Targeted anticancer prodrugs that can be controllably activated are highly desired for personalized precision medicine in cancer therapy. Such prodrugs with unique action modes are also promising to overcome drug resistance. Herein, we report coumaplatin, an oxaliplatin-based and photocaged Pt­(IV) prodrug, to realize nuclear accumulation along with “on-demand” activation. This prodrug is based on a Pt­(IV) complex that can be efficiently photoactivated via water oxidation without the requirement of a reducing agent. Coumaplatin accumulates very efficiently in the nucleoli, and upon photoactivation, this prodrug exhibits a level of photocytotoxicity up to 2 orders of magnitude higher than that of oxaliplatin. Unexpectedly, this prodrug presents strikingly enhanced tumor penetration ability and utilizes a distinct action mode to overcome drug resistance; i.e., coumaplatin but not oxaliplatin induces cell senescence, p53-independent cell death, and immunogenic cell death along with T cell activation. Our findings not only provide a novel strategy for the rational design of controllably activated and nucleolus-targeted Pt­(IV) anticancer prodrugs but also demonstrate that accumulating conventional platinum drugs to the nucleus is a practical way to change its canonical mechanism of action and to achieve reduced resistance.

Polypyridyl and related ligands have been widely used for the development of water oxidation catalysts. Supposedly these ligands are oxidation-resistant and can stabilize high-oxidation-state intermediates. In this work a series of ruthenium(II) complexes [Ru(qpy)(L)2 ](2+) (qpy=2,2':6',2'':6'',2'''-quaterpyridine; L=substituted pyridine) have been synthesized and found to catalyze Ce(IV) -driven water oxidation, with turnover numbers of up to 2100. However, these ruthenium complexes are found to function only as precatalysts; first, they have to be oxidized to the qpy-N,N'''-dioxide (ONNO) complexes [Ru(ONNO)(L)2 ](3+) which are the real catalysts for water oxidation.

Metal oxo species (MO) play key roles as oxidants in chemical and biological systems. Although Brønsted acids have long been known to enhance the oxidizing power of metal oxo complexes, the use of Lewis acids (LAs), such as metal ions, to activate these complexes has received much less attention until recently. The report of the presence of a Mn 4 CaO 5 cluster active site in the oxygen-evolving center of photosystem II in 2004 has stimulated intense interest in understanding the interaction of LAs with metal oxo species. This Perspective analyzes the various modes of activation of metal oxos by LAs and the pathways for the oxidation of various substrates by LA/MO systems. The interaction of LAs with metal nitrides will also be discussed, although it is much less studied than that with metal oxo complexes.