Crystal and Molecular Structures of Asymmetric cis- and trans-Platinum(II/IV) Compounds and Their Reactions with DNA Fragments

Article abstract of DOI:10.1021/ic960983u

The asymmetrically substituted platinum(II) complexes cis-Pt(NH₃)(c-C₅H₁₁NH₂)Cl ₂ and trans-Pt(NH₃)(c-C₆H₁₁-NH₂)Cl ₂ have been synthesized and their crystal structures have been determined. Crystals of cis-Pt(NH₃)(c-C₆H₁₁NH₂)Cl ₂ (1) are orthorhombic, space group Pbca (no. 61) with a = 10.1994(12), b = 10.494(2), c = 18.826(2) ?, Z = 8. The structure refinement converged to R1 = 0.0518 and wR2 = 0.1143. Crystals of trans-Pt(NH₃)(c-C₆H₁₁NH₂)Cl ₂ (2) are monoclinic, space group P2₁/c (no. 14) with a = 12.141(3), b = 6.0965(9), c = 19.864(3) ?, β= 118.71(2)°, Z = 4. The structure refinement converged to R1 = 0.0711 and wR2 = 0.1846. In addition, the Pt(IV) analogues with axial hydroxide ligands have been synthesized. Also the corresponding bis(carboxylato)-platinum(IV) compound of formula trans,cis,cis-Pt(NH₃)(c-C₆H₁₁NH ₂)Cl₂(OOCCH₃)₂ has been obtained by conversion of the hydroxide with acetic anhydride. Reactions of these platinum complexes with 9-methylhy-poxanthine and guanosine-5′-monophosphate (5′-GMP) have been studied in significant detail. The course of the reactions was followed by NMR spectroscopy, and ¹H and ¹⁹⁵Pt techniques were used to identify the formation of the products. It was found that the Pt(II) compounds easily react with the bases at the N7 position, whereas the Pt(IV) compounds react very slowly (for trans,cis,cis-Pt(NH₃)(c-C₆H₁₁NH ₂)Cl₂(OOCCH₃)₂) or not at all (for trans,trans,trans-Pt(NH₃)(c-C₆H₁₁NH ₂)Cl₂(OH)₂). Only in the presence of glutathione does a reaction of the latter with 5′-GMP takes place. In this case a major product was found to be the reduced trans-Pt(II) complex with one molecule of 5′-GMP and one molecule of S-bonded glutathione.

Full text of DOI:10.1021/ic960983u

854
Inorg. Chem. 1997, 36, 854-861
Crystal and Molecular Structures of Asymmetric cis- and trans-Platinum(II/IV) Compounds
and Their Reactions with DNA Fragments
Eduard G. Talman,‡ Wolfgang Bru1ning,‡ Jan Reedijk,*,‡ Anthony L. Spek,†,§ and
Nora Veldman§
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University. P.O. Box 9502,
2300 RA Leiden, The Netherlands, and Bijvoet Center for Biomolecular Research, Crystal and
Structural Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
ReceiVed August 14, 1996X
The asymmetrically substituted platinum(II) complexes cis-Pt(NH3)(c-C6H11NH2)Cl2 and trans-Pt(NH3)(c-C6H11-
NH2)Cl2 have been synthesized and their crystal structures have been determined. Crystals of cis-Pt(NH3)(c-
C6H11NH2)Cl2 (1) are orthorhombic, space group Pbca (no. 61) with a ) 10.1994(12), b ) 10.494(2), c ) 18.826(2)
Å, Z ) 8. The structure refinement converged to R1 ) 0.0518 and wR2 ) 0.1143. Crystals of trans-Pt(NH3)(c-
C6H11NH2)Cl2 (2) are monoclinic, space group P21/c (no. 14) with a ) 12.141(3), b ) 6.0965(9), c ) 19.864(3)
Å, â ) 118.71(2)°, Z ) 4. The structure refinement converged to R1 ) 0.0711 and wR2 ) 0.1846. In addition,
the Pt(IV) analogues with axial hydroxide ligands have been synthesized. Also the corresponding bis(carboxylato)-
platinum(IV) compound of formula trans,cis,cis-Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2 has been obtained by
conversion of the hydroxide with acetic anhydride. Reactions of these platinum complexes with 9-methylhy-
poxanthine and guanosine-5′-monophosphate (5′-GMP) have been studied in significant detail. The course of
the reactions was followed by NMR spectroscopy, and 1H and 195Pt techniques were used to identify the formation
of the products. It was found that the Pt(II) compounds easily react with the bases at the N7 position, whereas
the Pt(IV) compounds react very slowly (for trans,cis,cis-Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2) or not at all (for
trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2). Only in the presence of glutathione does a reaction of the
latter with 5′-GMP takes place. In this case a major product was found to be the reduced trans-Pt(II) complex
with one molecule of 5′-GMP and one molecule of S-bonded glutathione.
Introduction
cisplatin. Most known derivative drugs, e.g. carboplatin, show
cross-resistance with cisplatin. Thus new antitumor drugs that
do have activity against cells that cannot be treated with cisplatin
are highly desired. Other metals, like ruthenium, have also been
investigated for their antitumor activity and some show promis-
ing in Vitro activity.4 More recently, even unconventional
platinum complexes, like those with N-donor atoms in trans
position, have been investigated.5 In this respect it is very
interesting that a platinum(IV) compound with trans configu-
ration, trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2, abbre-
viated to JM-335, has been reported to be antitumor active.6
Cisplatin is a well-established antitumor drug. One of its
disadvantages is the need to apply it intravenously. This has
resulted in investigations toward orally applicable platinum
complexes. A large class of compounds under investigation is
a group of platinum(IV) compounds.1 The kinetics of plati-
num(IV) are much slower than those of platinum(II). This
property is most probably one of the reasons why they can be
applied orally and are not degraded too early in the gastrointes-
tinal tract. A group of platinum(IV) compounds with one
ammine and one cyclohexylamine ligand has recently been
found to be particularly promising in antitumor tests, JM-216
(cis,cis,trans-Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2) being al-
ready in clinical trials.2 The X-ray structure of this compound
has been published recently.3
(2) (a) Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J.
F.; Barnard, C. F. J.; Harrap, K. R.; Goddard, P. M.; Kelland, L. R.;
Morgan, S. E. In Platinum and Other Metal Coordination Compounds
in Cancer Chemotherapy; Howell, S. B., Ed.; Plenum Press: New
York, 1991; pp 93-100. (b) Barnard, C. F. J. Europ. Pat. Appl.
92301845, 1992. (c) Rose, W. C.; Crosswell, A. R.; Schurig, J. E.;
Casazza, A. M. Cancer Chemother. Pharmacol. 1993, 32, 197-203.
(3) Neidle, S.; Snook, C. F. Acta Crystallogr., Sect. C 1995, 51, 822-
824.
(4) (a) van Vliet, P. M.; Toekimin, S. M. S.; Haasnoot, J. G.; Reedijk, J.;
Nova´kova´, O.; Vra´na, O.; Brabec, V. Inorg. Chim. Acta 1995, 231,
57-64. (b) Clarke, M. J. In Metal Complexes in Cancer Chemo-
therapy; Keppler, B. K., Ed.; VCH: Weinheim, Germany, 1993; pp
129-156. (c) Mestroni, G.; Alessio, E.; Sava, G.; Pacor, S.; Coluccia,
M. In Metal Complexes in Cancer Chemotherapy; Keppler, B. K.,
Ed.; VCH: Weinheim, Germany, 1993; pp 157-185. (d) Keppler, B.
K.; Lipponer, K.-G.; Stenzel, B.; Kratz, F. In Metal Complexes in
Cancer Chemotherapy; Keppler, B. K., Ed.; VCH: Weinheim,
Germany, 1993; pp 187-220.
Another reason for research toward new compounds origi-
nates from the build-up of resistance in cells treated with
* To whom correspondence should be addressed.
† Crystallographic studies supervised by this author.
‡ Leiden University.
§ Utrecht University.
X Abstract published in AdVance ACS Abstracts, February 1, 1997.
(1) (a) Abrams, M. J. In The Chemistry of Antitumor Agents; William, D.
E. V. Ed.; Chapman and Hall: New York, 1990; p 331. (b) Afcharian,
A.; Botour, J. L.; Castan, P.; Wimmer, S. Met. Ions Biol. Med., Proc.
Int. Symp. 1990, 514. (c) Cleare, M. J.; Hydes, P. C.; Hepburn, D. R.;
Malerbi, B. W. In Cisplatin: Current Status and New DeVelopments;
Prestayko, A. W., Crooke, S. T., Carter, S. K., Eds.; Academic Press
Inc., New York, 1980; p 149. (d) Khokhar, A. R.; Deng, Y.; Al-Baker,
S.; Yoshida, M.; Siddik, Z. H. J. Inorg. Biochem. 1993, 51, 677-
687. (e) Kidani, Y.; Kizu, R.; Miyazaki, M.; Noji, M.; Matsuzawa,
A.; Takeda, Y.; Akiyama, N.; Eriguchi, M. In Platinum and Other
Metal Coordination Compounds in Cancer Chemotherapy 2; Pinedo,
H. M.; Schornagel, J. H., Eds.; Plenum Press: New York and London,
1996; pp 43-51.
(5) (a) Farrell, N. Met. Ions Biol. Syst. 1996, 32, 603-639. (b) Natile,
G.; Coluccia, M. in 7th International Symposium on PLATINUM and
other metal coordination compounds in CANCER CHEMOTHERAPY,
Amsterdam, the Netherlands, 1995, S.004.
(6) Kelland, L. R.; Barnard, C. F. J.; Mellish, K. J.; Jones, M.; Goddard,
P. M.; Valenti, M.; Bryant, A.; Murrer, B. A.; Harrap, K. R. Cancer
Res. 1994, 54, 5618-5622.
S0020-1669(96)00983-4 CCC: $14.00 © 1997 American Chemical Society

cis- and trans-Platinum(II/IV) Compounds
Inorganic Chemistry, Vol. 36, No. 5, 1997 855
This observation, combined with the fact that Pt(IV) compounds
are usually seen as prodrugs for Pt(II) compounds and the
generally accepted fact that classical amine complexes have cis
geometry, makes these compounds particularly interesting for
mechanistic studies and reactions with DNA fragments.7
In the present study the binding of mixed ammine-cyclo-
hexylamine platinum compounds to simple derivatives of DNA,
i.e. 9-methylhypoxanthine and 5′-GMP is reported. Both Pt(IV)
and Pt(II) compounds are investigated. In addition, attention
is given to the possible glutathione-assisted reduction of the
Pt(IV) compounds to their Pt(II) derivatives.8 Furthermore, the
present paper describes the X-ray structures of both cis-Pt-
(NH3)(c-C6H11NH2)Cl2 (1) and trans-Pt(NH3)(c-C6H11NH2)Cl2
(2).
Figure 1. Synthesis of trans-[Pt(NH3)(c-C6H11NH2)Cl2] (2) (JM-334).
was filtered off and washed with ethanol several times. The crude
product was recrystallized from hot water and dried in air. Yield: 3.6
g (65%) colorless needles. 1H-NMR (D2O) δ (ppm): 8.07 (H2), 8.03
(H8), 3.78 (N-CH3). MS (m/e): 149.2 (M+). Anal. Calcd for C6H7N5
(Mw ) 149.16): C, 48.32; N, 46.95; H, 4.73. Found: C, 48.0; N,
47.0; H, 4.8.
9-Methylhypoxanthine. The reaction was carried out in a 250 mL
two-necked flask equipped with a reflux condenser. A 2.7 g (0.018
mol) sample of 9-methyladenine was dissolved in 140 mL of 0.8 M
HCl. A solution of 1.37 g of NaNO2 in 45 mL of water was added
dropwise. The solution was heated for 1 h to 90 °C. After additional
stirring for 0.5 h at room temperature, the solution was evaporated to
dryness. The yellowish residue was dissolved in 150 mL of hot water
and neutralized with solid NaOH. After treatment with charcoal, the
solution was filtered off hot. On cooling, colorless needles deposited,
which were filtered and dried in air. Yield: 1.01 g (37%). 1H-NMR
(D2O) (pH* ) 5.44) δ (ppm): 8.17 (H2), 8.04 (H8), 3.82 (N-CH3).
Anal. Calcd for C6H6N4O (Mw ) 150.14): C, 48.00; N, 37.32; H,
4.03. Found: C, 47.8; N, 37.8; H, 4.0.
Experimental Section
Infrared Spectroscopy. Infrared spectra have been recorded as KBr
or CsI pellets in the range 4000-250 cm-1 on a Perkin-Elmer 580B
spectrophotometer. Fourier transform infrared spectra have been
recorded as KBr or CsI pellets in the range 4000-400 cm-1 and as
polyethylene (PE) pellets in the range 600-100 cm-1. A Bruker IFS
113V FT-IR spectrophotometer was used for this purpose.
Elemental Analyses. C, H, and N determinations were performed
by the microanalytical laboratory of the University of Dortmund,
Dortmund, Germany, using a Carlo Erba Strumentazione element
analyzer (Model 1106).
Mass Spectrometry. A Finnigan MAT 900 mass spectrometer was
used.
Syntheses of the Platinum Complexes. trans-Pt(NH3)(c-C6H11NH2)-
Cl2 (2). A suspension of 1.0 g (3.33 mmol) of cis-Pt(NH3)2Cl2 in 20
mL water was treated with a slight excess of cyclohexylamine (677
mg, 6.83 mmol). The mixture was stirred and heated to 90 °C for 3 h
and subsequently allowed to cool down to room temperature and
filtered. The filtrate was treated with 4.2 mL of concentrated HCl and
gently refluxed for 13 h. After the filtrate was cooled in an ice bath,
a slightly yellow precipitate deposited, which was filtered off, washed
with water, and dried in air. A second fraction was obtained by
evaporating half of the filtrate. The product was recrystallized from
boiling 0.01 M HCl. Yield: 0.823 g (65%). Crystals suitable for X-ray
determination were obtained by crystallization from acetonitrile. Anal.
Calcd for PtC6Cl2H16N2 (Mw ) 382.19): C, 18.86; N, 7.33; H, 4.22.
Found: C, 19.0; N, 7.3; H, 4.3. IR (KBr) (cm-1): 3291, 3236 s
((NH3)a+s); 3201, 3129 s ((NH2)a+s). FIR(PE) (cm-1): 537, 525 m (Pt-
N); 332 vs (Pt-Cl). 195Pt-NMR (DMF-d7) δ (ppm): -2163. Figure
1 shows a schematic diagram of this reaction.
cis-Pt(c-C6H11NH2)2I2. K2PtCl4 (2.0 g, 4.82 mmol) was dissolved
in 100 mL of water and treated with 8.0 g (47 mmol) of KI. The
solution was stirred for 10 min at room temperature. Two equivalents
of cyclohexylamine (0.958 g, 9.64 mmol) was added dropwise to the
resulting K2PtI4 solution. The reaction mixture was stirred for 1 h.
The yellow precipitate was filtered off and recrystallized from DMF/
H2O. After the precipitate was washed with water, methanol, and
diethyl ether, the final product cis-Pt(c-C6H11NH2)2I2 was dried in air.
Yield: 2.8 g (90%). Anal. Calcd for PtC12H26I2N2 (Mw ) 647.24):
C, 22.27; N, 4.33; H, 4.05. Found: C, 22.2; N, 4.3; H, 4.1.
NMR Measurements. 1H spectra were recorded on a Bruker DPX-
300 spectrometer operating at a frequency of 300 MHz. D2O was used
as a solvent with trace amounts of the reference TMA (tetramethyl-
ammonium nitrate; δ ) 3.18 ppm). 13C spectra were recorded on a
Bruker DPX-300 spectrometer operating at a frequency of 75.5 MHz.
Chemical shifts were reported relative to the reference TMS (tetra-
methylsilane). 195Pt spectra were recorded with a Bruker DPX-300 or
Bruker AM-200 spectrometer operating at frequencies of 64.5 and 43.0
MHz. Chemical shifts are reported relative to the external reference
K2PtCl4 (δ ) -1631 ppm vs K2PtCl6 δ ) 0 ppm).9
pH Measurements. pH titrations were performed by adding NaOD
or DCl (c ) 0.1 M) to the sample until the required pH was reached.
pH values were measured with a radiometer PHM-80 pH meter
equipped with an Ingold 6030-02 electrode. All pH measurements were
performed at 298 K. The pH meter was calibrated with buffer solutions
of pH 4.00, 7.00, and 11.00. Meter readings, reported as pH*, were
not corrected for deuterium isotope effects.10 The pKa values mentioned
in the discussions are valid for H2O and obtained from literature.11 Our
conclusions will not be affected by this discrepancy because the effect
of metal binding is much larger than the deuterium isotope effect.
Starting Materials. cis-Pt(NH3)2Cl2 was prepared according to
Dhara’s method.12 9-Methyladenine and 9-methylhypoxanthine were
prepared according to literature procedures13,14 as detailed below.
9-Methyladenine. The reaction was carried out in a 250 mL two-
necked flask equipped with a reflux condenser and a dropping funnel.
A 5 g (0.037 mol) sample of adenine was dissolved in a solution of
1.5 g (0.037 mol) of NaOH in 150 mL of ethanol. After dissolving,
the solution was cooled to -5 °C in a salt ice bath. 5.3 g (0.037 mol)
of iodomethane was added dropwise, with vigorous stirring. The
temperature was kept between 0 and 10 °C during the addition. The
solution was heated under reflux for 1 h and stirred for 15 min at room
temperature. The solution was cooled to 0 °C. The white precipitate
[Pt(c-C6H11NH2)I2]2. A suspension of cis-Pt(c-C6H11NH2)2I2 (2.8
g, 4.33 mmol) in 22 mL of water and 70 mL of ethanol was treated
with 4.4 mL of HClO4 (70%) over a period of 8 days. During reaction
the yellow precipitate turned into a red brown precipitate. The
suspension was filtered and the precipitate washed with water and dried
in air. Yield: 2.21 g (93%). Anal. Calcd for Pt2C12H26I4N2 (Mw
)
1096.13): C, 13.15; N, 2.56; H, 2.39. Found: C, 13.9; N, 2.9; H, 2.4.
(7) (a) Reedijk, J. Inorg. Chim. Acta 1992, 198-200, 873-881. (b)
Reedijk, J. J. Chem. Soc., Chem. Commun. 1996, 801-806.
(8) Shi, T.; Berglund, J.; Elding, L. I. Inorg. Chem. 1996, 35, 3498-
3503.
(9) Pregosin, P. S. Coord. Chem. ReV. 1982, 44, 247-291.
(10) Martin, R. B. Science 1963, 139, 1198.
(11) Martin, R. B. Met. Ions Biol. Syst. 1996, 32, 61-89.
(12) Dhara, S. Indian J. Chem. 1970, 8, 193.
(13) Kru¨ger, G. Z. Physiol. Chem. 1893, 18, 423-475.
(14) Elion, G. B. J. Org. Chem. 1962, 27, 2478-2491.
195Pt-NMR (DMF-d7) δ (ppm): -3998 and -4014.
cis-Pt(NH3)(c-C6H11NH2)I2. A suspension of [Pt(c-C6H11NH2)I2]2
(2.0 g, 1.82 mmol) in 9 mL of water was mixed with 1.82 mL of 1.5
M NH4OH (2.73 mmol). The reaction mixture was stirred for 1 day
at room temperature. The yellow precipitate was filtered, washed with
water, and dried in air. Yield: 1.81 g (88%). Anal. Calcd for
PtC6H16I2N2 (Mw ) 565.10): C, 12.75; N, 4.96; H, 2.85. Found: C,
13.9; N, 4.3; H, 2.9. 195Pt-NMR (DMF-d7) δ (ppm): -3307.

856 Inorganic Chemistry, Vol. 36, No. 5, 1997
Talman et al.
was filtered and tetraphenylphosphonium chloride (0.641 g, 1.7 mmol)
in 10 mL of water was added. An orange precipitate formed and was
filtered off, washed with water, and dried under vacuum. Yield: 0.53
g (48%). IR (KBr) (cm-1): 325 s, b, 340 b (Pt-Cl).
K[Pt(NH3)Cl3]. Potassium hexafluorophosphate (142 mg, 0.77
mmol) was dissolved in 10 mL of water. This solution was added to
a solution of 0.53 g (0.81 mmol) of Ph4P[Pt(NH3)Cl3] in 20 mL of
dichloromethane in a separatory funnel. The resulting mixture was
shaken and the water layer lyophilized. Yield: 0.25 g (85%). IR (KBr)
(cm-1): 3280, 3220 s ((NH3)s+a); 1610 b, 1310 s ((NH3)def); 315 s, b
(Pt-Cl).
An alternative synthesis for cis-Pt(NH3)(c-C6H11NH2)Cl2 was also
investigated: 350 mg (0.98 mmol) of K[Pt(NH3)Cl3] was dissolved in
15 mL of water. A solution of 6.8 mg (4 mmol) KI in 5 mL of water
was added. To this solution 1.2 equiv of cyclohexylamine (9.9 mg)
was added dropwise and the solution was stirred for 1 h. During this
time a brown precipitate formed which was filtered off, washed with
water, and dried in air. Yield: 0.5 g (78%). The brown precipitate
was dissolved in 50 mL of water and treated overnight with 1.85 equiv
of AgNO3 (0.325 g) in the dark. Then 4 equiv (2.17 mmol, 162 mg)
KCl was added to the solution. The reaction mixture was stirred for
1 h at 40 °C and was chilled to 4 °C overnight. During this time a
yellow precipitate deposited which was filtered off and recrystallized
from 80 °C 0.01 M HCl. Yield: 0.24 g (80%).
The latter synthesis for cis-Pt(NH3)(c-C6H11NH2)Cl2 is very similar
to the one published recently by Giandomenico et al.15
trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2 (JM-335) was ob-
tained as a gift from Johnson Matthey. It was used without further
purification.
trans,cis,cis-Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2. A suspension
of trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2 (200 mg, 0.48
mmol) in acetic anhydride was stirred for 8 days. The suspension was
filtered off and washed several times with diethyl ether and dried in
air. Yield: 0.16 g (67%). Anal. Calcd for PtC10Cl2H22N2O4 (Mw
)
500.28): C, 24.01; N, 5.60; H, 4.43. Found: C, 24.2; N, 5.6; H, 4.6.
cis,cis,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2. To a suspension of
cis-Pt(NH3)(c-C6H11NH2)Cl2 (200 mg, 0.52 mmol) in 50 mL of water
was added hydrogen peroxide (30 % w/v, 286 µL, 2.5 mmol). The
reaction mixture was heated under reflux for 2 h and chilled on ice. A
yellow precipitate formed which was filtered off, washed with water
and small amounts of acetone, and dried in air. Yield: 113 mg (52%).
Anal. Calcd for PtC6Cl2H18N2O2 (Mw ) 416.21): C, 17.32; N, 6.73;
H, 4.36. Found: C, 16.9; N, 6.5; H, 4.5.
Figure 2. Synthesis of cis-[Pt(NH3)(c-C6H11NH2)Cl2] (1).
cis-Pt(NH3)(c-C6H11NH2)Cl2 (1). A suspension of cis-Pt(NH3)(c-
C6H11NH2)I2 (1.1 g, 1.95 mmol) in 100 mL of water was treated with
1.85 equiv (0.612 g, 3.6 mmol) of AgNO3 for 1 day in the dark. AgI
was filtered off and 4 equiv (0.58 g, 54 mmol) of KCl was added to
the filtrate. The reaction mixture was stirred for 1 h at 40 °C and
allowed to stay 1 day at 4 °C. While the mixture was chilled, a yellow
precipitate deposited which was filtered, washed with water, and dried
in air. A second fraction was obtained by evaporating half of the
solvent. The crude product was recrystallized from 80 °C hot 0.01 M
Reactions of Platinum Complexes with 9-Methylhypoxanthine
and 5′-GMP. Recipes for most of the used reactions are given below.
A suspension of trans-Pt(NH3)(c-C6H11NH2)Cl2 (2) in D2O was
reacted with 2.5 equiv of 9-methylhypoxanthine at pH* ) 6, both at
room temperature and in the temperature range between 37 and 45 °C.
The same reaction was carried out using H8-deuterated 9-methylhy-
poxanthine to confirm assignments of the H8 and H2 signals. The
HCl. Yield: 0.357 g (48%). Anal. Calcd for PtC6Cl2H16N2 (Mw
)
1
382.19): C, 18.86; N, 7.33; H, 4.22. Found: C, 18.8; N, 7.0; H, 4.0.
IR (KBr) (cm-1): 3289, 3237 s ((NH3)a+s); 3201, 3129 s ((NH2)a+s).
FIR(PE) (cm-1): 537, 524 m (Pt-N); 327 vs (Pt-Cl). The infrared
spectrum of this compound showed one large broad stretching (Pt-
Cl) vibration at 327 cm-1, while the trans isomer (2) showed one band
reaction progress was followed by H NMR spectroscopy.
The progress of reaction of cis-Pt(NH3)(c-C6H11NH2)Cl2 (1) with
2.5 equiv of 9-methylhypoxanthine at pH* ) 6.4 was followed by 1H
NMR spectroscopy. The reaction was carried out in D2O in the
temperature range 37-45 °C. Due to the low solubility of 1, the
reaction was started with a suspension. At the end of the reaction, a
homogeneous solution had formed.
The reaction of 1 and 2 with 5′-GMP in an 1:2.5 stoichiometric
ratio was carried out in NMR tubes in D2O containing 50 mM phospate
buffer (pH* ) 6.5). If necessary the pH was adjusted to a value of
6.5 with small amounts of 0.1 M NaOD or DCl solution. The reaction
was started with a suspension of the poorly soluble chloride complex.
At the end of the reaction period a homogeneous solution had formed.
The temperature was kept between 37 and 45 °C. The total concentra-
tion of Pt(II) was 5 mM. 1H-NMR spectra of the mixtures were
recorded over a period of 9 days.
at a slightly higher wavenumber, i.e. 332 cm-1
. Therefore, the
configuration of the two isomers of Pt(NH3)(c-C6H11NH2)Cl2 could not
be determined using IR-spectroscopy as the only method, and to prove
the identity of the compounds, X-ray determinations were carried out
(vide infra). 195Pt-NMR (DMF-d7) δ (ppm): -2165. The reaction
scheme for the synthesis of cis-Pt(NH3)(c-C6H11NH2)Cl2 via the iodo-
bridged dimer is shown in Figure 2.
Ph4P[Pt(NH3)Cl3]. cis-Pt(NH3)2Cl2 (0.5 g, 1.67 mmol) and tetra-
ethylammonium chloride (0.33 g, 2.0 mmol) were dissolved in 200
mL of dimethylacetamide and heated to 100 °C for 6 h. During this
time, a slow stream of air was bubbled through the reaction mixture.
The remaining red viscous solution (60 mL) was allowed to cool down
to room temperature. A mixture of ethyl acetate/n-hexane (450 mL,
1:1 v/v) was added slowly. An orange precipitate deposited. The
reaction mixture was allowed to stand overnight at -20 °C. A clear,
colorless solution and a thick orange oil formed. The clear solution
was discarded and the oil dissolved in 10 mL of water. The solution
trans,cis,cis-Pt(NH3)(c-C6H11NH2)Cl2(OOCH3)2 was suspended in a
phosphate buffer solution in D2O (pH* ) 6.5, c(Pt(IV)) ) 5 mM).
(15) Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.;
Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins, J. D. Inorg.
Chem. 1995, 34, 1015-1021.

cis- and trans-Platinum(II/IV) Compounds
Inorganic Chemistry, Vol. 36, No. 5, 1997 857
Table 1. Crystallographic Data for 1 (cis) and 2 (trans)
Table 2. Final Atomic Coordinates and Equivalent Isotropic
Thermal Parameters for 1 (cis) (Esds in Parentheses)
1
2
atom
x
y
z
U(eq)a, Å2
formula
space group
cryst syst
Z
a, Å
b, Å
C6H16Cl2N2Pt
Pbca (No. 61)
orthorhombic
8
10.1994(12)
10.494(2)
18.826(2)
C6H16Cl2N2Pt.C2H3N
P21/c (No. 14)
monoclinic
4
12.141(3)
6.0965(9)
19.864(3)
118.71(2)
1289.5(5)
423.25
2.180
112.7
150
0.0711
Pt(1)
Cl(1)
Cl(2)
N(1)
N(2)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
0.37197(4)
0.5450(3)
0.4236(3)
0.3290(9)
0.2201(10)
0.2728(11)
0.2724(11)
0.2241(12)
0.0853(12)
0.0797(12)
0.1324(11)
0.61706(4)
0.6407(3)
0.8032(3)
0.4457(9)
0.5961(9)
0.4516(10)
0.3212(12)
0.3295(13)
0.3825(13)
0.5089(12)
0.5021(11)
0.02213(3)
0.0994(2
0.0179(1)
0.0260(10)
0.0261(9)
0.020(3)
0.020(3)
0.018(4)
0.023(4)
0.032(5)
0.028(4)
0.029(4)
0.023(4)
-0.0358(2)
0.0707(6)
-0.0454(6)
0.1425(8)
0.1761(8)
0.2522(9)
0.2539(8)
0.2153(9)
0.1391(8)
c, Å
â, deg
V, Å3
2015.0(5)
382.19
2.520
144.0
150
0.0518
0.1143
MW
D
µ
calcd, g cm-3
calcd, cm-1
T, K
1
a U(eq) ) /3 of the trace of the orthogonalized U.
R1a
wR2b
0.1773
were corrected for Lp effects and for linear decay of 1 and 2% of the
three periodically measured reference reflections [2h1h4h, 12h3h, 23h2h] and
[21h5, 322, 402], during 6.8 and 13.8 h of X-ray exposure time. An
empirical absorption/extinction correction was applied (DIFABS18 as
implemented in PLATON,19 transmission range 0.196-1.000 and
0.151-1.000). The structure for 2 was solved by automated Patterson
methods and subsequent difference Fourier techniques (SHELXS8620).
The structure for 1 was solved by automated Patterson methods and
subsequent difference Fourier techniques (DIRDIF-9221). Refinement
on F2 was carried out by full-matrix least-squares techniques (SHELXL-
9322); no observance criterion was applied during refinement. All non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were included in the refinement on calculated positions
riding on their carrier atoms. The hydrogen atoms were refined with
a fixed isotropic thermal parameter related to the value of the equivalent
isotropic thermal parameter of their carrier atoms by a factor of 1.5 for
the methyl/NH3 hydrogen atoms and a factor 1.2 for the other hydrogen
atoms. Weights were optimized in the final refinement cycles. For 1
convergence was reached at wR2 ) 0.1143 for all 2308 unique
reflections, R1 ) 0.0518 for 1472 reflections with Fo > 4σ(Fo), w )
a R1 ) ∑||Fo| - |Fc||/∑|Fo|. b wR2 ) [∑[w(Fo2 - Fc2)2]/∑[w(Fo2)2]]1/2.
Then 2.5 equiv of 9-methylhypoxanthine was added, and the reaction
was followed in time by 1H NMR spectroscopy for 14 days. The
temperature was kept between 37 and 45 °C.
trans,cis,cis-Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2 was suspended in
D2O containing 50 mM phosphate buffer and treated with 2.5 equiv of
5′-GMP (c(Pt(IV)) ) 5 mM). The temperature was kept between 37
and 45 °C. During 14 days the course of reaction was followed by 1H
NMR spectroscopy.
Both cis,cis,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2 and trans,trans,
trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2 were suspended in separate phos-
phate buffer solutions (pH* ) 6.5, c(Pt(IV)) ) 5 mM) and treated
with 2.5 equiv of 9-methylhypoxanthine or 5′-GMP. The temperature
was kept between 37 and 45 °C, and the reaction was followed by 1H
NMR spectroscopy. Over 3 weeks, no substantial product formation
was observed.
trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2 was reacted with 5′-
GMP in the presence of glutathione (abbreviated as GSH). Two
different 1H NMR experiments were carried out. In the first experiment
(A) a suspension of the trans-Pt(IV) complex was prepared in
phosphate-buffered D2O (c(Pt(IV) ) 5 mM, pH* ) 6.5) and treated
with a D2O solution of 2 equiv of GSH and 5′-GMP. The temperature
2
1/[σ2(Fo ) + 0.0545P2], where P ) (Fo2 + 2Fc2)/3, S ) 0.977, for 101
parameters. For 2 convergence was reached at wR2 ) 0.1773 for 2941
reflections, R1 ) 0.0711 for 2654 reflections with Fo > 4σ(Fo), w )
2
2
1/[σ2(Fo ) + 0.0302P2 + 113.34P], where P ) (Fo + 2Fc2)/3, S )
1.16, for 129 parameters. Final difference Fourier maps showed no
residual density outside -1.32 and +1.38 e Å-3 and -4.26 and +4.66
e Å-3 near the heavy atom, probably due to absorption artifacts or
unresolved twinning. Positional parameters are listed in Tables 2 and
3. Neutral atom scattering factors and anomalous dispersion corrections
were taken from ref 23.
1
was kept between 37 and 45 °C, and H-NMR spectra were recorded
repeatedly over a period of 8 days. In the second experiment (B), a
suspension of the trans,trans,trans-Pt(IV) complex was reacted for 2
days with 2 equiv of GSH in a phosphate buffered solution at 40 °C.
After this period, 2 equiv of 5′-GMP was added and spectra were taken
immediately after the addition of 5′-GMP and after 4 days at 40 °C.
A suspension of trans-Pt(NH3)(c-C6H11NH2)Cl2 (5 mM) in phosphate-
buffered D2O was treated with 2 equiv of GSH. After 45 h at 40 °C,
2 equiv of 5′-GMP was added to the solution, and the reaction mixture
was stored at 40 °C for 4 days.
Crystal Structure Determinations of cis- (1) and trans-Pt(NH3)-
(c-C6H11NH2)Cl2 (2). The data on these two crystal-structure deter-
minations are given in the order 1, 2 unless specified explicitly.
Crystals suitable for X-ray determination, 0.03 × 0.15 × 0.55 mm
and 0.15 × 0.50 × 0.50 mm, respectively, were mounted on a
Lindemann-glass capillary and transferred into the cold nitrogen stream
on an Enraf-Nonius CAD4-T diffractometer with a rotating anode (Mo
KR, 0.710 73 Å, graphite monochromator). Accurate lattice parameters
were determined by least-squares treatment, using the setting angles
(SET4) of 25 and 23 reflections in the ranges 11.4° < θ < 14.0° and
10.2° < θ < 14.0°.16 Most reflection profiles are structured. The unit-
cell parameters were checked for the presence of higher lattice
symmetry.17 Crystal data and details on data collection and refinement
are presented in Table 1. Data were collected in ω/2θ mode with scan
angle ∆ω ) a + 0.35 tan θ°, where a ) 0.86 and 0.95, respectively.
Intensity data of 2651 and 4292 reflections were collected in the range
1.9° < θ < 27.5°, of which 2308 and 2947 are independent. Data
Results and Discussion
Structure of cis-Pt(NH3)(c-C6H11NH2)Cl2 (1). Figure 3
shows a labeled diagram of the structure of 1. Selected bond
distances and angles are given in Table 4. A square-planar
geometry is found for the platinum atom with angles close to
the expected values of 90 and 180°. Compared with an ideal
square-planar complex with angles of 90 and 180° of the ligands,
the angles between the halide ligand and the ammine/substituted
ammine are slightly smaller. The Pt-Cl bond distances
[2.300(3) and 2.298(3) Å] are of the expected length. The Pt-N
bond lengths [2.064(10) and 2.016(11) Å] are normal and agree
well with the published values on other mixed amine/ammine
(18) Walker, N.; Stuart, D. Acta Crystallogr., Sect. A 1983, 39, 158.
(19) Spek, A. L. Acta Crystallogr., Sect. A 1990, 46, C34.
(20) Sheldrick, G. M. SHELXS86 Program for crystal structure determi-
nation. University of Go¨ttingen, Germany 1986.
(21) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; Garc´ıa-
Granda, S.; Gould, R. O.; Smits, J. M. M.; Smykalla, C. The DIRDIF
program system. Technical report of the Crystallographic Laboratory;
University of Nijmegen: Nijmegen, The Netherlands, 1992.
(22) Sheldrick, G. M. SHELXL-93 Program for crystal structure refinement.
University of Go¨ttingen, Germany 1993.
(16) de Boer, J. L.; Duisenberg, A. J. M. Acta Crystallogr., Sect. A 1984,
40, C410.
(17) Spek, A. L. J. Appl. Crystallogr. 1988, 21, 578.
(23) Wilson, A. J. C., Ed. International Tables for Crystallography; Kluwer
Academic Publishers: Dordrecht, The Netherlands, 1992; Vol. C.

858 Inorganic Chemistry, Vol. 36, No. 5, 1997
Talman et al.
Table 3. Final Atomic Coordinates and Equivalent Isotropic
Thermal Parameters for 2 (trans) (Esds in Parentheses)
atom
x
y
z
U(eq)a, Å2
Pt(1)
Cl(1)
Cl(2)
N(1)
N(2)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
N(3)
C(7)
C(8)
0.24298(5)
0.1044(3)
0.3868(4)
0.2997(12)
0.1890(13)
0.2124(15)
0.2630(17)
0.171(2)
0.144(2)
0.095(2)
0.1869(16)
0.4034(17)
0.4653(17)
0.544(2)
0.46701(9)
0.7298(6)
0.2092(6)
0.673(2)
0.263(2)
0.692(3)
0.856(3)
0.882(3)
0.662(4)
0.501(3)
0.475(3)
0.235(3)
0.232(3)
0.226(4)
0.48009(3)
0.4740(2)
0.4895(2)
0.4199(8)
0.5413(7)
0.3379(9)
0.3012(10)
0.2154(11)
0.1740(11)
0.2116(10)
0.2983(9)
0.2079(9)
0.2720(10)
0.3552(10)
0.0129(2)
0.0182(12)
0.0201(12)
0.017(4)
0.016(3)
0.019(4)
0.023(5)
0.031(6)
0.033(6)
0.030(5)
0.021(4)
0.031(5)
0.024(5)
0.034(6)
Figure 3. Structure of cis-[Pt(NH3)(c-C6H11NH2)Cl2] (1).
1
a U(eq) ) /3 of the trace of the orthogonalized U.
Table 4. Selected Bond Distances (Å), Bond Angles (deg), and
Torsion Angles (deg) of 1 (cis) and 2 (trans)
1 (cis)
2 (trans)
Bond Distances
2.300(3)
Pt-Cl(1)
Pt-Cl(2)
Pt-N(1)
Pt-N(2)
N(1)-C(1)
2.284(4)
2.289(5)
2.067(14)
2.054(14)
1.46(2)
2.298(3)
2.064(10)
2.016(11)
1.470(18)
Figure 4. Structure of trans-[Pt(NH3)(c-C6H11NH2)Cl2]‚CH3CN (2)
Bond Angles
91.87(12)
88.7(3)
(JM-334).
Cl(1)-Pt-Cl(2)
Cl(1)-Pt-N(1)
Cl(1)-Pt-N(2)
Cl(2)-Pt-N(1)
Cl(2)-Pt-N(2)
N(1)-Pt-N(2)
Pt-N(1)-C(1)
178.18(15)
89.1(4)
91.1(4)
90.7(4)
89.1(4)
N(2)--H(2B)‚‚‚Cl(2) [-1/2 + x, 11/2 - y, -z]:
3.549(11) Å; ) 154(7)° (iii)
179.9(5)
177.6(3)
88.3(3)
91.2(4)
117.0(7)
179.2(5)
115.4(11)
Structure of trans-Pt(NH3)(c-C6H11NH2)Cl2 (2). Figure 4
shows a labeled diagram of the structure of 2. Selected bond
distances and angles are given in Table 4. Like for 1 a square-
planar geometry around the platinum atom is found with angles
even closer to the expected values of 90° and 180°. Bond
distances of Pt-Cl and Pt-N are all within the expected range.
The Pt-N distance for the ammine ligand is slightly longer in
the trans complex [2.054(14) compared with 2.016(11) Å in
the cis compound]. In addition one molecule of acetonitrile is
present in the lattice forming a hydrogen bond to an amine NH.
Torsion Angles
71.9(8)
Cl(1)-Pt-N(1)-C(1)
N(2)-Pt-N(1)-C(1)
Cl(2)-Pt-N(1)-C(1)
-75.3(11)
-108.0(8)
106.5(1)
platinum compounds.24 The NH2 moiety of the amine has an
equatorial orientation toward the ring. The C-C bond distances
of the organic ligand are normal. When this structure is
compared with the recently published structure of cyclohexyl-
ammonium chloride, the C-N distance [1.470(18) Å] in the
present Pt compound is slightly shorter than the value in
cyclohexylammonium chloride [1.510(5) Å].25 In an earlier
publication this value was found to be [1.488(8) Å].26 The
closely related Pt(IV) compound JM216 has similar Pt-N
distances [2.07 Å] and Pt-Cl distances [2.31 Å], but the
N-Pt-N angle in JM216 is larger [94.3(4)°].3
N(2)--H(2C)‚‚‚N(3) [1/2 - x, -y, 1/2 + z]: 3.07(2) Å;
) 160(8)°
Other hydrogen bonding interactions are listed as follows:
N(1)--H(1A)‚‚‚Cl(2) [x, y + 1, z]: 3.509 (13) Å;
) 166.2(17)° (ia)
Intermolecular hydrogen bonds from NH to Cl play a
significant role in the packing of this compound, as follows:
N(1)--H(1B)‚‚‚Cl(2) [x + 1, 11/2 - y, 11/2 + z]:
3.415 (17) Å; ) 130.8(13)° (iia)
N(1)--H(1A)‚‚‚Cl(2) [1/2 - x, 1/2 + y, z]: 3.591(10) Å;
) 171.2(10)° (i)
N(2)--H(2A)‚‚‚Cl(1) [x, y - 1, z]: 3.477 (13) Å;
) 164(5)° (iiia)
N(2)--H(2A)‚‚‚Cl(1) [-1/2 + x, 11/2 - y, -z]:
3.443(10) Å; ) 134(4)° (ii)
N(2)--H(2B)‚‚‚Cl(1) [x + 1, 11/2 - y, 11/2 + z]:
3.427 (18) Å; ) 140(6)° (iv)
These hydrogen bonding interactions are all intermolecular as
expected. No intramolecular hydrogen bonds are observed in
this case.
Reactions of cis- (1) and trans-[Pt(NH3)(c-C6H11NH2)Cl2]
(2) with 9-Methylhypoxanthine. During the reaction of 2 and
9-methylhypoxanthine the pH was found to remain constant.
(24) (a) Dion, C.; Beauchamp, A. L.; Rochon, F. D.; Melanson, R. Acta
Crystallogr., Sect. C 1989, 45, 852-856. (b) Rochon, F. D.; Melanson,
R. Acta Crystallogr., Sect. C 1986, 42, 1291-1294.
(25) Smith, H. W.; Mastropaolo, D.; Camerman, A.; Camerman, N. J.
Chem. Crystallogr. 1994, 24, 239-242.
(26) Rao, S. T.; Sundaralingam, M. Acta Crystallogr., Sect. B 1969, 25,
2509.

cis- and trans-Platinum(II/IV) Compounds
Inorganic Chemistry, Vol. 36, No. 5, 1997 859
Table 5. Products of Reactions of cis- and trans-[Pt(NH3)-
(c-C6H11NH2)Cl2] with 9-Methylhypoxanthine and Chemical Shifts
of Base Protons
Table 6. Products of Reactions of cis- and trans-[Pt(NH3)-
(c-C6H11NH2)Cl2] with 5′-GMP, Chemical Shift of H8, and
Coupling Constant of H1′ to H2′ (pH* ) 6)
δ(H2), δ(H8),
pH* ppm ppm
δ(H8), 3J(H1′-H2′),
compound
compound
ppm
Hz
9-mehyp
6
8.05 8.19
5′-GMP
8.16
6.1
trans-[Pt(NH3)(c-C6H11NH2)(9-mehyp-N7)(H2O)]2+
trans-[Pt(NH3)(c-C6H11NH2)(9-mehyp-N7)2]2+
trans-[Pt(NH3)(c-C6H11NH2)(9-mehyp-N7)Cl]+
6
6
6
8.32 8.64
8.35 8.86
8.31 8.69
trans-[Pt(NH3)(c-C6H11NH2)(GMP-N7)2]2+
trans-[Pt(NH3)(c-C6H11NH2)(GMP-N7)Cl]+
8.92
8.82
5.7
5.7
5.7
trans-[Pt(NH3)(c-C6H11NH2)(GMP-N7)(H2O)]2+ 8.76
cis-[Pt(NH3)(c-C6H11NH2)(GMP-N7)2]2+
cis-[Pt(NH3)(c-C6H11NH2)(GMP-N7)X]+
8.56, 8.53
8.53, 8.52
2.6, 2.2
4
cis-[Pt(NH3)(c-C6H11NH2)Cl2]with 9-mehyp, species A 5.8 8.29 8.53
cis-[Pt(NH3)(c-C6H11NH2)Cl2]with 9-mehyp, species B 5.8 8.27 8.49
cis-[Pt(NH3)(c-C6H11NH2)Cl2]with 9-mehyp, species C 5.8 8.26 8.39
cis-[Pt(NH3)(c-C6H11NH2)Cl2]with 9-mehyp, species D 5.8 8.30 8.59
H2/H8 region emerged. The 1H NMR results are listed in Table
5. The four products are denoted as A, B, C, and D. During
these measurements no considerable pH drop was observed, and
therefore the possibility of N1 coordination has been ruled out.
The pH dependence of the H2 and H8 signals of the products
shows the same behavior as is the case for the products of the
trans isomer. Therefore, it was concluded that in the observed
products N7 coordination occurs. The assignment of an
evolving signal to a particular species formed during the course
of reaction was not possible for the majority of signals. The
assignment of the H2/H8 signals, however, was possible by
carrying out deuteration experiments. Because of their similar
behavior in pH-titration experiments, products B and C have
tentatively been identified as the 1:2 complex, whereas product
A is assigned to the 1:1 aqua adduct. The signals of this product
increased first and then decreased during the reaction. Product
D is always present in trace amounts during the reaction and,
therefore, could well be the 1:1 chloro adduct. 1H NMR spectra
recorded at 288 K and 333 K indicate that rotation about the
Pt-N7 bond is still possible.
Reactions of cis- (1) and trans-[Pt(NH3)(c-C6H11NH2)Cl2]
(2) with 5′-GMP. 1H NMR was used to monitor the reactions
of both 1 and 2 with 5′-GMP. New signals appearing in the
H8 and H1′ region of the spectra after 2 h (the reaction was
essentially complete after 8 days), besides those of the free
nucleotide, indicate that Pt-GMP adducts are formed. Upon
reaction with 2, one signal occurs at 8.82 ppm after 2 h at 37
°C. Upon further reaction a second signal at 8.92 ppm appears.
The intensity of that second signal rises during the course of
the reaction and was found to be higher than the intensity of
the first detected signal after 23 h, strongly suggesting that the
first signal is the signal of a monosubstituted complex, whereas
the second signal is the signal of a bis(nucleotide) complex
formed when the reaction continues. The majority of the
observed signals are summarized in Table 6. Tentative assign-
ments are based on results obtained by Marcelis et al. with
transplatin.30 A 195Pt NMR recorded at the end of the reaction
showed one signal at δ ) -2474 ppm, indicating a PtN4
coordination sphere around the Pt and in agreement with results
obtained by Miller and Marzilli.28 The H1′ doublet of the sugar
residue in the 1:2 complex shows a vicinal coupling constant
of 5.7 Hz, which is negligibly lower than that of free 5′-GMP
(6 Hz). Compared with transplatin this value was found to be
0.7 Hz higher in the 1:2 complex trans-Pt(NH3)2(5′-GMP-N7)2
at the same pH.
The subsequent formation of two products was observed.
Initially, one molecule of 9-methylhypoxanthine coordinates via
N7 which results in the major intermediate product [Pt(NH3)(c-
C6H11NH2)(9-methylhypoxanthine-N7)(H2O)]2+. A second sig-
nal appears more downfield with respect to the 1:1 complex
after 40 h. This signal has been assigned as the 1:2 complex
[Pt(NH3)(c-C6H11NH2)(9-methylhypoxanthine-N7)2]2+. NMR
data are listed in Table 5. When carried out between 37 and
45 °C, this reaction was found to be complete within 8 days,
whereas at room temperature it was not found to be complete
after 1 month. The main reason for this difference in reactivity
is the low solubility of the starting material at room temperature.
Signals at δ ) 8.69 (H8) and 8.31 (H2) ppm, only observed in
the experiment at room temperature, were assigned to [Pt-
(NH3)(c-C6H11NH2)(9-methylhypoxanthine-N7)Cl]+. These sig-
nals disappeared when small amounts of AgNO3 were added
to the solution. A 195Pt NMR recorded at the end of the reaction
showed only one signal at δ ) -2449 ppm, indicative of a
PtN4 coordination sphere.27 This chemical shift is in excellent
agreement with results obtained for a platinum coordinated to
two ammine and two purine(N7) ligands.28 Measurements of
the pH dependence of H8 and H2 signals proves that platinum
coordinates to 9-methylhypoxanthine at N7 in both the mono
adduct and the bis adduct. The H8 signal of uncoordinated
9-methylhypoxanthine shows a large downfield shift upon
lowering the pH* below 2. This is the result of protonation of
N7. The shift of H2 is smaller. At pH* ) 9.5 a small upfield
shift occurs for both H8 and H2 because of deprotonation of
N1. In the products there is no shift seen below pH* ) 2. This
indicates that platinum is coordinating at N7, preventing
protonation at this site. Platinum coordination at N7 also results
in the well-known lowering of the pKa of the N1 deprotonation
by approximately 1.5 pK units.29
The reaction of 1 with 9-methylhypoxanthine would be
expected to yield a more complex spectrum of reaction products,
due to its lower symmetry. Two different monosubstitution
products are expected, depending on whether the incoming
9-methylhypoxanthine ligand will occupy the trans position with
respect to either the ammine or the cyclohexylamine ligand.
For the disubstituted product, two H2 and two H8 signals are
expected, because of the nonequivalence of the 9-methylhy-
poxanthine ligand trans to the ammine and the cyclohexylamine
ligand. Indeed, upon reaction with 1 eight new signals in the
The reaction of 1 yields mainly two products. After 2 h one
small doublet signal is detected in the aromatic region of the
1H NMR. Upon further reaction two new signals form
gradually, whereas the former doublet signal disappears. The
two new signals maintain identical intensities during the
reaction. The reaction of 1 with 5′-GMP was found complete
(27) (a) James, D. W.; Nolan, M. J. J. Raman Spectrosc. 1973, 1, 271-
284. (b) Adams, D. M.; Chandler, P. J. J. Chem. Soc. 1967, 1009. (c)
Faggiani, R.; Howard-Lock, H. E.; Lock, C. J. L.; Lippert, B.;
Rosenberg, B. Can. J. Chem. 1982, 60, 529-534. (d) Kuroda, R.;
Neidle, S.; Ismail, M. I.; Sadler, P. J. Inorg. Chem. 1983, 22, 3620.
(28) Miller, S. K.; Marzilli, L. G. Inorg. Chem. 1985, 24, 2421-2425.
(29) (a) den Hartog, J. H. J.; Salm, M. L.; Reedijk, J. Inorg. Chem. 1984,
23, 2001-2005. (b) Marcelis, A. T. M.; Korte, H. J. K.; Krebs, B.;
Reedijk, J. Inorg. Chem. 1982, 21, 4059-4063. (c) van der Veer, J.
L.; Ligtvoet, G. J.; Reedijk, J. J. Inorg. Biochem. 1987, 29, 217-
213.
(30) Marcelis, A. T. M.; van Kralingen, C. G.; Reedijk, J. J. Inorg. Biochem.
1980, 13, 213-222.

860 Inorganic Chemistry, Vol. 36, No. 5, 1997
Talman et al.
Table 7. Products of Reactions of Pt(IV) Complexes with
9-Methylhypoxanthine and 5′-GMP, Chemical Shifts of H2 and H8,
and Coupling Constant of H1′ to H2′ (pH* ) 6.5)
9-methylhypoxanthine, two signals at δ ) 2.10 and 2.02 ppm
were detected which were assigned to the methyl group of the
acetate ligand. Upon reaction, the latter signal increased in
intensity, but no characteristic Pt(IV) satellites were observed.
The H8 signals of the two products, A and B, exhibit no
coupling with platinum either. This strongly suggests that
reduction of platinum(IV) to platinum(II) has occurred.35
During the reaction of trans,cis,cis-Pt(NH3)(c-C6H11NH2)-
Cl2(OOCCH3)2 with 5′-GMP, a second signal in the H8 region
of 5′-GMP was observed after 141 h, which was shifted
downfield with respect to that of free 5′-GMP. The signal
increased during the experiment and showed no Pt(IV) satellites,
suggesting that reduction to platinum(II) has occurred here as
well. Table 7 gives a listing of selected 1H NMR shifts. Similar
to the reaction with 9-methylhypoxanthine, two signals were
observed for the acetate ligand at δ ) 2.10 ppm, and 1.92 ppm
indicating that two different kinds of acetate species are present
in solution. The H1′ doublet of the sugar residue in platinated
product A shows a vicinal coupling of 5.9 Hz, suggesting that
the equilibrium between N- and S-type sugar-ring conformation
remains almost unchanged upon platination.
So, the platinum(IV) complex trans,cis,cis-Pt(NH3)(c-C6H11-
NH2)Cl2(OOCCH3)2 reacts with 9-methylhypoxanthine and 5′-
GMP to yield mainly one product. It appears that these products
contain ligands coordinated to Pt(II) via the N7 positions. The
absence of 1H-195Pt(IV) couplings suggests that a reduction of
Pt(IV) to Pt(II) has occurred, although no unambiguous assign-
ment of the product is possible.
cis,cis,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2 and its all trans
analogue do not react under the conditions described above (pH*
) 6.5, T ) 37-45 °C, t ) 14 days), neither with 9-methylhy-
poxanthine nor with 5′-GMP. Therefore, it was decided to
perform this reaction in the presence of a cellular reducing agent.
Reactions of trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2-
(OH)2 with 5′-GMP in the Presence of GSH. The reaction
of trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2(OH)2 with 2 equiv
of GSH and 2 equiv of 5′-GMP was carried out in two different
ways. In the first experiment (A) the Pt(IV) solution was treated
with a solution containing both the glutathione and the 5′-GMP.
In the second experiment (B), the Pt(IV) solution was first
treated with glutathione, and after 2 days, 2 equiv of 5′-GMP
was added.
During both reactions the cystein-âCH2 signals change from
a multiplet at 2.96 ppm to two multiplets at 2.96 and 3.32 ppm.
This is the result of the oxidation of GSH to GSSG by Pt(IV).
However, in a solution of equimolar amounts of 5′-GMP and
GSH oxidation of GSH was observed as well. Therefore, this
experiment was repeated under argon atmosphere: no change
in the NMR spectra was seen in a period of over one month.
Experiment A was also repeated under argon atmosphere. The
spectra were very similar to the ones obtained when dioxygen
was not excluded. It is clear that the reduction of Pt(IV) by
GSH is not influenced by the presence of dioxygen from the
air.
In experiment A two new signals in the H8 region are
observed at 8.90 and 8.87 ppm. These increase with respect to
the H8 of unreacted 5′-GMP during the reaction. On raising
the temperature the two H8 signals merge, indicating that the
two peaks belong to rotamers from the same product and that
rotation about the Pt-N7 bond is hindered at low temperature.
δ(H2), δ(H8), 3J(H1′-H2′),
compound
ppm ppm
Hz
t,c,c-[Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2 8.37 8.87
with 9-mehyp, product A
t,c,c-[Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2 8.35 8.86
with 9-mehyp, product B
t,c,c-[Pt(NH3)(c-C6H11NH2)Cl2(OOCCH3)2
with 5′-GMP, product A
8.89
5.9
after 8 days at 37 °C. Two signals are observed in the 1H NMR
spectrum of the final reaction mixture. It appears that these
signals originate from the bis(nucleotide) complex cis-Pt-
(NH3)(c-C6H11NH2)(5′-GMP-N7)2 because of the nonequiva-
lence of the H8 signals. Unfortunately, 195Pt NMR measure-
ments failed due to the poor solubility of the products. When
the pH was lowered below 6, a white precipitate formed and
the intensity of the signals of the bis(nucleotide) complex
decreased. In fact, Chu and co-workers observed a similar effect
when cisplatin was reacted with 5′-GMP.31 Spectra recorded
at 288 and 330 K showed no remarkable changes, and hence,
no evidence for diastereoisomers was found. The results are
included in Table 6. Platinum coordination to nucleotides is
known to cause a change in the sugar-ring conformation from
S-type (C2′-endo) to N-type (C3′-endo), which results in a
change of the H1′-H2′ coupling constant.32 The H1′ doublet
of the sugar residue in the assumed 1:2 complex shows a vicinal
coupling constant 3J(H1′-H2′) ) 2.6 and 2.2 Hz, whereas the
corresponding value for free 5′-GMP was found to be 6.0 Hz.
Compared to the corresponding trans isomer, the decrease
observed for the cis isomer is more remarkable. In the 1:2
complex both H8 signals should have the same intensity. In
the recorded spectra, this was not the case. This might be due
to a possible overlap with signals from 1:1 complexes but can
also be caused by a difference in H/D exchange rate.
The pH dependence of the chemical shift of the H8 protons
in the reaction mixtures confirms that in the case of the cis, as
well as the trans isomer, N7 coordination of 5′-GMP occurs.
An increase in chemical shift for H8 around pH* 2, as observed
for protonation of N7 in free 5′-GMP (pKa of N7 ) 2.5) is not
found in the reaction products because N7 is platinated and no
longer accessible to protonation.33 Moreover, the H8 resonance
is shifted to a lower field in the pH region around 6, because of
5′-phospate deprotonation (pKa ) 6.2) and shifted again to
higher field around pH 9, where N1 is deprotonated (pKa )
9.5).
Reaction of trans,cis,cis-Pt(NH3)(c-C6H11NH2)Cl2(OOCH3)2
with 9-Methylhypoxanthine and 5′-GMP. Upon reaction of
trans,cis,cis-Pt(NH3)(c-C6H11NH2)Cl2(OOCH3)2 with 2.5 equiv
of 9-methylhypoxanthine at 37 °C, pH ) 6.5, substantial product
formation was observed after 70 h. Two new signals are
observed for the H8 protons at δ ) 8.87 and 8.86 ppm. The
intensity of the latter increases with the reaction time. The
reaction was stopped after 14 days, because the gradual
deuterium exchange on H8 reduced signal intensity.34 Table 7
1
gives a listing of the H NMR data.
Interestingly, 1H NMR data of the starting material could not
be obtained due to its poor solubility. Upon reaction with
(31) Chu, G. Y. H.; Mansy, S.; Duncan, R. E.; Tobias, R. S. J. Am. Chem.
Soc. 1978, 100, 593-606.
(32) Okamoto, K.; Behnam, V.; Phan Viet, M. T.; Polissiou, M.; Gauthier,
J.-Y.; Hanessian, S.; Theophanides, T. Inorg. Chim. Acta 1986, 123,
L3.
(33) Dijt, F. J.; Canters, G. W.; den Hartog, J. H. J.; Marcelis, A. T. M.;
Reedijk, J. J. Am. Chem. Soc. 1984, 106, 3644.
(34) Girault, G. P. Biochem. Biophys. Res. Commun. 1982, 109, 1157.
(35) (a) Roat, R. M.; Reedijk, J. J. Inorg. Biochem. 1993, 52, 263-274.
(b) van der Veer, J. L.; Ligtvoet, G. J.; Reedijk, J. J. Inorg. Biochem.
1987, 29, 217-223. (c) van der Veer, J. L.; Peters, A. R.; Reedijk, J.
J. Inorg. Biochem. 1986, 26, 137-142. (d) Kuroda, R.; Ismail, I. M.;
Sadler, P. J. J. Inorg. Biochem. 1984, 22, 103.

cis- and trans-Platinum(II/IV) Compounds
Inorganic Chemistry, Vol. 36, No. 5, 1997 861
unknown, species is formed, which behaves differently in the
reaction with 5′-GMP (experiment B).
It is clear that glutathione facilitates the reaction of the Pt(IV)
compound with GMP and that it does so by reducing the
platinum center to Pt(II).
Concluding Remarks
The crystal structures of cis-Pt(NH3)(c-C6H11NH2)Cl2 and
trans-Pt(NH3)(c-C6H11NH2)Cl2 show square planar geometry
with normal Pt-N and Pt-Cl bond lengths. The reactions of
these Pt compounds with 9-methylhypoxanthine and 5′-GMP
yield N7 coordinated adducts. The final product is [Pt(NH3)(c-
C6H11NH2)(nucleobase-N7)2]2+, as expected. We have also
been able to show that the new Pt compounds trans-Pt(NH3)(c-
C6H11NH2)Cl2 and the Pt(IV) analogues with additional acetate
or hydroxy ligands yield quite similar 5′-GMP adducts. How-
ever, in the case of trans,trans,trans-Pt(NH3)(c-C6H11NH2)Cl2-
(OH)2 a coreducing agent, like glutathione, is required. Further
experiments are required to elucidate the pathways by which
glutathione is facilitating the reaction of these types of Pt(IV)
compounds.
Figure 5. Likely product from the reaction of trans-[Pt(NH3)(c-C6H11-
NH2)Cl2] and 5′-GMP in the presence of GSH, experiment A.
In experiment B new signals in the H8 region are observed at
8.81 and 8.69 ppm. This reaction proceeds much slower than
in experiment A.
For comparison, trans-Pt(NH3)(c-C6H11NH2)Cl2 was treated
in the same way as the Pt(IV) complex in experiment B
described above. In this case, new signals in the H8 region
appeared at 8.91 and 8.88 ppm, suggesting that in this
experiment the same product is formed as in experiment A
described above. The H8 signal of these reaction products, as
well as that from experiment A, lies in the range expected for
a disubstitution product of trans-Pt(NH3)(c-C6H11NH2)Cl2 and
5′-GMP, as shown above. However, contrary to experiment
A, no hindered rotation was observed, suggesting the formation
of a Pt(II) complex with two GMP ligands. As an explanation
for the observed NMR data in experiment A a Pt(II) complex
with one GMP and one GS- ligand, as is depicted in Figure 3,
is a likely possibility.
Acknowledgment. The authors wish to thank Johnson &
Matthey (Reading, U.K.) for their generous loan of K2PtCl4 and
for a gift of the compounds JM-334 and JM-335. Financial
support by the European Union, allowing regular exchange of
preliminary results with several European colleagues, under
Contracts ERBCHRXCT920016 and COST D1/92/0002 is
thankfully acknowledged. The authors are indebted to the EU
for a grant as Host Institute in the EU Programme Human
Capital and Mobility (1994-1997). This work has been
performed under the auspices of the joint BIOMAC Research
Graduate School of Leiden University and Delft University of
Technology. W.B. thanks ERASMUS for a student exchange
fellowship (from Dortmund). This work was supported in part
(A.L.S. and N.V.) by the Netherlands Foundation of Chemical
Research (SON) with financial aid from the Netherlands
Organization for Scientific Research (NWO).
Unfortunately the structure of the products in experiment B
could not be elucidated from the NMR data. From the
downfield shift of the H8 signals, however, it is very likely
that GMP is platinated at the N7 position.
Supporting Information Available: Figures showing the pH
dependence of the products of the reactions of 1 and 2 with
9-methylhypoxathine and tables of crystallographic data for the
compounds 1 and 2 (9 pages). Ordering information is given on any
current masthead page.
Comparing experiment A and B one can conclude that GSH
reacts with Pt(IV) compounds in at least two steps. At least
one reactive intermediate is present, which after reaction with
5′-GMP yields the complex depicted in Figure 5. When GSH
is allowed to complete its reaction with Pt(IV) another, as yet
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