Drugs active trans complexes

The Ru(in) compounds [HIm][trans-RuCl4(Im)(DMSO-5)] and [HInd][tran5-RuCl4(Ind)2] (Im = imidazole, Ind = indazole, Eig. 22.22) have completed phase I clinical trials as anti-cancer drugs. The former complex selectively targets metastases of solid tumours. The range of ruthenium-based compounds that exhibits anti-cancer activity includes organometallic ruthenium(II) complexes. ... 

While transplatin is not an active anticancer drug some trans platinum complexes, however, are highly cytotoxic. In the search for active trans platinum compounds several complexes with triphenylphosphine or dimethylphenylphos-phine ligands have been studied (Fig. 13.5), and found to be active on various cancer cell lines, with no cross resistance to cisplatin observed [22]. Apoptotic cell death with no G1 and G2/M accumulation in the cell cycle, typical for the cisplatin, was observed indicating a non-classical mechanism of action. 

We shall now describe the chemistry of those inorganic complexes which are known to have anti-tumour activity in an effort to outline the permutations which such molecules permit and to indicate possible functional modes. We start from the basic observation of Rosenberg (1).Cis [PtCl2 (NH8)d is a very effective anti-tumour drug. Compounds related to it such as trans [PtCl2(NH3)2] are ineffective. Out of a wide range of transition metal complexes tested few have proved to be effective. The successful compounds have certain common features which can be used to circumscribe some of the factors which are probably required for such a drug. 

The fourth criteria, that of oral administration, is being developed and evaluated for ZD0473 as just mentioned. Another candidate in this field, JM216, cis, trans, cw-[dichlorodiacetatoammine(cyclohexylamine)platinum(IV)] (see Figure 7.6D), is an orally active platinum(IV) drug being evaluated in clinical trials. This platinum (IV) complex has demonstrated activity in cisplatin-resistant tumors and exhibits less nephrotoxicity and neurotoxicity than does cisDDP. 

However, because of the slowness of Ptn conversions, the various (NH3)2Ptn species may not be at equilibrium with ambient 4 mM chloride in the cell nucleus. The (NH3)2Ptn species may be more nearly in equilibrium with the ambient 104 mM chloride of the blood plasma, where the administered drug has circulated. For conversion from administered dichloro to diaqua complexes in acidic solutions the successive half lives at 45 °C are 1.0 and 0.8 h for cis and 0.18 and 48 h for trans isomers [3], These times agree with the well-documented trans-activating order Cl > NH3 > H20. Therefore, we have performed a similar analysis of the reaction rate with inosine N(7) assuming that the (NH3)2Ptn species are in equilibrium with the blood plasma and the results appear under the columns labeled 104 mu in Table 3. At 104 mM CP, the total reactivities of all cA-species are 1/3, and those of all trans-species 2/3 those at 4 mM. 

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