Ligand-Based Radical\nReactivity of Metal Thiosemicarbazones\nPrompts the Identification of Platinum(II)-Based Cytoprotectants

CuATSM,\na copper­(II) complex of a bis­(thiosemicarbazone)\nof diacetyl,\nprevents oxidative cell death and acts as a neuroprotectant <i>in vivo</i>, prompting its evaluation to treat amyotrophic lateral\nsclerosis and other neurodegenerative conditions in the clinic. We\nrecently demonstrated that CuATSM functions as a potent radical-trapping\nantioxidant (RTA), inhibiting lipid peroxidation and associated ferroptotic\ncell death by a noncanonical mechanism based on radical addition to\nthe ligand backbone. Herein we report our investigations of the generality\nof this reactivity, which include studies of corresponding complexes\nof various other metals, including Co, Ru, Ni, Pd, Pt, and Au. Inhibited\nautoxidations of styrene and dioxane reveal that most of these complexes\nexhibit RTA activity, consistent with ligand-based reactivity, but\nthe identity of the metal atom nevertheless plays a role. In particular,\nanalyses of the electronic structures of the complexes of metals within\nthe same group (i.e., the group 10 metals Ni, Pd and Pt) highlight\nhow the metal atom can modulate the ligand-based reactivity by enabling\nspin delocalization to the other thiosemicarbazone moiety. The RTA\nactivity determined in organic solution largely translates to phospholipid\nbilayers and mammalian cells, where most complexes inhibited lipid\nperoxidation and associated ferroptotic cell death. A preliminary\nstructure–activity study revealed Pt complexes with potencies\neclipsing those of archetype ferroptosis inhibitors ferrostatin-1\nand liproxstatin-1, suggesting that Pt (and to a lesser extent Ni)\nbis­(thiosemicarbazone)­s may be better suited to optimization for therapeutic\ndevelopment than those based on Cu.