Copper complexes antitumour activity

However, treatment with inorganic copper was not as effective as therapy with copper complexes. A single 5 mg/kg dose of Cu(II)(dimethylglyoxime)2 increased the life-span of mice bearing Ehrlich ascites or Sarcoma 180 tumours 2- to 3-times that of non-treated controls [358]. Other copper complexes reported to have similar antitumour activities in rodents are Cu(II)(3,4,7,8,-tetramethyl-1,10-phenanthroline) [360], Cu(IIX2-keto-3-... 

However, Oberley and Buettner pointed out that all tumour cell lines have markedly decreased superoxide dismutase activity [355]. The marked decrease in manganese-dependent SOD activity is consistent with a decrease in aerobic metabolism and a decrease or only a modest increase in Cu-Zn SOD activity is consistent with an impaired response leading to transformation. As a result of the observed lowered SOD activities in tumour cells and an awareness of the SOD-mimetic activity of copper salicylate complexes, salicylate and other copper complexes were investigated as antitumour agents. 

Some tumour growth inhibition was observed for Cu(SOD) itself [83]. The demonstrated SOD-mimetic activity (albeit low) of copper complexes such as bis(isopropylsalicylato)copper(II), prompted a study of its antitumour effect, the reasoning being that this lipid-soluble analogue would have greater uptake in cells. The complex (Structure 63) is probably of the cupric acetate type ... 

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. 

Although as a class the chelates are definitely bacteriostatic, the relative contributions of uptake and dissociation for both inert and labile species need to be more clearly defined before a full picture is obtained. The results suggest that kinetic reactivity may be more important than thermodynamic stability [30]. In the case of copper(II) complexes with 1,10-phenanthroline and 2,9-dimethyl-1,10-phenanthrolines, more recent studies showed that the major mode of action on P. denitrificans in vitro was in fact inhibition of respiratory electron transport in the cytoplasmic membrane, no correlation with inhibition of macromolecular synthesis being apparent [31]. These results are relevant in view of the discrepancy in the reported antitumour activity of these species (see Section 6.2). 

The key step will now be to estabhsh whether complexes of this type, which exhibit a reasonable spectrum of antitumour activity in animal models, attack DNA, and if so, by what mechanism. Perhaps copper could play an important role in this. Cu(II) potentiates the cytotoxicity of dppe and [Au(dppe)2]Cl is reactive towards Cu(II) ions. There is a potential wealth of Cu(I)phosphine chemistry (particularly aqueous) involving chelate ring opening, halide (Cl ) competition and free radical reactions which could be explored. The mechanism of cytotoxicity of metal diphosphine complexes seems likely to be different from that of cisplatin. This could be a promising sign for possible combination chemotherapy. 

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-... 

---