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 (ML2) complexes with the uranyl ion (UO22+). 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 ML2 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.
Srivastava et al. (Tue,) studied this question.