Dual O<sub>2</sub>‑Mediated Reactivity of a\nMononuclear Cobalt Complex with Amyloid‑β Peptides

Alzheimer’s disease is characterized by the accumulation\nof amyloid-β (Aβ) aggregates, leading to neuronal degeneration\nand cognitive decline. Transition metal complexes have emerged as\npromising agents for chemically modifying Aβ peptides, owing\nto their versatile chemical reactivity, thereby altering their aggregation\nbehavior and toxicity. Examples of transition metal complexes capable\nof inducing chemical transformations of Aβ peptides remain scarce,\nhowever. Here we report the dual reactivity of a mononuclear Co(II)\ncomplex, [Co(TBDAP)(H<sub>2</sub>O)(NO<sub>3</sub>)](NO<sub>3</sub>) (<b>1</b>), toward Aβ peptides in a site-specific manner.\nThis reactivity includes chemical transformation at <i>N</i>-terminal Asp1, resulting in the generation of a pyruvamide moiety,\nand fragmentation between Val12 and His13. These site-specific chemical\nmodifications achieved by <b>1</b> redirect the aggregation\nof Aβ peptides from on-pathway to off-pathway, yielding less\ntoxic amorphous aggregates and relatively short fibrils. Our mechanistic\ninvestigations reveal that the oxidation of the Co(II) center to Co(III)\nby O<sub>2</sub> is a crucial step for these reactivities, supported\nby similar reactivities observed with a newly synthesized Co(III)\ncomplex, [Co(TBDAP)(Cl)<sub>2</sub>](NO<sub>3</sub>) (<b>2</b>). Computational analyses further uncover the most energetically\nfavorable, plausible reaction pathway for <i>N</i>-terminal\nchemical transformation of Aβ peptides mediated by <b>2</b> (inner-sphere hydride transfer between <b>2</b> and Aβ,\nsubsequent to decarboxylation and deamination of Asp1). Overall, our\nwork provides valuable insights into the novel reactivities of transition\nmetal complexes with Aβ peptides, offering an innovative avenue\nto chemically transform Aβ peptides through the utilization\nof these complexes.