Kinetics and Mechanism of the Complexation of trans-Diamminedichloroplatinum(II) with the Purine Nucleoside Inosine in Aqueous Solution

Abstract

Kinetics of the complexation of truns-[PtClz(NH3)~] (l), and its hydrolysis products trans-[PtCl(NH3)z(H~O)]+ (2) and rruns-[Pt(NH3)z(H~O)~l~+ (31, with the purine nucleoside inosine (L) has been studied by HPLC in aqueous solution at 318.2 K (pH = 2.8-3.4, I = 0.1 M). The relative ability of 1-3 to bind inosine is about 1:200:10 as given by the second-order rate constants k3 = (6.5 f 0.4) x M-l s-l (l), l~ = 1.4 f 0.1 M-' s-l (2), and k5 = (6.6 f 0.6) x M-' s-l (3). An excess of ligand gives stepwise formation of the 1:2 complex. When [L] < 0.02 M, hydrolysis of the first chloro ligand (kl = (1.05 f 0.03) x loW3 s-l) is the rate-limiting step in the binding of inosine to 1 as well as to the 1:l complex (4), in which the fourth ligand is C1-(k = (9.4 f 0.7) x s-l). In higher ligand concentration direct substitution of C1-becomes significant both in 1 and 4; the second-order rate constant for the latter is k7 = (8 f 1) x M-I s-l. Under acidic conditions aquation of 2 is very slow (k2 = (4 f 2) x s-l) and strongly reversible. In basic solution (pH > ll), instead, hydrolysis of 2 is irreversible ( k z ,~~ = (2 f 0.2) x s-l). Competition of inosine and C1-for 2 and 3 was employed to study the C1-anation of aquated Pt(II) species. The second-order rate constants are k-1 = 2.2 f 0.4 M-' s-l for 2 and k-2 = 0.20 f 0.02 M-' s-l for 3. Thus, the equilibrium constants for the stepwise hydrolysis of 1 are K1 = (4.8 f 1.2) x M. The rate constant for the chloride anation of the 1:l complex (5) bearing HzO as the fourth ligand is k-6 = 0.62 f 0.12 M-' s-l, which gives the equilibrium constant K6 = (1.5 & 0.5) x M for the reaction between 4 and 5. The second-order rate constant for the conversion of 5 into the 1:2 complex (6) is kg = 0.35 f 0.03 M-' s-l. Comparison of the kinetic data obtainedto those of the cis isomer reveals considerable differences in the hydrolysis reactions and in the formation of monofunctional adducts. In particular, the properties of the diaqua species differ markedly. By contrast, the second complexation step appears to be kinetically similar in both configurations.M and KZ = (1.8 f 0.8) x

Hydrolysis Triggers Oxidation of a trans Diamine Platinum(II) Anticancer Complex

“…This has indeed been reported to be the case. [14,16,19,20] In fact, it is very difficult to remove the second Cl À ligand from trans-…”

“…[13,19] [21] To investigate whether the presence of air influences the course of the hydrolysis reactions of 1, aqua adducts were prepared by treating [ 15 NH 3 ]1 with 0.95 mol equivalents of AgNO 3 under argon. In the absence of air, no 1 H NMR signals were observed in the d = 5.2-6.5 ppm region of the 1D 1 H (Figure 1 d).…”

Facile Preparation of PtII-Nucleobase Monoadducts with trans Geometry: Structural Characterization and Kinetics for Cl− Hydrolysis Reactions of trans-[PtCl(NH3)2(L-N7)]n+ (L=9-Methyladenine or 9-Methylhypoxanthine)

“…[18] In the case of 6-oxopurines, further electron removal from the 6-membered ring may be due to the electron-withdrawing effect of the oxo group, in line with the extended hydrogen-bond network involving this group as described above. [6,19] which complicates the kinetic measurements. This can be avoided by studying hydrolysis under basic conditions, since deprotonation of the aqua ligand yields a hydroxo group which, relative to the aqua ligand, can be considered inert to substitution reactions.…”

“…, namely (9.4 AE 0.7) Â 10 À5 s À1 at 318.2 K. [6] Thus, deprotonation of the N1H in the 6-oxopurine moiety does not significantly affect the Cl À hydrolysis rate in trans-Pt II complexes, although increased electron density of the heteroaromatic ring due to the proton loss [cf. the upfield shift of C(8)] might have been anticipated to strengthen the trans effect of the N7 site and result in faster Cl À hydrolysis.…”

“…[5] In particular, the first hydrolysis step is highly reversible, [6] which may result in severe problems in the preparation of 1:1 adducts with nucleobases due to the insolubility of the dichloro species. Therefore, it is not surprising that only a limited number of nucleobase monoadducts with different trans-Pt II compounds have been characterized by X-ray crystallography.…”