GoldIII complexes

Gold(III) is harder than gold(I) and generally prefers hard donor atoms such as nitrogen, oxygen and carbon. Four-coordinate Au(III) compounds exist in square-planar geometries and in this regard, resemble cisplatin. Gold(III) is an oxidizing species and so might be considered unstable in the reducing mammalian environment. However, despite this, there is ample evidence that Au(III) complexes are cytotoxic; indeed, cytotoxic screening for Au(III) complexes can be traced back to the mid-1970s.79

In vivo redox chemistry of gold

In vivo, 'gold' exists as Au(I) species, usually metabolites of the administered drugs, as demonstrated by model studies.37 This is also true when Au(III) is administered to rats.80 The body is replete with reducing species with an affinity for gold, such as cysteine and methionine embedded in proteins. It has been known for over 20 years that disulphide bonds can reduce Au(III) to Au(I).81 Thus, it is most likely that any administered Au(III) complex will be metabolized to an Au(I) species. The above notwithstanding, oxidation of Au(I) to Au(III), in vivo, has been observed.82,83 Myeloperoxidase, already mentioned above in section 26.4.3 generates the oxidizing agent hypochlorous acid (HOCl) during the oxidative burst associated with inflammation, and can oxidize disodium aurothiomalate to Au(III).84 A redox cycle can thus be established where Au(I) is oxidized to Au(III) and Au(III), in turn, can be reduced, by the above mentioned sulphur-containing species, to Au(I).

Gold(III) complexes with anti-tumour activity

As with some of the Au(I) complexes investigated for anti-tumour potential, the combination of Au(III) with biologically active molecules has been the motivation for some studies. For example, the combination of Au(III) with

MeO. H2N'

O

Ti

N

O

h2n""

[fr

,OH OMe

,co2h

,OH OMe

NMe2

Figure 26.5 Chemical structures of streptonigrin (14) and generic 2-[(dimethylamino) methyl]phenylgold(III)X2 (15)

streptonigrin (14) (Figure 26.5) to give a square-planar complex, for which the precise chemical structure is not known, is a cytotoxic species but one that has a comparable profile of potency to the uncomplexed streptonigrin.85 Organo-gold(III) complexes have also been studied and arguably one of the most promising of these is based on 2-[(dimethylamino)methyl]phenylgold(III)X2 (15), where X = halide, carboxylate, etc.;86 the generic structure is shown in Figure 26.5. These complexes have a similar profile of cytotoxicity to cisplatin against the chosen panel of cell lines. Further, they demonstrate moderate anti-tumour activity in laboratory animals.86 The question whether these and related square-planar Au(III) complexes interact with DNA, as do metabolites of cisplatin, is still controversial.87

A recent comprehensive review of the types of Au(III) complexes screened and their cytotoxicity profiles is available.56

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