Uranium Chelation by Pyrazine-2-amidoxime: Speciation, Decorporation, and Computational Studies

Uranium, being chemo-radiotoxic, requires confinement within a safe environment to prevent severe health consequences. Chelation therapy, utilizing multidentate ligands, is a widely accepted approach for developing effective uranium decorporation treatments. In this study, a systematic investigation of uranium complexation by pyrazine-2-amidoxime (PAM) was undertaken for the first time, employing chemical speciation, in vitro studies, and computational calculations. Potentiometric and spectrophotometric titrations, corroborated by electrospray ionization mass spectrometry (ESI-MS), revealed that PAM forms 1:1 (ML) and 1:2 (ML 2 ) complexes with the uranyl ion (UO 2 2+ ). PAM acts as a bidentate chelator, coordinating via the oxygen and nitrogen atoms of amidoxime, with high stability constants (log β) of 8.54 ± 0.04 for ML and 16.33 ± 0.07 for ML 2 complexes. Density functional theory (DFT) calculations further elucidated the preferred coordination mode, donor-site contributions, and electronic factors governing the stability of the PAM–uranyl complexes. Ex vivo experiments with human erythrocytes (RBCs) confirmed that PAM is cytocompatible and significantly enhanced uranium decorporation from human RBCs, facilitating removal of 25–40% of uranium at 100–200 μM compared to uranium-treated controls. Additionally, PAM effectively reduced uranium content by 10–20% from physiologically relevant proteins such as human serum albumin and from native human blood plasma.