Probing the Platinum(IV) Prodrug Hypothesis. Are Platinum(IV) Complexes Really Prodrugs of Cisplatin?

Abstract

Amongst the metallopharmaceuticals in development, platinum(IV) complexes are unique because they are native prodrugs of clinically-relevant platinum(II) pharmacophores such as cisplatin and oxaliplatin (Fig. 3.1) These platinum(II) drugs are some of the most effective anticancer agents in clinical use and the first line treatment for many malignancies today (Fig. 3.1) (Hall et al. J Med Chem 50:3403–3411, 2007 [1]; Hall et al. Coord Chem Rev 232:49–67, 2002 [2]; Chin et al. J Med Chem 55:7571–7582, 2012 [3]). The general consensus is that these platinum(IV) prodrug complexes are themselves pharmacologically inactive and must undergo reductive elimination by endogenous reductants to release the active square-planar platinum(II) core with concomitant dissociation of the axial ligands (Fig. 3.2) (Hall et al. J Med Chem 50:3403–3411, 2007 [1]; Hall et al. Coord Chem Rev 232:49–67, 2002 [2]; Chin et al. J Med Chem 55:7571–7582, 2012 [3]). As such, the axial ligands confers unique possibilities of tuning the pharmacokinetic parameters such as lipophilicity and solubility as well as the attaching any targeting groups or synergistic co-drugs without altering the cellular mechanism of action of the innate platinum(II) pharmacophore (Hall et al. J Med Chem 50:3403–3411, 2007 [1]; Hall et al. Coord Chem Rev 232:49–67, 2002 [2]; Chin et al. J Med Chem 55:7571–7582, 2012 [3]). Open image in new window Fig. 3.1 Top: cisplatin and oxaliplatin are two platinum(II) agents in clinical use today. Bottom: Satraplatin is a promising platinum(IV) anticancer prodrug under clinical trials. Complexes 1 and 2 are newly synthesized asymmetrical platinum(IV) complexes bearing a benzaldehyde moiety for facile imine ligation to any therapeutically-relevant substrate Open image in new window Fig. 3.2 The platinum(IV) prodrug hypothesis: reductive elimination of platinum(IV) prodrugs occurs with the release the active platinum(II) core as well as both axial carboxylate ligands