Cisplatin activation reactions

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... 

Figure 1. Activation reactions for the anticancer drugs cyclophosphamide and cisplatin.

The determination of Au and Au isotopes in fallout samples produced in the Au(n, 2n) Au and Au(n, y) Au neutron activation reactions has been described . Fallout samples containing neutron activated nuclides and actinides have been collected with polyperchloroethylene filters. Counting procedures showed the concentrations of Au to be 0.24-0.42 ngg in tumour-type tissues . 1,2-Diarylethylenediamine Pt complexes have been examined by determining via NAA the content of platinum in tumour tissue and in the different organs of mice. The measurements of the induced radioactivity of Au served as indications of the Pt concentration . The contribution of this type of radiation is given. Irradiated platinum has been purified from Au by extraction from acidic solutions with ethyl acetate . The distribution of cis-dichlorodiamine platinum ( cisplatin ) in various organs of mice has been determined . 

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. 

On the basis of the calculations presented here, especially considering the relative stability of the reactant and product complexes, it is clear that the form of activated cisplatin that partakes in subsequent reactions will be highly dependent on the composition of the environment in which it acts this explains, to some extent, the disparate conclusions of the experimental work [53, 54]. 

Fig. 4.8 The first substitution reactions between activated cisplatin and adenine.

Glutathione readily replaces the GSMe on platinum in the reaction with [Pt(dien)(GSMe)]2+ (GSMe = S-methylglutathione) - this system is claimed to be an effective model for cisplatin-protein interaction 224). Rate constants and activation parameters have been... 

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... 

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