Desferrithiocin analogue uranium decorporation agents

Abstract

Purpose Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. Materials and Methods The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. Results The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. Conclusions While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue.

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for 230U Targeted α-Therapy

“…All four complexes display excellent kinetic stability in plasma and remain >98% intact after incubation for 14 days (Figure b). Previous studies have reported ligands capable of complexing UO 2 2+ in blood, serum, or plasma. ,,,, However, none of these investigations examined the long-term (>10 days) stability of the complexes. This study is the first report to demonstrate the long-term stability of uranium complexes in human plasma, reflecting the potential value of these ligands for 230 U in TAT.…”

Recent advances in uranyl binding in proteins thanks to biomimetic peptides

“…At least one of these compounds was demonstrated to clear uranium globally, as well as from the kidney and the bone. [17] Insert Figure 3.…”

The Role of Chelation in the Treatment of Other Metal Poisonings

“…While hydrophilic chelators enhance renal excretion, their mainly extracellular localization limits activity to extracellular metal pools; lipophilic chelators might access and decrease intracellular stores, but may redistribute toxic metals to vulnerable compartments [2]. This may create a fundamental efficacy-safety paradox: the more lipophilic a chelator, the better its "clearing efficiency"; however, the more lipophilic the chelator, the greater its toxicity [3]. Thus, in an aggressive attempt to "mobilize" a metal from one target compartment in order to effect excretion, chelation might facilitate translocation of the metal to other organs.…”

“…DTPA is cleared by glomerular filtration. Unfortunately, DTPA has not demonstrated any benefit at all in enhancing uranium clearance [3]. In fact, the package inserts for both calcium DTPA and zinc DPTA state that "treatments are not expected to be effective for uranium and neptunium" [159,160].…”