Aqueous Solution Chemistry of cis-Pt

When cis-Pt is dissolved in water, the labile chloride ions are slowly replaced by water molecules (hydrolysis) in a stepwise manner as shown in Eqs. (1)—(7) (33-35). The whole process of hydrolysis takes a few hours at 37°C. 

The relative amounts of all these Pt species vary as a function of the pH and the chloride concentration. Only platinum species with a coordinated water molecule are regarded to be reactive, because, in contrast to coordinated chloride or hydroxide, this ligand can be easily substituted by other donor molecules. Hydroxo species are formed as indicated in Eqs. (3)-(7) (34, 35), with [ds-Pt(NH3)2(OH)2] as the stable end product in basic solution (36). It should be noted, however, that this species very easily dimerizes and trimerizes at higher concentrations, producing ions such as [cis-Pt(NH3)2]2(jU.-OH)2 and [cis-Pt(NH3)2]3(ju,-OH)3, as has been proved with, e.g., 195Pt NMR spectroscopy (36a, b). Very recently, accurate pAa values have been presented for the (de)hy-dronation equilibria (36b) the pKa values have been added to Eqs. (5)—(7). Miller and House (36c) have accurately determined the kinetic parameters for the several hydrolysis reactions. They concluded that acid hydrolysis of cis-Pt in vivo is unlikely to proceed beyond [cis-Pt(NH3)2Cl(H20)]+. 

In blood plasma, the chloride ion concentration is sufficiently large (about 100 mAf) to prevent cis-Pt hydrolysis, and the neutral platinum species most likely crosses the cell membrane. Inside the cell the chloride ion concentration is much lower (about 4mM), which allows for hydrolysis (35, 37). Because water is a far better leaving group than chloride or hydroxide (38, 39), the aqua species are most likely the reactive form of cis-Pt in vivo. Thus hydrolysis is the rate-limiting step in the reaction of cis-Pt with biomolecules such as proteins, RNA, and DNA (40). 

In fact, the very recent 195Pt NMR results of Bancroft et al. (41) indicate that, in agreement with Miller and House (36c), most likely [cis-Pt(NH3)2Cl(H20)]+ is the predominant species that reacts with biomolecules (at least with DNA). Other Pt amine compounds that are antitumor active have different kinetics of the hydrolysis reactions, and usually react much slower. The second-generation drug CBDCA (Fig. 2) is known to hydrolyze (in a 1 mAf solution) with a half-life at 37°C of a few days (41a) (compared to only 1 hour for cis-Pt). 

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