Complexes with Trypanocidal Drugs. Dual-Function Agents

METAL COMPLEXES WITH TRYPANOCIDAL DRUGS. DUAL-FUNCTION AGENTS 

Chelating agents may serve to effect an imbalance by depletion or activation of an essential metal ion in the target cell, rather than host cell. Cytotoxic metal ions or complexes may also be directed specifically toward the target cell, limiting their toxic effect to the host, and this is clearly of importance in design of antitumour agents. 

An interesting aspect of these complexes is the relative activity of the free complexes and their berenil analogues in tumours and trypanosomes. Thus, while rhodium butyrate is very active in vitro in LI 210 emd not active vs. T. rhodesiense, the opposite is true for its bridged berenil analogue, [Rh2(OBu)3(Ber)J (Ber = anion of berenil), which has only slight antitumour activity. Thus, a situation is emerging where the relative activities of two closely related species are dictated by the activity of the carrier group. 

The tetrachloroplatinate(II) salt of ethidium, (Eth)2PtCl4, formed from EthBr and K2PtCl4 (see Section 3.1), is considerably less toxic than the simple ethidium bromide derivative, resulting in a five-fold increase in therapeutic index [67]. The curative dose for trypanosomiasis is approxi- 

The interplay of antiparasitic drugs and metal complexes may give a synergistic effect and the way activity is affected is shown by the unusual result that a chloroquine adduct of rhodium acetate, Rh2-(acetate)4(chloroquine)], is more active in vitro in T, rhodesiense than either component [98]. This complex is also as active in malaria in vivo as the free chloroquine, although no enhancement over free drug is seen [98]. An interesting historical note to the metallation of trypanocidal drugs is that the platinum salt of Salvarsan was reported by Ehrlich in 1915 in one of his last papers [99]. 

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