As mentioned above, Auranofin (6) is known to possess some anti-tumour activity and this fact, coupled with the conclusion that this drug is in fact a prodrug, led to studies based on the following premise. If the phosphinegold(I) thiolate is metabolized upon administration to patients to liberate the thiolate, it makes sense to couple the phosphinegold(I) entity with thiols that possess anti-tumour activity. Thus, a particular focus of the study of Auranofin analogues has been to couple biologically active thiols with phosphinegold(I) entities in the hope that upon administration of the prodrug, both the phosphinegold(I) entity and thiol would provide therapeutic benefit.70 An obvious example of a biologically active thiol, already mentioned, is 6-mercaptopurine (8), shown in Figure 26.2. That this approach may work can be ascertained from the following data. The IC50 values (i.e. the concentration of material required to inhibit the growth of a particular cell line by 50%), in this case against cisplatin-resistant L1210/DDP leukaemia cells, are 3.3, 0.14 and 0.05 mM for 6-mercap-topurine (8; 6-MPH), Ph3PAuCl and Ph3PAu(6-MP) (11; Figure 26.4), respectively.71 These results demonstrate the obvious advantage of coupling the phosphinegold(I) and 6-mercaptopurine entities. Further, in vivo studies conducted on Balb/C mice inoculated with PC6 tumours (cisplatin-sensitive plastocytoma) show that while neither 6-mercaptopurine (8) nor Ph3PAuCl had any measurable effect on the growth inhibition of the tumours, Ph3PAu(6-MP) inhibited tumour growth by 60%.71,72 Work in this area continues and a review summarizing this aspect of gold-drug development has appeared recently.70 Notable aspects of this research include the observation that while no hard and fast structure-activity relationship exists, for the 6-mercaptopurinate series, potency (i.e. based on in vitro studies) varies in the order Cy3P > Ph3P > Et3P.73 However, exceptions to this rule exist. Thus, for the isomeric series of compounds, R3PAu(SC6H4CO2H-n), n = 2, 3 and 4 (12) (Figure 26.4), the n = 2 complexes were the most potent and of these, the R = Et Et species was the most promising, in particular against the A498 (renal cancer) and H226 (non-small-cell lung cancer) cell lines.74,75 Similarly, for the related dithiocarbamate complexes, it is the Et3PAu(S2CNEt2) complex (13) (Figure 26.4)
Figure 26.4 Chemical structures of Ph3PAu(6-MP) (11), R3PAu(SC6H4CO2H-n) (12) and Et3PAu(S2CNEt2) (13)
that is the most potent, at least of the derivatives investigated.76 More encouraging have been the recent observations that the promising in vitro potency is translated into animal studies for these and related complexes.77
Despite the earlier observations indicating it was the analogues of Auranofin (6) that gave the greatest promise for the development of anti-tumour agents, new developments suggest that other types of gold complexes should also be investigated. For example, a recent report highlights the possible utility of Au(I) carbene complexes as anti-tumour agents.78 Also very important in gold-drug development are complexes containing the Au(III) centre.
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