Impact of Mitochondrion-Targeting Group on the Reactivity and Cytostatic Pathway of Platinum(IV) Complexes

Platinum­(IV) complexes are prodrugs of cisplatin with multiple potential advantages over platinum­(II) drugs. Mitochondria play pivotal roles in producing energy and inducing death of cancer cells. Two platinum­(IV) complexes, namely, c,c,t-[Pt­(NH3)2Cl2(OH)­(OCOCH2­CH2CH2CH2PPh3)]Br and c,c,t-[Pt­(NH3)2Cl2­(OCOCH2CH2CH2­CH2PPh3)2]­Br2, were designed to explore the effect of mitochondrion-targeting group(s) on the bioactivity and cytotoxicity of platinum­(IV) complexes. The complexes were characterized by electrospray ionization mass spectrometry, reverse-phase high-performance liquid chromatography, and multinuclear (1H, 13C, 31P, and 195Pt) NMR spectroscopy. The introduction of triphenylphosphonium targeting group(s) markedly influences the reactivity and cytotoxicity of the Pt­(IV) complexes. The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin. The lipophilicity of the Pt­(IV) complexes is enhanced by the targeting group(s), while their reactivity to DNA is decreased. As a result, the mitochondrial morphology and adenosine triphosphate producing ability are impaired, which constitutes an alternative pathway to inhibit cancer cells. This study shows that both the reactivity of platinum­(IV) center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted Pt­(IV) complexes. For targeting groups with pharmacological activities, their intrinsic function could enrich the anticancer mechanism of Pt­(IV) complexes.