Gold complexes antitumour activity

When coordinated to a gold centre, the Fc functionalised NHC ligand devised by Horvath et al. shows cytotoxic properties [144]. It is not quite clear what the role of the ferrocene substituent is since the ferrocene is in the para position of the phenyl wingtip group. One might think that such an architecture would render the Fc group sterically irrelevant and electronically somewhat of lesser importance. However, gold(I) phosphane and NHC complexes are known for their antitumour activity [184]. 

B. Gold Complexes of Ligands with Antitumour Activity. 649... 

Figure 8 DPPE, DPPE-O2, and three DPPE-gold complexes with antitumour activity...

An evaluation of the antitumour activity of auranofin showed that it was active against P388 leukemia in vivo but ineffective in other models such as B16 and M5076 [93]. Auranofin showed no preference for DNA synthesis inhibition in comparison to that of RNA and protein, but the drug appeared to be inactivated by serum [93]. The structure of auranofin (structure 111, Figure 11.1) allows for a considerable number of structure-activity relationships, and this was explored to produce new series of structurally unique gold complexes with antitumour potential. 

Fig. 6.3. Gold complexes with demonstrated antitumour activity.

Some dissociation of free phosphine is also observed in solution [97]. A relevant finding in this work is that the free phosphine is also active [95] (originally reported in 1966 [110]), and the implication is that the gold complex serves as a releasing mechanism for the cytotoxic ligand. Since copper salts potentiate the activity of free phosphine [111] there is a possibility of in vivo phosphine release followed by copper activation — similar in concept to the possible antitumour mechanisms of 1,10-phenan-throline and the thiosemicarbazones. In pursuit of this line, Cu(II) was shown to displace dppe from [Au(dppe)2]Cl [112] to give a Cu(I) complex. Further synthesis and testing of copper-diphosphine complexes struc-... 

Non-platinum metal complexes with antitumour activity in murine screens are known for a wide diversity of structural types and the transition metals most studied include rhodium, ruthenium, gold, copper and titanium. The spectrum of activity is generally different to cisplatin (Ti, Au) and in some cases the complexes show lack of cross-resistance with cisplatin-resistant lines. 

There is increasing interest in the biological chemistry of phosphines and their metal complexes, Table 1. PH3 is a fumigant widely used against stored product commodities in many third world countries. Auranofin is a gold(I)phosphine complex which has recently been introduced into the clinic for treating rheumatoid arthritis. Auranofin also has limited antitumour activity in animals and this has lead to the discovery of other phosphines with broad spectrum anticancer activity. l,2-bis(diphenylphosphino)ethane (diphos) and its Au(I), Ag(I) and Cu(I) complexes are particularly effective. 

The antitumour activity and cytotoxicity of a large number of gold(I) complexes have also been evaluated Au(I) thiolate complexes exhibit very low cytotoxicity to cancer... 

Fig. 4. The comparative cytotoxicity (top clonogenic assay, 2 h treatment of B16 mouse melanoma cells) and antitumour activity (P388 leukaemia, ILS at the maximum tolerated dose) of gold(I) phosphine complexes ( ) EtsPAuSR where SR = SGlu (P-D-thioglucose), SGlu(Ac)4 (tetraacetyl-P-D-thioglucose) or TM (thiomalate), and the non-phosphine analogues [AuSR] (O). Data from Ref. 55...

McKeage MJ, Berners-Price SJ, Galettis P, et al. Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes. Cancer Chemother Pharmacol. 2000 5 343-350. 

---