Reactions with Biomolecules Other Than DNA

Substitution of aqua ligands by nitrogen donors such as the nucleic acid bases leads to mono- and disubstituted complexes whose properties, of course, have been extensively studied (Chapter 4). Once inside the cell, however, only a small proportion of the platinum is complexed to the DNA. Metabolism of the platinum complexes therefore takes place with other biomolecules besides DNA. Amino acid reactions may take place which may sequester the complex. Further, in the case of substitution by nucleophiles with strong tram influence, especially those of sulfur, displacement of amine and deactivation may occur. Interestingly, amine labilization tram to a thioether in d5-[Pt(NH3)2(Me2S)2] has been observed [107]. In vivo, thioethers such as methionine could effect the same chemistry and the characterization of [Pt(methionine)2], assigned the structure as shown, as a metabolite of cisplatin [108] confirms this view  

This is evidence that amine loss can result in detoxification and the role of this reaction in nephrotoxicity is implicated but unclear. Certainly, the strong affinity of sulfur for platinum makes this reaction a feasible one. Indeed, platinum complexes such as K2PtCl4 and [PtCl2(am)2] have been used as heavy metal markers in protein crystallography and some of these uses have been tabulated [91]. 

A general role for a thiol reaction with platinum complexes as deactivation cannot at present be stated, although tissue binding involving sulfhydryl groups is well documented and biochemical aspects have been discussed (Chapter 2.4). The reactions of Pt complexes with methionine 

As stated, sulfur nucleophiles are expected to labilize amines in a tram position and the isolation of the platinum—methionine metabolite is further evidence that these reactions occur in vivo. Evidence for amine displacement, even of chelated ethylenediamine, has also been obtained from solution studies with methionine-containing peptides and RNase A [117]. In connection with these results the dissociation of doubly labelled [PtCl2(en)] (on the Pt and C) in vivo has been confirmed, negating earlier results [118]. 

although the chemistry of [PtCl2am2] will be dictated by the formation of reactive species through chloride loss, many deactivating reactions are possible with intracellular nucleophiles, before reaction with cellular targets. The intracellular concentration of phosphates, for example, has recently been claimed to be sufficient to displace chloride also 

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