Phosphine complexes, cytotoxicity

McKeage, M.J., Maharaj, L. and Berners-Price, S.J. (2002) Mechanisms of cytotoxicity and antitumor activity of gold(I) phosphine complexes the possible role of mitochondria. Coordination Chemistry Reviews, 232, 127—135. 

The cytotoxicity of Au(I) complexes is markedly dependent on the ligands. A large number of Au(I) phosphine complexes are toxic to cells in the micromolar concentration range. For example, some linear Au(I) phosphine complexes, including the antiarthritic complex aura-nofin (see Section VII), are potently cytotoxic toward cancer cells in culture (189). 

Many gold phosphine complexes have been found to be potent cytotoxic agents, to have antitumor activity against P388 leukaemia and to be active against a spectrum of transplantable tumour models . It has been of particular interest to obtain some of them labeUed with radioactive isotopes of gold and carbon for cellular, binding, metabolism and biodistribution studies. 

A small number of non-NHC silver compounds have been studied as potential anticancer agents. Berners-Price and coworkers synthesized bischelated silver(I) diphosphine and pyridiyl phosphine complexes, which proved to have in vitro cytotoxic properties against a variety of cancer cell lines tested, including cis-platin-resistant lines [28,29]. Additionally, a series of coordination polymers... 

As far as the biological chemistry of metal phosphine complexes is concerned, our interest in the properties of phosphines coordinated to metals arises for two reasons. Firstly, because the biological (in particular cytotoxic) activity of phosphines could involve coordination to metals (e.g. Fe, Cu or Zn) in critical sites. This point is discussed further in Sects. 3.7 and 4.5. Secondly, alteration of the substituents on PR3 can cause substantial changes in the reactivity of transition-metal complexes. Therefore, by understanding the factors that influence the reactivity it may be possible to design rationally metal-phosphine complexes as chemotherapeutic agents. 

Cytotoxicity and Antitumour Activity ofAu(I) Phosphine Complexes... 

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...

Little is known about the mechanisms by which some phosphines and metal phosphine complexes are able to kill cells. However, studies to date indicate that the phosphine itself is the cytotoxic agent. In the case of auranofin and other monophosphine Au(I) complexes, the role of the metal may be largely to protect the phosphine and deliver it to cellular targets. Auranofin is potently cytotoxic to cells in vitro, but its activity in vivo is limited This may be because Au(I) is very reactive towards biologically important ligands, particularly thiols so that it binds to proteins and is prevented firom reaching the critical targets. 

The presence of an ethyl moiety as the N-substituent instead of a phosphine did not affect the activity with the MCF-7 cells (IC50 = 3.0 pM) but a decrease was observed with HT-29 celk (7.7 pM) (complex 48k). Concerning the MDA-MB 231 cells, similar cytotoxicity was measured with cisplatin (6.9 pM). The backbone of the imidazole ring ivas modified and phenyl rings were introduced. The cytotoxic activity ivas clearly enhanced with IC50 of... 

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-... 

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