Mn(II) Polypyridyl Complexes: Precursors to High Valent Mn(V)=O Species and Inhibitors of Cancer Cell Proliferation.

The reaction of [(L)MnII ]2+ (L = neutral polypyridine ligand framework) in the presence of mCPBA (mCPBA = m-Chloroperoxybenzoic acid) generates a putative MnV =O species at RT. The proposed MnV =O species is capable of performing the aromatic hydroxylation of Cl-benzoic acid derived from mCPBA to give [(L)MnIII (m-Cl-salicylate)]+ , which in the presence of excess mCPBA generates a metastable [(L)MnV (O)(m-Cl-salicylate)]+ , characterized by UV/Vis absorption, EPR, resonance Raman spectroscopy, and ESI-MS studies. The current study highlights the fact that [(L)MnIII (m-Cl-salicylate)]+ formation may not be a dead end for catalysis. Further, a plausible mechanism has been proposed for the formation of [(L)MnV (O)-m-Cl-salicylate)]+ from [(L)MnIII (m-Cl-salicylate)]+ . The characterized transient [(L)MnV (O)-m-Cl-salicylate)]+ reported in the current work exhibits high reactivity for oxygen atom transfer reactions, supported by the electrophilic character depicted from Hammett studies using a series of para-substituted thioanisoles. The unprecedented study starting from a non-heme neutral polypyridine ligand framework paves a path for mimicking the natural active site of photosystem II under ambient conditions. Finally, evaluating the intracellular effect of Mn(II) complexes revealed an enhanced intracellular ROS and mitochondrial dysfunction to prevent the proliferation of hepatocellular carcinoma and breast cancer cells.

Diazepam-based covalent modifiers of GPX4 induce ferroptosis in liver cancer cells.

Developing new chemotherapeutics that are structurally and mechanistically unique is needed due to the rapid rise of the cancer incidence across the globe. Here, we report the identification of irreversible, thiol-reactive diazepam derivatives as GPX4 modifiers and nanomolar inducers of ferroptosis in liver cancer cells.

Redox modulator iron complexes trigger intrinsic apoptosis pathway in cancer cells.

The emergence of multidrug resistance in cancer cells necessitates the development of new therapeutic modalities. One way cancer cells orchestrate energy metabolism and redox homeostasis is through overloaded iron pools directed by iron regulatory proteins, including transferrin. Here, we demonstrate that targeting redox homeostasis using nitrogen-based heterocyclic iron chelators and their iron complexes efficiently prevents the proliferation of liver cancer cells (EC50: 340 nM for IITK4003) and liver cancer 3D spheroids. These iron complexes generate highly reactive Fe(IV)=O species and accumulate lipid peroxides to promote oxidative stress in cells that impair mitochondrial function. Subsequent leakage of mitochondrial cytochrome c activates the caspase cascade to trigger the intrinsic apoptosis pathway in cancer cells. This strategy could be applied to leverage the inherent iron overload in cancer cells to selectively promote intrinsic cellular apoptosis for the development of unique iron-complex-based anticancer therapeutics.