“…Multidentate hydroxypyridinone (HOPO) and catecholamide (CAM) ligands are known to chelate both actinide (An) and lanthanide (Ln) cations exceptionally well both in vitro and in vivo , ,, and have been shown to be effective decorporation agents of trivalent and tetravalent actinides in multiple animal models. ,, The octadentate 3,4,3-LI(1,2-HOPO) (Scheme ), denoted 343-HOPO hereafter, was designed for tetravalent plutonium (Pu) chelation, , and has proven exemplary for coordinating a range of tetravalent p-, d-, and f-block metals. − Moreover, it has been shown to significantly increase excretion in vivo of actinyl species such as U VI and Np V , although the mechanism for these latter findings is not well understood. The coordination chemistry and solution thermodynamics of [UO 2 ] 2+ -343-HOPO binding have been investigated in several studies, revealing that 343-HOPO binding with hexavalent uranium is less thermodynamically favorable than that of other targets such as Pu IV . ,, We recently observed 343-HOPO chelation-driven activation and concurrent reduction of the neptunyl(V) cation to Np IV , , and here we extended these efforts to investigate whether a similar chelation-induced reduction mechanism could occur in uranium systems.…”