Aquation cisplatin

As mentioned above, results from kinetic experiments [53, 54, 62] are inconclusive about the state of activated cisplatin, and have under some experimental conditions (chloride-depleted environment) revealed the most probable state of activated cisplatin to be the mono-aquated form, cis-Pt[Cl][NH3]2[H20]+. The first aquation reaction has been determined to be approximately two orders of magnitude faster than the second. This opinion is far from undisputed, however, and results from other experiments, based on the ratio of the amounts of DNA adducts formed by the different aquated cisplatin moieties [54], strongly indicates that the likely state of cisplatin binding to DNA is in fact the diaquated state. 

Figure 4 Hydrolysis scheme for cisplatin-based anticancer agents. Where L = U = NH3 cisplatin is indicated. When L = NH3 and V = 2-picoline or cha the rates of aquation of the trans-chloride ligands are different.

Fig. 4.6 Optimised structures of the second aquation reaction of cisplatin. Both RC2 and RC2a t converge to the same transition struc-... 

Fig. 4.7 Reaction energy surfaces for the first and second aquation reactions of cisplatin starting from (a) the syn arrangement of the initial reactant complex and (b) the...

Two examples of aquation/anation studies of chloro-platinum(II) complexes of possible medical relevance appeared in subsection 1 above 202,207). Aquation of cisplatin is slower in the presence of DNA but not in the presence of phosphate 220). DNA also inhibits substitution in [Pt(terpy)(py)]2+ and related complexes. For reaction of these charged complexes with iodide ion inhibition is attributable to electrostatic interactions - the complex is concentrated on the double helix and thus separated from the iodide, which distances itself from the helix. Intercalation of these complexes within the helix also serves to make nucleophilic approach by neutral reagents such as thiourea more difficult 221). 

It has been postulated that carboplatin and its analogs act as prodrugs, reacting with chloride in plasma to give cisplatin. However, the rate of aquation of carboplatin is too slow to account for its in vivo activity (half-life 11 days in water), and the reactions of carboplatin with phosphate, chloride, or water are slower than direct reactions... 

The crystal structure of the sodium salt of 30 (NAMI) is shown in Fig. 9, where Na(I) bridges two molecules of 30 via oxygens of S-bound DMSO and water. This complex may be readily reduced in vivo (E1/2, -0.001 V) (166), whereas the bis-imidazole complex 28 has a lower redox potential and is more difficult to reduce. The reduction potential of 28 is strongly pH dependent (AE = —118 mV/pH unit near pH 7), reduction being more favorable at acidic pH values (167). This complex hydrolyses at a similar rate to cisplatin (ty ca. 3 h at 310 K) and, like cis-platin, aquation appears to be necessary for DNA binding (168). 

Fig. 11.23. Aquation of cisplatin (11.174) to the cationic monoaqua and dicationic diaqua species, and ionization equilibria of these species...

Aquation is a significant activation reaction, since the monoaqua and diaqua species are 10 - 70 times more reactive toward nucleophiles than cisplatin itself [187]. In fact, the monoaqua species is considered to be the most... 

So, in aqueous solution cisplatin will loose Cl-, and an aqua or/and hydroxo (at high pH) ligand becomes coordinated. In the body, the Cl- concentration outside cells is rather high (about 100 mM), and therefore hydrolysis is largely prevented there. Inside cells, however, the Cl- concentration is about 4 mM, promoting the hydrolysis process. According to calculations by Martin35), the aquated species in the body fluids is present only for a few percent, whereas it amounts to about 50% of the total present inside the cell. 

Interpretation of pharmacokinetic data is also complicated by biotransformation processes. Cisplatin is metabolized to various aquated species and in the low-chloride intracellular environment these predominate. Plati-num(IV) compounds are converted rapidly to platinum(II) derivatives in plasma, and multiple distinct circulating molecular species may be produced [223], While some HPLC assays may distinguish among metabolites, sensitivity often limits resolution of the various molecular species. Pharmacokinetic data should be interpreted accordingly. Recently it has been possible... 

The aquation-anation and acid-base equilibria of cisplatin, as well as its dimerization reaction, are presented in Scheme 1. It is also noteworthy that proton exchange occurs on the ammine ligands [9]. 

Scheme 1. Aquation-Anation, Acid-Base Equilibria and Dimerization Reaction of Cisplatin...

The chloromonoadducts are unstable in aqueous solution and lead to intra and/or interstrand diadducts after aquation of the chloride ligand (vide infra). They can also cross-link DNA to proteins either directly or after aquation [25]. The half-life of the monoadducts formed from cisplatin and PtCl(R2-en) (with R2-en = rac-(lS,2S,4.S )-e-W-2-amino-2-(aminomethyl)-7-oxabicyclo[2.2.1]heptane) on DNA at 310K are 2 h 40 30 min and 8 h 20 20 min [49], respectively, a rather long time on the scale of cellular processing . 

Scheme 2. Mechanism of Formation of Cisplatin-DNA Adducts. kx, k2, k3 are aquation-rate constants (fcj and k2 are in Scheme l).kpl and kp2 are platination-rate constants, kc is the chelation-rate constant.

Following activation via intracellular aquation reactions, cisplatin forms a variety of stable bifunctional adducts with DNA, as depicted in Figure 3. Cisplatin mainly forms 1,2-intrastrand cross-links on adjacent purine bases. It has been found that 60-65% of the platinum bound to DNA is in the form of l,2-d(GG) intrastrand cross-links and 20-25% in intrastrand l,2-d(AG) cross-links. Other adducts formed are the l,3-d(GXG) and l,4-d(GXXG) cross-links, accounting for at most 6%. Only a small percentage of cisplatin (1.5%) was found to be involved in interstrand adducts. It remains... 

It is well documented that the aquated form of cisplatin localizes within the mitochondria, and that the inhibition of respiration and spontaneous release of calcium ions into the... 

Leeuwenkamp OR, van der Vijgh WJ, Neijt JP, Pmedo HM. Reaction kinetics of cisplatin and its mono-aquated species with the (potential) renal protecting agents (di)mesna and thiosulfate. Estimation of the effect of protectmg agents on the plasma and peritoneal AUCs of CDDP. Cancer Chemother Pharmacol 1990 27(2) 111-14. 

Prior hydration with hypertonic salt seems to reduce cisplatin-induced acute renal failure [42]. As previous studies indicated that the degree of azotemia produced by cisplatin was highly dependent on the sodium chloride content of the vehicle used for its administration [42] it has been suggested that the increase in chloride concentration in the urine that occurs after hypertonic salt infusion may reduce the conversion of cisplatin to toxic aquated metabolites, a process known to be sensitive to Cl ion concentration. 

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