BI~INORGANIC
CHEMISTRY
6,83-89
(1976)
83
Reactions between Nucleosides and Platinum Dimethylsulfoxide Complexes PI-CHANG KONG, DANIEL IYAMUREMYE Dgpartement de chimie, Universiti Quibec, Canada, H3C 3P8
AND FERNANDE
du QuGbec 2 MontGal.
D; ROCHON
C. P. SS’SS, Mont&al,
ABSTRACT Nucleosides (Nut) react with cis-[Pt(DMSO),Cl,] in dimethysulfoxide (DMSO) solution, to produce trans-[Pt(DMSO)(Nuc)C1, 1, which then isomerize to ck-[Pt@MSO)(Nuc)Cl,]. They also displace chlorine from K[Pt@MSO)Cl, ] in water to form trans-[Pt(DMSO)(Nuc)Cl, 1. KjPt(inosine) CI, ] and DMSO give in water cis-[ Pt(DhfSO)(Inosine)C1, ] . The configuration assignment of the compounds was based on chemical reactions, NMR techniques, analytical results, conductivity measurements and comparison with pyridine analogues. Chemical shifts in NMR and coupling constants of the aromatic protons of the nucleosides with 195Pt were used for the assignment of the binding sites of the nucleosides.
INTRODUCTION Recently, we have been interested in platinum complexes of nucleosides [l-3] and nucleotides [4]. The synthesis of characterized compounds as well as solution studies may be helpful in understanding variations in the antitumor activities of the platinum compounds [5,6]. Nuclear magnetic resonance has been a very successful technique for the elucidation of the structures of these complexes 17 ] _ Dimethylsulphoxide (DMSO) has often been selected as solvent for the NMR studies, since the nucleosides have adequate solubilities in DMSO without any proton transfer [8] _ In the present study, we have chosen to study by NMR, the reactions in DMSO between nucleosides and cis-[Pt(DMSO)aCla]. The latter was chosen partry because DMSO has been used as solvent for testing the antitumor activity of some platinum compounds and partly because it has some common features with cis-[Pt(NHs)aClz] a potent antitumor compound, both having two chlorine atoms and two neutral ligands in cis-positions. Although the preliminary results of the tumour test for cis-[Pt(DMSO)aCl~] were not promising [VI, it is still interesting to compare the reaction mechanism of the two platinum complexes with nucleosides. The binding sites of the nucleosides in the reaction products are-also worth investigating. @American Elsevier Publishing Company, hrc., 1976
84
PICHANG
KONG et al.
In order to facilitate the configuration assignment of the platinum complexes in DMSO solution, compounds from the reactions between K[Pt(DMSO)Cls J and nucleosides in water, were also studiedEXPERIMENTAL
SECTION
Preparation: cis-Dichlorobis(dimethylsulphoxide)platinum(II), cis-IPt(DMSO)sCIs J was prepared from the reaction between KzPtC14 and aqueous dimethylsulphoxide by the method of Wayland ef a2. [IO] Potassium trichloro(dimethylsuiphoxide)platmate(II), K[Pt(DMSO)Cls 1, WAS prepared by one of the three methods reported by Kukushkin J I I I, namely, the reaction between equixnoIar amounts of K,PtCI, and dimethylsulphoxide. This method was recommended by Romeo and Tobe [ 12Jcis-Dichloro(guanosie)(dimethyisuIphoxide)plat~um(~I). OS mmole amounts of cis-CPt(DMSO), CI, I and guanosine were dissolved in 4 ml of DMSO. The solution was left at .room temperature for three days. A 1: 1 mixture of alcohol and petroleum ether (30-60”) was added and a white precipitate appeared immediately_ The precipitate was filtered off after cooling overnight in a refrigerator, washed with alcohol and dried. Calcd. C23.49, H:3.10, N:9.14; Found. C123.23, H:3.24, N:9.50.
Instruments: NMR spectra were obtained on a Perkin-Elmer R-12 Spectrometer. Infrared spectra were measured with a Perk&Elmer 621 grating spectrophotometer. Conductivities were measured with a Radiometer, Copenhagen, Type CDM2C.
RESULTS AND DISCUSSION Pt( DiMSO)* Cl, was prepared from the reaction between KaPtC4 and dimethylsuiphoxide in water. X-ray diffraction studies in our laboratories of the compound have shown that it has the &s-configuration and is sulphur bonded to the platinum atom (131. NMR studies have also shown that cis-[Pt(NHs)a (DMSO)s J(C104)2 in DMSO is sulphur bonded [ 141. Kukushkin el al. J15) attempted, without success, to prepare platinum compounds containing three or four DMSO molecules by dissolving fPt(DMSO)a Cl2 I in DMSO. After evaporating the soIvent, the initial compound was found unchanged_ It is therefore reasonable to consider cis-[Pt(DMSO)pClz J as the predominant species in DMSO sohition. We have measured its conductivity in DMSO and found no dissociation
REACTIONS
BETWEEN NUCLEOSIDES
AND COMPLEXES
85
of the Pt-Cl bond_ It seems unlikely that it would associate to form the chlorine bridged dimer [Pt(DMSO)Clz 1t and liberate DMSO, a strong ligand for platinum_ The reactions between nucleosides and cis-[Pt(DMSO)zClz 1 were studied in DMSO solution_ Conductivity measurements have shown that there were no chlorine displacements when the nucleosides are added to a DMSO solution of the platinum complex_ The NMR spectra of the product formed, have shown that each platinum atom is coordinated with just one molecule of nucleosides, even when the nucleosides are added in excess. The spectra have also shown that two kinds of nucleoside complexes are consecutively formed. The final products were isolated and the experimental formula for the guanosine complex was Pt(DMSO)(Guo)Clz _ The two consecutive complexes formed in the reaction are the trans and the cis isomers. Before discussing the configuration of the trans and cis isomers, it would be helpful to mention some notable features of some pyridine analogues which were well characterized_ Two isomers of pyridine complexes were obtained by Kukushkin [ 111 from the following reactions in water: K[Pt(DMSO)Cla K[PtPyC13]
] + Py + trans-[Pt(DMSO)PyCIz
i- DMSO + cis-[Pt(DMSO)PyCl,
] + KC1
1 + KC1
The assignment of the configuration was based on chemical evidence assuming a high trans-effect for sulphur-bonded DMSO. The assumption was confirmed by ] (Zpic = X-my diffraction studies of cis- and trans-[Pt(DMSO)(Zpic)Clz 2-picohne = o-CHsCs Hq N), which have shown that DMSO is sulphur bonded to the platinum atom [ 161. Cis- and trans-[Pt(DMSO)(4pic)Cla ] were chosen as models of nucleoside complexes for NMR studies. The 2- and 6-proton signals of picoline in the trans isomer are in a field -25 ppm higher than in the cis isomer. We have also found that a 1: 1 molar ratio of cis-Pt(DMSO)zClz ] and 4picoline dissolved in DMSO, form the trans-isomer trans-[Pt(DMS0)(4pic)Cls ] which then isomerize to the &-form. Both isomers were isolated by adding suitable solvents as diluenfs for the DMSO solution [ 171. The above findings were used as criteria to assign the configuration of the nucleoside complexes. As already mentioned, when the nucleosides are added to a DMSO solution of ci.+[Pt(DMSO)zCla 1 two consecutive isomers are formed. The NMR spectrum of compound (I) which is formed first, showed a downfield shift of the Ha signal with a coupling constant Jpt_~, of about 20 Hz (Table 1 and Fig. 1). After twenty minutes of mixing, compound (II) started to show a Ha signal in a region lower than compound (I). The intensity of this signal gradually increased until the reaction was complete. Coupling constants were then measured (Table 2 and Fig. 1). The large shift as weIl as the coupling constants of the Ha signal indicated that in both compounds (I) and (II) Ha is the dosest to the binding site, ie. NT I1,21 (Fig 2). Therefore the nucleoside in compound (I) and (II) is bonded to platinum through NT_ By analogy to the picoline compounds, compound (I) with the Ha signal in a higher field is the trans-isomer and compound (II) is the cis-isomer. Therefore, cis-[Pt(DMSO)zClz] reacts with
86
PI-CHANG
KONG et al.
TABLE 1 NMR Spectra of the Nucleosides and the trans-tPt(D~SOXNuc)Cl~
Compounds Inosine (Ino) Pt(DMSO)(Ino)Cla Xanthosine (Xao) Pt(DMSO)(Xao)Cla Guanosine (Guo) Pt(DMSO)(Guo)Ci2
H8
8.45 9.13 8.02 8.70 8.06 8.77
H2
8.18 8.35 -
HI’
6.00 6.03 5.85 5.90 5.80 5.90
Complexes=
NrH
NH2
‘R-H,
12.53 11.04 11.38 10.84 11.27
6.55 6.90
20 20 20
%pectra were taken within twenty minutes of mixing cis-[Pt@MSO),C1, ] and the nudeoside in DMSO_ Chemicalshifts in s(ppm) and coupling constant in Hz_ TMS used as standard. nucleosides in DMSO solution to produce trans-_[Pt(DMSO)(Nuc)Cla] which then isomerize to cis-[Pt~DMSO)(Nuc)C12 ] _ -Further evidence for the above assignments was obtained from the reactions in water of K[Pt(DMSO)&] with inosine and of K[Pt(Ino)Cla] which was recently prepared in our laboratory [3], with DMSO. The product obtained
from the former reaction should be the trans-isomer and the product
from the
latter reaction should be the cis-isomer according to Kukushkin’s reasoning [ 1 1 ] _ Both reactions gave yellow sohrtions rather than immediate precipitates which allowed us to carry out NMR studies As expected, the signal of Ha in the trans.-compound is in a higher fieId than in the c&compound (Table 3). The trans-compound of guanosine, isolated from water, isomerized in DMSO to the c&form TABLE 2 NMR Spectra of the Nucleosides and the cis-[Pt(DMSO)(Nuc)C12
Compounds
H8
H2
HI’
] Complexesa
NrH
NH2
‘P&H,
Inosine (Ino)
8-45
8.18
6.00
-
-
-
Pt(DMSO)(Ino)Cla
9.38 9-40
8.50
6.12
13.36
-
26
Xanthosine (Xao)
8.02
-
5.85
11-04
-
-
Pt(DMSO)(Xao)C12
8.81 8.85
-
5.98
11.50
-
26
Guanosine (Guo)
8.06
-
5-80
lo-84
6.55
-
Pt(DMSO)(Guo)Cla
8.92
-
5-92
11.52
7-00
26
OSpectrawere taken after 24 hrs. of mixing cis-[Pt(DMSO),C~] and l Je nucleosidein DklSO- Chemicalshifts in S(ppm) and couplingconstantsin HZ_This IIS& a~ standard.
REACTIONS
BETWEEN
NUCLEOSIDES
AND COMPLEXES
87
11
10
9
0
7
6
11
10
9
8
7
6
b
C -a*
I?.
11
10
8
7
6
FIG. 1. (a) free guanosine in DMSO; (b) guanosine and cis-Pt(DMSO),Cl, in DMSO, three species can be observed, free guanosine, tram- and c&-P~(DMSO)(GUO)C&; (c) cis-Pt@MSO)(Guo)Cl, . The signals of Ha in the cis-compounds of Ino and Xao (Tables 2 and 3) are split into two by l-3 Hz- This is probably because the rotations around the Pt-S bond in the c&compounds is hindered by the nucleoside ligands and there could be two different conformations of the molecule. NMR studies of some alkyl sulphoxide complexes of Pt(I1) and Pd(iI), have shown preferred conformations of the sulphoxide molecules in the complexes [ 18]_ The displacement of the two cis-chlorine atoms is required for the antitumor activity in this type of platinum complexes [5,6,19]. Exceptions are the blue Pt-complexes which can be prepared from the diaquo species of cis-[Pt(NHa)a Cl, I and uridine_ The structure of these complexes are uncertain at the moment
PICHANG
88
KONG
et aL
dH
i)H
XrH=lnosine X=NH2= Guanosine X=OH=Xanthosine FIG. 2. Structuresof cis-Pt@MSO) (Nut)
cl,.
[20] _ When cis-[Pt(DMSOk Cl2 I reacts with nucleosides, a molecule cf DMSO is displaced instead of’the chlorine atoms as in the reaction of cis-[Pt(NH3)+Clz J with nucleosides- Thus it appears that cis-[Pt(DMSO)2C12] should not be an antitumor compound. This finding might be relevant to a recent report that c%[Pt(DMSO), Cl, J had no response on Sarcoma 180 [9]_ The authors
are grateful
to
the
financial support and to Johnron potassium chloroplatinite.
National
Matthey
Research
Council
& Co_ Limited
of
for
Canada
the
TABLE 3 NMR Spectra of the Nucleosida and Their Complexes in Water’ Compounds
Ht?
Inosine (Ino) Trans-[Pt(DMSO)(Ino)Cl2 K[Pt(Ino)C13 1 Cis-[Pt(DMSO)(Ino)Clz Trans-[Pt(DMSO)(Xao)C12 Trans-[Pt(DMSO)(GuojC12
]
] ] ]
H2
HI’
JPt-H,
8.50
8.37
6.20
-
8.95 8.94
8.43 8.50
6.30 6.30
20 24
9.11 9.14
8.55
6.30
26
6.00 6.10
20 20
8.58 8.53
-
for
loan of
aTrans-compounds obtained from the reactions between K[Pt(DMSO) Cl31 and nudeosides Cis~mpounds obtained from the reactiohbetween KfPt(InoQ] and DMSO. Spectra were taken within 30 min after mixing- DSS used 35standard_
REACTIONS
BETWEEN
NUCLEOSIDES
AND
89
COMPLEXES
REFERENCES 1. 2. 3. 4. 5. 6. 7.
P. C. Kongand T. Theophanldes,lnorg C/rem 13,1167 (1974). P. C. Kong and T. Theophankles, Inorg Chem 13,198l (1974). P. C. Kong and F. D. Rochon, 1. C S. them Comm 599 (1975). P. C. Kong and T. Theophanides, Bioinorg. Chem 5,51(1975). B. Rosenberg, Phfinum Metals Rev. 15,42 (1971). M. J. CJeare, Coo& them Rev. 12,349 (1974). G. L. Bichhom, Inorganic Biochemistry (G- L Eicbbom, Ed-) Ebevier
Amsterdam,
(1973) chapter 33. 8. J. P. Kokko, J. H. Goldstein, and L Mandell,J..Amer. Chem Sot. 83,2909 (1961). 9. M. J. Cleare and J. D. Hoeschele, Bioinorg. Chem 2, 187 (1973). 10. J. H. Price, A. N. Williamson, R F. Scbramm, and B. B. Wayland, Inorg Chem 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
11,
1280 (1972). Yu. N. Kukushkin,Y. E. Vyazmenskli, and L. I. Zorina, Russ. J. Inorg. Chem 13,1573 (1968). R- Romeo and M. L Tobe, Ino= Chem 13,199l (1974). R. Melanson and F. D. pochon, Can J. Chem 53,237l (1975). S. Thomas and W- L Reynolds, Inorg Chem 8,1531
CHEMISTRY
6,83-89
(1976)
83
Reactions between Nucleosides and Platinum Dimethylsulfoxide Complexes PI-CHANG KONG, DANIEL IYAMUREMYE Dgpartement de chimie, Universiti Quibec, Canada, H3C 3P8
AND FERNANDE
du QuGbec 2 MontGal.
D; ROCHON
C. P. SS’SS, Mont&al,
ABSTRACT Nucleosides (Nut) react with cis-[Pt(DMSO),Cl,] in dimethysulfoxide (DMSO) solution, to produce trans-[Pt(DMSO)(Nuc)C1, 1, which then isomerize to ck-[Pt@MSO)(Nuc)Cl,]. They also displace chlorine from K[Pt@MSO)Cl, ] in water to form trans-[Pt(DMSO)(Nuc)Cl, 1. KjPt(inosine) CI, ] and DMSO give in water cis-[ Pt(DhfSO)(Inosine)C1, ] . The configuration assignment of the compounds was based on chemical reactions, NMR techniques, analytical results, conductivity measurements and comparison with pyridine analogues. Chemical shifts in NMR and coupling constants of the aromatic protons of the nucleosides with 195Pt were used for the assignment of the binding sites of the nucleosides.
INTRODUCTION Recently, we have been interested in platinum complexes of nucleosides [l-3] and nucleotides [4]. The synthesis of characterized compounds as well as solution studies may be helpful in understanding variations in the antitumor activities of the platinum compounds [5,6]. Nuclear magnetic resonance has been a very successful technique for the elucidation of the structures of these complexes 17 ] _ Dimethylsulphoxide (DMSO) has often been selected as solvent for the NMR studies, since the nucleosides have adequate solubilities in DMSO without any proton transfer [8] _ In the present study, we have chosen to study by NMR, the reactions in DMSO between nucleosides and cis-[Pt(DMSO)aCla]. The latter was chosen partry because DMSO has been used as solvent for testing the antitumor activity of some platinum compounds and partly because it has some common features with cis-[Pt(NHs)aClz] a potent antitumor compound, both having two chlorine atoms and two neutral ligands in cis-positions. Although the preliminary results of the tumour test for cis-[Pt(DMSO)aCl~] were not promising [VI, it is still interesting to compare the reaction mechanism of the two platinum complexes with nucleosides. The binding sites of the nucleosides in the reaction products are-also worth investigating. @American Elsevier Publishing Company, hrc., 1976
84
PICHANG
KONG et al.
In order to facilitate the configuration assignment of the platinum complexes in DMSO solution, compounds from the reactions between K[Pt(DMSO)Cls J and nucleosides in water, were also studiedEXPERIMENTAL
SECTION
Preparation: cis-Dichlorobis(dimethylsulphoxide)platinum(II), cis-IPt(DMSO)sCIs J was prepared from the reaction between KzPtC14 and aqueous dimethylsulphoxide by the method of Wayland ef a2. [IO] Potassium trichloro(dimethylsuiphoxide)platmate(II), K[Pt(DMSO)Cls 1, WAS prepared by one of the three methods reported by Kukushkin J I I I, namely, the reaction between equixnoIar amounts of K,PtCI, and dimethylsulphoxide. This method was recommended by Romeo and Tobe [ 12Jcis-Dichloro(guanosie)(dimethyisuIphoxide)plat~um(~I). OS mmole amounts of cis-CPt(DMSO), CI, I and guanosine were dissolved in 4 ml of DMSO. The solution was left at .room temperature for three days. A 1: 1 mixture of alcohol and petroleum ether (30-60”) was added and a white precipitate appeared immediately_ The precipitate was filtered off after cooling overnight in a refrigerator, washed with alcohol and dried. Calcd. C23.49, H:3.10, N:9.14; Found. C123.23, H:3.24, N:9.50.
Instruments: NMR spectra were obtained on a Perkin-Elmer R-12 Spectrometer. Infrared spectra were measured with a Perk&Elmer 621 grating spectrophotometer. Conductivities were measured with a Radiometer, Copenhagen, Type CDM2C.
RESULTS AND DISCUSSION Pt( DiMSO)* Cl, was prepared from the reaction between KaPtC4 and dimethylsuiphoxide in water. X-ray diffraction studies in our laboratories of the compound have shown that it has the &s-configuration and is sulphur bonded to the platinum atom (131. NMR studies have also shown that cis-[Pt(NHs)a (DMSO)s J(C104)2 in DMSO is sulphur bonded [ 141. Kukushkin el al. J15) attempted, without success, to prepare platinum compounds containing three or four DMSO molecules by dissolving fPt(DMSO)a Cl2 I in DMSO. After evaporating the soIvent, the initial compound was found unchanged_ It is therefore reasonable to consider cis-[Pt(DMSO)pClz J as the predominant species in DMSO sohition. We have measured its conductivity in DMSO and found no dissociation
REACTIONS
BETWEEN NUCLEOSIDES
AND COMPLEXES
85
of the Pt-Cl bond_ It seems unlikely that it would associate to form the chlorine bridged dimer [Pt(DMSO)Clz 1t and liberate DMSO, a strong ligand for platinum_ The reactions between nucleosides and cis-[Pt(DMSO)zClz 1 were studied in DMSO solution_ Conductivity measurements have shown that there were no chlorine displacements when the nucleosides are added to a DMSO solution of the platinum complex_ The NMR spectra of the product formed, have shown that each platinum atom is coordinated with just one molecule of nucleosides, even when the nucleosides are added in excess. The spectra have also shown that two kinds of nucleoside complexes are consecutively formed. The final products were isolated and the experimental formula for the guanosine complex was Pt(DMSO)(Guo)Clz _ The two consecutive complexes formed in the reaction are the trans and the cis isomers. Before discussing the configuration of the trans and cis isomers, it would be helpful to mention some notable features of some pyridine analogues which were well characterized_ Two isomers of pyridine complexes were obtained by Kukushkin [ 111 from the following reactions in water: K[Pt(DMSO)Cla K[PtPyC13]
] + Py + trans-[Pt(DMSO)PyCIz
i- DMSO + cis-[Pt(DMSO)PyCl,
] + KC1
1 + KC1
The assignment of the configuration was based on chemical evidence assuming a high trans-effect for sulphur-bonded DMSO. The assumption was confirmed by ] (Zpic = X-my diffraction studies of cis- and trans-[Pt(DMSO)(Zpic)Clz 2-picohne = o-CHsCs Hq N), which have shown that DMSO is sulphur bonded to the platinum atom [ 161. Cis- and trans-[Pt(DMSO)(4pic)Cla ] were chosen as models of nucleoside complexes for NMR studies. The 2- and 6-proton signals of picoline in the trans isomer are in a field -25 ppm higher than in the cis isomer. We have also found that a 1: 1 molar ratio of cis-Pt(DMSO)zClz ] and 4picoline dissolved in DMSO, form the trans-isomer trans-[Pt(DMS0)(4pic)Cls ] which then isomerize to the &-form. Both isomers were isolated by adding suitable solvents as diluenfs for the DMSO solution [ 171. The above findings were used as criteria to assign the configuration of the nucleoside complexes. As already mentioned, when the nucleosides are added to a DMSO solution of ci.+[Pt(DMSO)zCla 1 two consecutive isomers are formed. The NMR spectrum of compound (I) which is formed first, showed a downfield shift of the Ha signal with a coupling constant Jpt_~, of about 20 Hz (Table 1 and Fig. 1). After twenty minutes of mixing, compound (II) started to show a Ha signal in a region lower than compound (I). The intensity of this signal gradually increased until the reaction was complete. Coupling constants were then measured (Table 2 and Fig. 1). The large shift as weIl as the coupling constants of the Ha signal indicated that in both compounds (I) and (II) Ha is the dosest to the binding site, ie. NT I1,21 (Fig 2). Therefore the nucleoside in compound (I) and (II) is bonded to platinum through NT_ By analogy to the picoline compounds, compound (I) with the Ha signal in a higher field is the trans-isomer and compound (II) is the cis-isomer. Therefore, cis-[Pt(DMSO)zClz] reacts with
86
PI-CHANG
KONG et al.
TABLE 1 NMR Spectra of the Nucleosides and the trans-tPt(D~SOXNuc)Cl~
Compounds Inosine (Ino) Pt(DMSO)(Ino)Cla Xanthosine (Xao) Pt(DMSO)(Xao)Cla Guanosine (Guo) Pt(DMSO)(Guo)Ci2
H8
8.45 9.13 8.02 8.70 8.06 8.77
H2
8.18 8.35 -
HI’
6.00 6.03 5.85 5.90 5.80 5.90
Complexes=
NrH
NH2
‘R-H,
12.53 11.04 11.38 10.84 11.27
6.55 6.90
20 20 20
%pectra were taken within twenty minutes of mixing cis-[Pt@MSO),C1, ] and the nudeoside in DMSO_ Chemicalshifts in s(ppm) and coupling constant in Hz_ TMS used as standard. nucleosides in DMSO solution to produce trans-_[Pt(DMSO)(Nuc)Cla] which then isomerize to cis-[Pt~DMSO)(Nuc)C12 ] _ -Further evidence for the above assignments was obtained from the reactions in water of K[Pt(DMSO)&] with inosine and of K[Pt(Ino)Cla] which was recently prepared in our laboratory [3], with DMSO. The product obtained
from the former reaction should be the trans-isomer and the product
from the
latter reaction should be the cis-isomer according to Kukushkin’s reasoning [ 1 1 ] _ Both reactions gave yellow sohrtions rather than immediate precipitates which allowed us to carry out NMR studies As expected, the signal of Ha in the trans.-compound is in a higher fieId than in the c&compound (Table 3). The trans-compound of guanosine, isolated from water, isomerized in DMSO to the c&form TABLE 2 NMR Spectra of the Nucleosides and the cis-[Pt(DMSO)(Nuc)C12
Compounds
H8
H2
HI’
] Complexesa
NrH
NH2
‘P&H,
Inosine (Ino)
8-45
8.18
6.00
-
-
-
Pt(DMSO)(Ino)Cla
9.38 9-40
8.50
6.12
13.36
-
26
Xanthosine (Xao)
8.02
-
5.85
11-04
-
-
Pt(DMSO)(Xao)C12
8.81 8.85
-
5.98
11.50
-
26
Guanosine (Guo)
8.06
-
5-80
lo-84
6.55
-
Pt(DMSO)(Guo)Cla
8.92
-
5-92
11.52
7-00
26
OSpectrawere taken after 24 hrs. of mixing cis-[Pt(DMSO),C~] and l Je nucleosidein DklSO- Chemicalshifts in S(ppm) and couplingconstantsin HZ_This IIS& a~ standard.
REACTIONS
BETWEEN
NUCLEOSIDES
AND COMPLEXES
87
11
10
9
0
7
6
11
10
9
8
7
6
b
C -a*
I?.
11
10
8
7
6
FIG. 1. (a) free guanosine in DMSO; (b) guanosine and cis-Pt(DMSO),Cl, in DMSO, three species can be observed, free guanosine, tram- and c&-P~(DMSO)(GUO)C&; (c) cis-Pt@MSO)(Guo)Cl, . The signals of Ha in the cis-compounds of Ino and Xao (Tables 2 and 3) are split into two by l-3 Hz- This is probably because the rotations around the Pt-S bond in the c&compounds is hindered by the nucleoside ligands and there could be two different conformations of the molecule. NMR studies of some alkyl sulphoxide complexes of Pt(I1) and Pd(iI), have shown preferred conformations of the sulphoxide molecules in the complexes [ 18]_ The displacement of the two cis-chlorine atoms is required for the antitumor activity in this type of platinum complexes [5,6,19]. Exceptions are the blue Pt-complexes which can be prepared from the diaquo species of cis-[Pt(NHa)a Cl, I and uridine_ The structure of these complexes are uncertain at the moment
PICHANG
88
KONG
et aL
dH
i)H
XrH=lnosine X=NH2= Guanosine X=OH=Xanthosine FIG. 2. Structuresof cis-Pt@MSO) (Nut)
cl,.
[20] _ When cis-[Pt(DMSOk Cl2 I reacts with nucleosides, a molecule cf DMSO is displaced instead of’the chlorine atoms as in the reaction of cis-[Pt(NH3)+Clz J with nucleosides- Thus it appears that cis-[Pt(DMSO)2C12] should not be an antitumor compound. This finding might be relevant to a recent report that c%[Pt(DMSO), Cl, J had no response on Sarcoma 180 [9]_ The authors
are grateful
to
the
financial support and to Johnron potassium chloroplatinite.
National
Matthey
Research
Council
& Co_ Limited
of
for
Canada
the
TABLE 3 NMR Spectra of the Nucleosida and Their Complexes in Water’ Compounds
Ht?
Inosine (Ino) Trans-[Pt(DMSO)(Ino)Cl2 K[Pt(Ino)C13 1 Cis-[Pt(DMSO)(Ino)Clz Trans-[Pt(DMSO)(Xao)C12 Trans-[Pt(DMSO)(GuojC12
]
] ] ]
H2
HI’
JPt-H,
8.50
8.37
6.20
-
8.95 8.94
8.43 8.50
6.30 6.30
20 24
9.11 9.14
8.55
6.30
26
6.00 6.10
20 20
8.58 8.53
-
for
loan of
aTrans-compounds obtained from the reactions between K[Pt(DMSO) Cl31 and nudeosides Cis~mpounds obtained from the reactiohbetween KfPt(InoQ] and DMSO. Spectra were taken within 30 min after mixing- DSS used 35standard_
REACTIONS
BETWEEN
NUCLEOSIDES
AND
89
COMPLEXES
REFERENCES 1. 2. 3. 4. 5. 6. 7.
P. C. Kongand T. Theophanldes,lnorg C/rem 13,1167 (1974). P. C. Kong and T. Theophankles, Inorg Chem 13,198l (1974). P. C. Kong and F. D. Rochon, 1. C S. them Comm 599 (1975). P. C. Kong and T. Theophanides, Bioinorg. Chem 5,51(1975). B. Rosenberg, Phfinum Metals Rev. 15,42 (1971). M. J. CJeare, Coo& them Rev. 12,349 (1974). G. L. Bichhom, Inorganic Biochemistry (G- L Eicbbom, Ed-) Ebevier
Amsterdam,
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