Platinum compounds hydrolysis

Studies of cisplatin bound to DNA have also been reported by others. Eastman111,112) has used radiolabeled PtCl2(en) to detect and quantify the adducts after enzymatic hydrolysis. Johnson113,114) has used an acid-catalyzed depurination followed by electrophoresis. Rahn115) used radiolabeled platinum compounds for detection, whereas Olinsky and Walter116) have used the SnCl2 method to quantify the amounts of the various cisplatin-DNA adducts. 

The discovery, ca. 1968, by B. Rosenberg, that the cis isomer has anti-tumor activity stimulated the synthesis and screening of over 2000 different types of complexes with different amines and anionic ligands. Platinum compounds are among the most effective medications for the treatment of advanced cancer PtCl2(NH3)2 ( Cisplatin ) is mainly used for the treatment of testicular and ovarian cancer. One of its drawbacks are the severe toxic side-effects which may be related to the facile hydrolysis of Cl ligands under physiological conditions ... 

Recent immunochemical studies have shown that antibodies against the c is-Pt(NH3)2-DNA complex formed in vitro do not recognize the platinum-DNA complex isolated from rats which have been treated with C s-DDP (64). The present results show that the platinum-DNA adducts isolated from treated bacteria and mammalian cells do not give the same electrophoresis patterns after acid hydrolysis as the corresponding adducts formed in vitro It seems that, in vivo some of the modes of fixation of platinum compounds to DNA may be different than those found in vitro. 

Other drug substances susceptible to hydrolysis include chloramphenicol, 13 chlorambucil,120 121 spirohydantoin mustard,122 alkyl halides such as clindamycin,123 azathio-prine,124 sulfides such as thimerosal,125-126 and platinum compounds such as carboplatin,127 as shown in Scheme 26. 

Scheme 26. Other drug substances that are susceptible to hydrolysis, including alkyl halides, sulfides, and platinum compounds.

The free chloride concentration inside cells is much lower (some 4 mM) and under these conditions hydrolysis of cisplatin can take place, albeit slowly. In fact the most important hydrolysis product is the [PtCl(H20)(NH3)2] cation which has a pK value of 6.5, and so above pH = 6 it starts to ionize to form [PtCl(OH)(NH3)2] The cationic Pt species with a labile aqua ligand is much more reactive than cisplatin, so the monoaqua species is most likely to react with DNA and other molecules in the cell. Carboplatin hydrolyses much slower, and far less is known in this case. Studies of this type for oxaliplatin, are also still lacking. Transport of platinum compounds through the nuclear membrane is also hardly studied. Whether a special nuclear localizing signal peptides (NLS) may play a role remains uncertain... 

Alkenes are reduced by addition of H2 in the presence of a catalyst such as platinum or palladium to yield alkanes, a process called catalytic hydrogenation. Alkenes are also oxidized by reaction with a peroxyacid to give epoxides, which can be converted into lTans-l,2-diols by acid-catalyzed epoxide hydrolysis. The corresponding cis-l,2-diols can be made directly from alkenes by hydroxylation with 0s04. Alkenes can also be cleaved to produce carbonyl compounds by reaction with ozone, followed by reduction with zinc metal. 

To investigate the kinetics in more detail, the reaction rates of a simple pair of model compounds, [Pt(dien)X] [(X = Cl-, H2O) with GSH, GS-Me and 5 -GMP have been investigated and compared (164). The reaction products with GSH and GS-Me are shown in Fig. 10 an overview of the reactions between [Pt(dien)Cl] and GSH is presented in Scheme 2. These products are the first well-identified complexes between S-containing biomolecules and platinum amine compounds (130) and therefore are ideally suited as model compounds for kinetic studies. The results of the reactions are summarized in Table IV. In agreement with the above-mentioned hypothesis, the chloride hydrolysis is the rate-determining step in the reaction of [Pt(dien)Cl]+ with 5-GMP,... 

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