KINETICS AND MECHANISM OF THE COMPLEXATION OF CIS-DIAMMINEDICHLOROPLATINUM(II) WITH THE PURINE NUCLEOSIDE INOSINE IN AQUEOUS-SOLUTION

Kinetics of the complexation of cis-Pt(NH3)2Cl2 (1), and its hydrolysis products cis-[Pt(NH3)2Cl(H2O)]+ (2) and cis-[Pt(NH3)2(H2O)2]2+ (3), with the purine nucleoside inosine (L) has been studied by HPLC in aqueous solution at 318.2 K (pH = 3.5-4.0, I = 0.1 M). The relative ability of cisplatin and its hydrolysis products to bind inosine is about 1:70:350, as given by the ratio of the second-order rate Constants k3 = (1.9 +/- 0.4) x 10(-3) M-1 s-1, k4 = 0.14 +/- 0.01 M-1 s-1, and k5 = 0.67 +/- 0.03 M-1 s-1 for compounds 1-3, respectively. Excess of ligand gives stepwise formation of the 1:2 complex. When [L] ranges from 0.002 to 0.01 M, hydrolysis of the first chloro ligand is the rate-limiting step in the binding of inosine to cisplatin (1) (k1 = (1.9 +/- 0.2) x 10(-4) s-1) as well as to the 1:1 Complex (4) (k6 = (2.1 +/- 0.1) x 10(-4) s-1), in which the fourth ligand is Cl-. Direct substitution of the chloro ligand becomes significant in higher ligand concentration ([L] > 0.01 M). By contrast, when [L] < 0.002 M second hydrolysis of 1 (k2 = (2.3 +/- 0.3) x 10(-4) s-1) competes with the formation of 4, thus giving rise to the formation of the 1:1 complex (5), which bears coordinated water molecule as the fourth ligand. The second-order rate constant for the chloride anation of 5 is k-6 = 0.75 +/- 0.07 M-1 s-1, which gives the value K6 = (2.8 +/- 0.4) x 10(-4) M for the equilibrium constant of the reaction between 4 and 5. Competition of inosine and Cl- for 2 and 3 were used to study the rate of chloride anation of aquated Pt(II) species. The second-order rate constants are k-1 = 0.060 +/- 0.015 M-1 s-1 for 2 and k-2 = 0.98 +/- 0.14 M-1 s-I for 3. Thus, the equilibrium constants for the stepwise hydrolysis of 1 are K1 = (3.2 +/- 1.5) x 10(-3) M and K2 = (2.3 +/- 0.9) X 10(-4) M. The kinetic data presented in this study are in line with the proposal that the first hydrolysis product is the active intermediate in the action of cisplatin, whereas the direct substitution of the chloro ligand as well as the role of the second hydrolysis product seem to be relative unimportant.