PlatinumIV Compounds

The mode of action of platinum agents can also be considerably affected by means other than changing of chemical structure. For instance, originally inactive compounds can be activated only after they are delivered to the target tumor cells or to their intracellular components. Platinum(IV) complexes represent one example of this class of anti-tumor agents. Such compounds are frequently designated as pro-drugs that have to be first, after their administration, activated by a reaction with reducing agents present in body liquids. In addition, being inert to substitution, Pt(IV) complexes theoretically have the advantage of demonstrating fewer side effects than their Pt(II) counterparts. One of the anti-tumor Pt(IV) drugs, which is an analogue of cisplatin, is bis-acetatoamminedichloro(cyclohexylamine)platinum(IV) (JM216, Figure 25.5) the first orally administrable platinum complex that has entered the clinic.48 The DNA-binding properties of JM216 on naked DNA or within tumor cells are similar to those of cisplatin, although there are some differences in the nature of the adducts.49 The search for a clinically useful orally available anti-tumor platinum drug also led to the design of several Pt(IV) compounds with trans-leaving ligands.50 An example of one of these complexes is trans-amine(cyclohexylamine)dichlorodihydroxoplatinum(IV) (JM335, Figure 25.5).

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