Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress

Prochelators are agents that have little affinity for metal ions until they undergo a chemical conversion. Three new aryl boronate prochelators are presented that are responsive to hydrogen peroxide to provide hexadentate ligands for chelating metal ions. TRENBSIM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)-2-aminoethyl]amine), TRENBSAM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-2-aminoethyl]amine), and TB (tris[(2-boronic acid-benzyl)2-aminoethyl]amine) convert to TRENSIM (tris[(salicylideneamino)ethyl]amine), TRENSAM (tris[(2-hydroxybenzoyl)-2-aminoethyl]amine), and TS (tris[2-hydroxybenzyl)2-aminoethyl]amine), respectively. The prochelators were characterized by 11B NMR, and the structures of TRENBSAM, TRENBSIM, and the Fe(III) complex of TS were determined by X-ray crystallography. Of the three prochelator/chelator pairs, TB/TS was identified as the most promising for biological applications, as they prevent iron and copper-induced hydroxyl radical generation in an in vitro assay. TB has negligible interactions with metal ions, whereas TS has apparent binding constants (log K′) at pH 7.4 of 15.87 for Cu(II), 9.67 Zn(II) and 14.42 for Fe(III). Up to 1 mM TB was nontoxic to retinal pigment epithelial cells, whereas 10 μM TS induced cell death. TS protected cells against H 2O 2-induced death, but only within a 1–10 μM range. TB, on the other hand, had a much broader window of protection, suggesting that it may be a useful agent for preventing metal-promoted oxidative damage. Three aryl boronate prochelators are presented that respond to H 2O 2 by converting into hexadentate chelating agents that prevent metal-induced reactive oxygen species formation. While the chelator TS (tris[2-hydroxybenzyl)2-aminoethyl]amine) itself is toxic, its prochelator version TB (tris[(2-boronic acid-benzyl)2-aminoethyl]amine) is nontoxic and protects retinal pigment epithelial cells from death induced by H 2O 2. [Display omitted] ► Boronate-masked prochelator TB is converted by H 2O 2 to multidentate amino/phenol chelator TS. ► Octahedral Fe-TS complex has negative redox potential and blocks Fenton chemistry. ► TB does not bind metals, but TS binds di- and trivalent metals with high affinity. ► Metal ion selectivity of prochelator/chelator combo derives from H 2O 2 stimulus. ► Masking metal binding groups converts toxic chelator to cytoprotective agent.