Attack of NADH and ascorbate toward metal-activated ligand of organoiridium(III) compound.

The half-sandwich Ir(III) compound [Ir(η5-Cp*)Cl(L1)]PF6 (1), which involves the metal-activated Schiff base ligand N-[1-(anthracene-9-yl)-methylidene]-3,5-di(pyridin-2-yl)-4H-1,2,4-triazol-4-amine (L1), was designed to incorporate a biologically non-innocent substituent (DNA-targeting anthracene) bound through a reactive linker (Schiff bond), which was hypothesized to promote interactions with small intracellular biomolecules; HCp* = pentamethylcyclopentadiene. 1 exhibited a different cleavage pathway of the Schiff base linker upon interaction with NADH and ascorbate, compared to its stability when mixed with glutathione. Compound 1 is more cytotoxic, interacts more strongly with DNA (due to the anthracene substituent) and induced the formation of a higher level of reactive oxygen species (attributable to the Schiff base bond's reactivity) than its analogue, which lacks the anthracene substituent (2). Density Functional Theory (DFT) calculations demonstrated a higher reactivity of the Schiff base linker for L1 coordinated in 1 than when L1 is free. The calculations specifically identified the C19 atom of the linker as the target site for nucleophilic attack of a hydride anion from NADH. This study sheds new light on the fate of coordination compounds involving a metal-activated ligand under mimicked intracellular conditions and offers a new strategy for the development of multi-component biomolecule-activated metallodrugs.