Design, Synthesis, Physicochemical Properties, and Evaluation of Novel Iron Chelators with Fluorescent Sensors

TLDR

The probes were designed to quantify intracellular labile iron pools. They were synthesized as novel 3‑hydroxypyridin‑4‑ones and 3‑hydroxypyran‑4‑ones bearing coumarin substituents, evaluated for iron(III)-induced fluorescence quenching, and tested for permeability across erythrocyte ghost membranes. Iron(III) binding quenches fluorescence with a 1:3 metal‑to‑ligand stoichiometry; hydroxypyridinone derivatives quench more efficiently than hydroxypyranones, with quenching extent modulated by coumarin attachment site, solvent polarity, and pH, and membrane permeability correlates with ClogP values.

Abstract

The synthesis of a range of novel 3-hydroxypyridin-4-ones and 3-hydroxypyran-4-ones linked with different coumarin substituents is described. These compounds have been developed in order to provide a series of molecular probes for the quantification of intracellular labile iron pools. An evaluation of the effect of iron(III) on fluorescence intensity was undertaken. Chelation of iron(III) causes quenching of fluorescence. The relationship between iron(III) concentration and the extent of fluorescence quenching indicates that the metal is chelated in a complex with a metal-to-ligand stoichiometry of 1:3. The fluorescence of hydroxypyridinone compounds was found to be more efficiently quenched by iron(III) than were the hydroxypyranones. The metal-to-ligand stoichiometry at which maximum quenching is observed was found to depend on the site at which coumarin is attached. The efficiency of fluorescence quenching by iron(III) is markedly influenced by solvent polarity and pH. The permeability of two representative fluorescent chelators across human erythrocyte ghost membranes was investigated. The rate of permeability for a series of probes was found to be related to the corresponding ClogP values.