium bro-
mide pellets on a Perkin Elmer 16F PC model FT-IR
spectrometer. Elemental analysis was performed at
the Advanced Analysis Center at KIST.
2.2. Preparation
2.2.1. cis,trans,cis-[PtIVCl2(OH)2(chpda)]
To a suspension of cis-[PtIICl2(chpda)] (2.0 g,
4.7 mmol) in water (100 ml) was added a 30%
aqueous solution of H2O2 (2.4 ml). The reaction
mixture was stirred at 70 8C for 2 h. After the resultant
solution was filtered off, the filtrate was reduced to
30 ml. The solution stood overnight to obtain the solid
product in 65% yield. m.p. 156 8C (dec.). Anal. Calcd
3. Results
3.1. Synthesis
cis-[PtIICl2(chpda)] was oxidized in the presence
of H2O2 to yield cis,trans,cis-[PtIVCl2(OH)2(chpda)]
as shown in Scheme 1. Further carboxylation of

Y.-A. Lee et al. / Journal of Molecular Structure 659 (2003) 129–133
131
Table 1
Crystallographic data for cis,trans,cis-[PtIVCl2(OCOCH3)2(chpda)]
melting. They are soluble in common organic
solvents, and are slightly soluble in water.
Formula
C13H26Cl2N2O4Pt·2H2O
3.2. Crystal structure of cis,trans,cis-
[PtIVCl2(OCOCH3)2(chpda)]
Formular weight
T (8C)
˚
l (A)
540.35
20(2)
0.71073
Crystal system
Space group
˚
a (A)
˚
b (A)
˚
c (A)
Monoclinic
The molecular structure is depicted in Fig. 1, and
selected bond distances and angles are listed in
Table 2. The local geometry around the platinum(IV)
approximates to a typical octahedral arrangement
with two acetate groups in a trans position (O(1)–Pt–
O(3) ¼ 174.9(6)8). Two chlorides are retained in a cis
position (Cl(1)–Pt–Cl(2) ¼ 89.3(2)8). Concomi-
tantly, the chpda is bonded to the platinum(IV) in a
chelate fashion. For the acetate groups, the bond
P21/a (No. 14)
7.947(1)
22.753(11)
10.581(3)
b (deg)
110.70(2)
3
˚
V (A )
1790(1)
Z
4
dcalcd (g/cm3)
Abs. coeff (mm21
Fð000Þ
2.006
)
8.156
1048
Crystal size (mm3)
umax (deg)
Index ranges
0.05 £ 0.10 £ 0.20
1.79–24.98
˚
lengths of C(1)–O(2) (1.18(2) A) and C(3)–O(4)
˚
(1.21(3) A) are shorter than those of C(1)–O(1)
0 # h # 9; 0 # k # 26; 12 # l # 11
1634
˚
(1.31(3) A) and C(3)–O(3) (1.31(2) A), indicating
˚
Reflections collected
Independent reflections
Parameters refined
GOF on F2
that both acetate groups act as monodentate ligands
1532 ½RðintÞ ¼ 0:0570ꢀ
199
˚
˚
(Pt–O(1) ¼ 2.00(1) A; Pt–O(2) ¼ 2.02(1) A). The
N(1)–Pt–N(2) bond angle (96.1(6)8) is slightly
splayed to sustain the 6-membered ring in contrast
to the corresponding angle of JM216 (94.3(4)8) [8].
There exist intramolecular hydrogen bonds between
the dangling oxygens of the acetate groups and the
1.057
Final R½I . 2sðIÞꢀ
R1 ¼ 0:0534; wR2 ¼ 0:0955
þ0.991 and 21.060
23
˚
Largest diff. peak (e A
)
P
P
P
P
R1 ¼ llFol 2 lFcll= lFol; wR2 ¼ wðFo2 2 Fc2Þ2= wðFo4Þ
1=2; where w ¼ 1={s2Fo2 þ ðaPÞ2 þ bP} where P ¼ {maxðFo2;
oÞ þ 2Fc2}=3:
amine
groups
(N(1)· · ·O(4) ¼ 2.72
and
˚
N(2)· · ·O(2) ¼ 2.68 A). These intramolecular hydro-
gen bonds may give rise to additional stability in the
solid state. The hydrogen bonds are slightly stronger
the hydroxide coordinated to the platinum(IV)
produces cis,trans,cis-[PtIVCl2(OCOR)2(chpda)].
Composition was in each case determined by
˚
than those of JM216 (2.84–2.86 A), presumably due
1
elemental analysis, IR, and H NMR data. The final
to the electronic effect of chpda ligand. Moreover, the
pattern of the hydrogen bonds is slightly different
from that of JM216, presumably due to the chelate
effects of the chpda ligand. For the present compound,
platinum(IV) complex is recrystallized in a mixture of
water and acetone to give colorless crystalline solids.
The products are solids that decompose prior to
Scheme 1.

132
Y.-A. Lee et al. / Journal of Molecular Structure 659 (2003) 129–133
[8]. The packing diagram of the present compound
shows that the hydrophilic groups are arranged in an
assembly that is surrounded by the hydrophobic
moieties.
3.3. Spectroscopic data and antitumor activity
The 1H NMR spectrum of cis,trans,cis-[PtIVCl2
(OCOCH3)2(chdpa)] exhibits apparently crowded
features owing to the presence of the rigid chelating
chpda. However, from the characteristic signals, the
basic configuration of the X-ray crystal structure is
retained and stable in solution for a few days even
though the weak and delicate hydrogen bonds may
be changed. The two axial acetate moieties give
signals at 1.88 and 1.92 ppm. The two chemical
shifts seem to originate from the presence of the
asymmetric chelating chpda. The acetylation of
cis,trans,cis-[PtIVCl2(OH)2(chpda)] is readily ident-
ified by the prominent change in the IR spectrum.
The dihydroxoplatinum(IV) compound showed the
characteristic O–H stretching frequency at
3452 cm21. Upon acetylation, the O–H band
disappears, replaced by strong CvO bands (1630,
1282 cm21).
Fig. 1. ORTEP view (top) and packing diagram (bottom) of
cis,trans,cis-[PtIVCl2(OCOCH3)2(chpda)]. For the ORTEP view,
hydrogen atoms are omitted for clarity.
Preliminary antitumor activities of the present
compound (ED50 ¼ 1.1 mM; T/C (%) ¼ 113.4 (oral);
ED50 ¼ effective dosage concentration that inhibit
cell growth to 50% of the control; T/C(%) ¼
Treat/Control £ 100) are inferior to JM216
(ED50 ¼ 0.6 mM; T/C (%) ¼ 160.0 (oral)). The
difference in antitumor activities of JM216 and
cis,trans,cis-[PtIVCl2(OCOCH3)2(chdpa)] may be
ascribed to the difference between the monodentate
amines in the former and the rigid chelating chpda in
the latter; the amine-core of both compounds is
retained. The activity difference may also be due to
the delicate change of intramolecular hydrogen bonds.
Besides the weak interactions, solubility can affect the
antitumor activity. Water-solubility of cis,trans,cis-
[PtIVCl2(OCOCH3)2(chpda)] is lower than JM216. On
the other hand, anticancer activities (ED50 ¼ 2.0 mM;
T/C (%) ¼ 100 (oral)) of cis,trans,cis-[PtIVCl2(-
OH)2(chdpa)] explains the importance of anions as
well as the chelate effects. That is, the hydroxo
analogue is ineffective compared with cis,trans,cis-
[PtIVCl2(OCOCH3)2(chdpa)] in anticancer activity.
a one-to-one interaction exists (N(1)· · ·O(4) and
N(2)· · ·O(2)). For JM216, N(1) interacts with two
oxygen donors (O(5)· · ·N(1)· · ·O(3)) while N(2)
interacts with only one oxygen (N(2)· · ·O(5)) donor
Table 2
˚
Selected bond lengths (A) and angles (deg) for cis,trans,cis-
[PtIVCl2(OCOCH3)2(chpda)]
Pt–O(1)
2.00(1)
2.05(1)
2.312(5)
1.31(3)
1.31(2)
175.0(6)
87.3(5)
96.1(6)
87.6(4)
172.9(4)
92.2(4)
84.4(4)
89.4(2)
125(1)
Pt–O(3)
2.02(1)
2.08(1)
2.324(5)
1.18(2)
1.21(2)
96.0(6)
87.4(6)
96.1(6)
88.8(4)
90.2(4)
84.3(4)
179.4(5)
125(2)
Pt–N(2)
Pt–N(1)
Pt–Cl(2)
Pt–Cl(1)
O(1)–C(1)
O(2)–C(1)
O(3)–C(3)
O(4)–C(3)
O(1)–Pt–O(3)
O(3)–Pt–N(2)
O(3)–Pt–N(1)
O(1)–Pt–Cl(2)
N(2)–Pt–Cl(2)
O(1)–Pt–Cl(1)
N(2)–Pt–Cl(1)
Cl(2)–Pt–Cl(1)
C(3)–O(3)–Pt
O(1)–Pt–N(2)
O(1)–Pt–N(1)
N(2)–Pt–N(1)
O(3)–Pt–Cl(2)
N(1)–Pt–Cl(2)
O(3)–Pt–Cl(1)
N(1)–Pt–Cl(1)
C(1)–O(1)–Pt

Y.-A. Lee et al. / Journal of Molecular Structure 659 (2003) 129–133
133
4. Conclusion
References
A new JM216 analogue, cis,trans,cis-[PtIVCl2(-
OCOCH3)2(chpda)] was synthesized and character-
ized. The chelate effects of neutral amine have been
observed on the in vitro and in vivo activities.
Understanding the features that can be used to control
the physicochemical properties may be a key to the
development of platinum complexes that exhibit
desirable biological activity.
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Acknowledgements
[11] (a) G.M. Sheldrick, SHELXS-97: A Program for Structure
¨
Determination, University of Gottingen, Germany, 1997. (b)
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Support for this research was provided by the
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PNU.
SHELXL-97:
A
Structure Refinement, University of Gottingen, Germany,
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