Znorg. zyxwvuts Chem. zyxwvu 1991, 30, 201-206 201 Contribution from the Department of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box zyxwv 9502, 2300 RA Leiden, The Netherlands Reaction Products of [Pt( ethylenediamine)(dimethyl sulfoxide)C1]C1 and zyx [Pt(ethylenediamine)C12] with d(GpG) and S’GMP. Unambiguous Evidence for Stable 1:l Intermediate N7 Adducts with Coordinated Dimethyl Sulfoxide Edwin L. M. Lempers, Marieke J. Bloemink, and Jan Reedijk* Received March zyxwvutsrqp 16, 1990 The reactions of [Pt(en)(Me,SO)CI]CI, [Pt(en)(Me2SO)(D20)](N03)z, [Pt(en)CI,], and [Pt(en)(D20)21(N03)2 with d(GpG) and with S’GMP have been investigated by ‘H magnetic resonance spectroscopy (en = ethylenediamine;Me2S0 = dimethyl sulfoxide). [Pt(en)(Me,SO)X] (X = D20,CI-) and S’GMP form an intermediate product [Pt(en)(Me2SO)(5’GMP-N7)] (l), which consists of two rotamers la and lb, the interconversion of which is slow on the NMR time scale at 294 K. The ratio 1a:lb shifts from 2.0 at pH 5 to 1.2 at pH 11, as a result of the dehydronation at the guanine NI atom. 1 may react further with a second equivalent of S’GMP, forming [Pt(en)(S’GMP-N7),] (2) and free Me2S0. When reacted with d(GpG). [Pt(en)(Mc,SO)X] (X = D20,CI-) forms two intermediate products [Pt(en)(MezSO)(d(GpG)-N7(2))] (5) and [Pt(en)(Me,SO)(d(GpG)-N7(2))] (6) with a ratio of 7030. Both 5 and 6 react further, each forming the chelate [Pt(en)(d(GpG)-N7(Z),N7(2))] (7) and free MQSO. Both 5 and 6 consist of two rotamers (Sa,b 6a,b), the interconversion of which occurs at an intermediate rate on the NMR time scale at 294 K. Also, [Pt(en)Xz] (X = D20, CI-) reacts with S’GMP and d(GpG), forming respectively 2 and 7. For the corresponding 1: 1 intermediates [Pt(en)(DzO)(5’GMP-N7)] (3), [Pt(en)CI(S’GMP-N7)] (4), [Pt(en)CI(d(GpG)-NI(Z))] (8), and [Pt(en)Cl(d(GpG)-N7(2))] (9), no rotamers were found at room temperature, which is rationalized by the smaller size of CI- and D20 compared to Me2S0. The overall reactions of [Pt(en)Cl,J with the guanine fragments are about a factor of 4-5 faster, compared to those of [Pt(en)(Me,SO)CI]CI. These results indicate that for [Pt(en)(Me#O)CI]Cl similar DNA adducts are formed as compared to the case of the well-known antitumor-active agents, like [ C ~ ~ - P ~ ( N H ~ ) ~ C I ~ ] , and therefore the mechanism of action of both types of compounds might well be related to each other. Introduction Most platinum antitumor complexes obey the general formula [ci~-Pt(Am)~X~] (Am is an amine ligand with at least one N H group, and X is a moderately strongly bound anionic leaving group such as chloride).’J The bifunctional nature is probably necessary to form an intrastrand cross-link between two adjacent guanine bases in the However, recently two cationic classes of platinum complexes with antitumor properties were described, which are much more soluble in water than the neutral complexes; they have the general formulas [cis-Pt(NHJ2(N-het)C1]C1 (N-het is a heterocyclic amine like pyridine) and [P“diam)(R’R’’SO)- CI](NO,) (diam is a bidentate amine and R’”’S0 is a substituted ~ulfoxide).~~ On the other hand, related monofunctional cationic complexes like [Pt(dien)Cl]Cl and [Pt(NH,)$l]Cl are antitumor inactive.’** Therefore, the mechanism of action of these new compounds is unlikely to be the same as that of [cis-Pt(Am)?X2]. In vivo activation of both compounds forming respectively [cis-Pt(NH3)(N-donor)I2+ and [Pt(diam)12+ could well explain the observed antitumor activity. However, a recent study9 in which the interactions between [cis-Pt(NH3)2(4-methylpyridine)CI]C1 and d(GpG) were investigated proved that such an activation, at least for this particular compound, is unlikely. A similar activation mechanism for [Pt(diam)(R’R’’SO)Cl](NOJ, however, is more reasonable in view of the known relatively labile sulfoxide ligand.’O Even then, there are a few possible reaction paths, as proposed by Farrell et a1.,6 i.e. (i) extracellular hydrolysis to yield [Pt- (diam)C12], which then enters the cell, like [cis-Pt(NHJ2C12], Cleare. M. J.: Hvdes. P. C.; HeDburn. D. R.; Malerbi. B. W. In Cis- platin, Curreni Status and Niw Developments; Prestayko, A. W., Crooke, S. T., Carter, S. K., Eds.; Academic Press: New York, 1980; p 149. Calvert, A. H. In Biochemical Mechanisms of Platinum Antiiumor Drugs; McBrien, D. C. H., Slater, T. F., Us.; IRL Press: Washington, DC, 1986; p 307. Reedijk, J.; Fichtinger-Schepman, A. M. J.; van Oosterom, A. T.; van de Putte, P. Siruct. Bonding (Berlin) 1987, 67, 53. Pinto, A. L.; Lippard, S. J. Biochim. Biophys. Acia 1985, 780, 167. Hollis, L. S.; Amundsen, A. R.; Stern, E. W. J. Med. Chem. 1989, 32, 128. Farrell, N.; Kiley, D. M.; Schmidt, W.; Hacker, M. P. Inorg. Chem. 1990, 29, 397. Cleare, M. J.; Hocschele, J. D. Bioinorg. Chem. 1973, 2, 187. Maquet, J. P.; Butour, J.-L. J. Nail. Cancer Imt. 1983, 70, 899. Lempers, E. L. M.; Blocmink, M. J.; Brouwer, J.; Kidani, zyxwvutsr Y.; Reedijk, J. J. Inorg. Blochem. 1990, 40, 23. Romeo, R.; Minniti, D.; Alibrandi, G.; De Cola, L.; Tobe, M. L. Inorg. Chem. 1986, 25, 1944. (ii) intracellular hydrolysis to yield the reactive diaqua species [cis-Pt(diam)(H2o),l2+,and (iii) intracellular hydrolysis to form [Pt(diam)(R’R’’SO)(H20)]2+, which reacts with DNA to give a well-defined sulfoxide-Pt-DNA intermediate with subsequent activation and displacement of sulfoxide by, most likely, a neighboring guanine base. Displacement studies as carried out by Farrell et a1.6 have pointed out that mechanism iii is most likely. Also, early replacement studies of [Pt(en)(Me2SO)C1]Cl with other ligands already pointed to a higher reactivity for C1- com- pared to Me2S0.” In the present study mechanism iii has been investigated in detail by reacting the simplest derivative, i.e. [Pt(en)(Me2SO)- ClIC1, with d(GpG) and with S’GMP and by comparing its re- 0 HZ [Pt(cn)( Me,SO)CI] + action products with those obtained from the neutral [Pt(en)C12]. By characterization of all intermediates and reaction products, we expect to obtain more insight into the mechanism of these new and intriguing antitumor-active compounds. Experimental Section Materials. d(GpG) was synthesized via an improved phasphotriester method and used as its sodium salt.12 5’-Guanosine monophosphate (S’GMP), guanosine (Guo), and ethylenediaminewere obtained from Sigma Chemicals and used without further purification. [cis-Pt- (Me2SO)2C12], [Pt(en)C12], and [ Pt(en)(H,0)2] were prepared (Me2SO)CI]CI was prepared from [~is-Pt(Me~S0)~Cl,] according to a procedure by Romeo et a1.I6 Anal. Calcd for PtC4Hl,N2Cl20S: C, from K,PtCI, according to literature procedures.I3-l5 men)- (1 1) Bonivento, M.; Cattalini, L.; Marangoni, G.; Michelon, G.; Schwab, A. P.; Tobe, M. L. Inorg. Chem. 1980, 19, 1743. (12) van der Marel, G. A.; van Boeckel, C. A. A,; Wille, G.; van Boom, J. H. Tetrahedron Lett. 1981, 3881. (13) Price, J. H.; Williamson, A. N.; Schramm, R. F.; Wayland, B. B. Inorg. Chem. 1972, 11, 1280. (14) Dhara, S. C. Indian J. Chem. 1970, 8, 193. (15) Lippert, B.; Lock, C. J. L.; Rosenberg, B.; Zvagulis, M. Inorg. Chem. 1977, 16, 1525. (16) Romeo, R.; Minniti, D.; Lanza, S.; Tok, M. L. Inorg. Chim. Acta 1977, 22, 87. 0020- 1669/9 1 / 1330-0201 $02.50/0 0 199 1 American Chemical Society