Chelating Agents for Uranium(vi): 2. Efficacy and Toxicity of Tetradentate Catecholate and Hydroxypyridinonate Ligands in Mice

Abstract

Uranium(VI) (UO2(2+), uranyl) is nephrotoxic. Depending on isotopic composition and dosage, U(VI) is also chemically toxic and carcinogenic in bone. Several ligands containing two, three, or four bidentate catecholate or hydroxypyridinonate metal binding groups, developed for in vivo chelation of other actinides, were found, on evaluation in mice, to be effective for in vivo chelation of U(VI). The most promising ligands contained two bidentate groups per chelator molecule (tetradentate) attached to linear 4- or 5-carbon backbones (4-LI, butylene; 5-LI, pentylene; 5-LIO, diethyl ether). New ligands were then prepared to optimize ligand affinity for U(VI) in vivo and low acute toxicity. Five bidentate binding groups--sulfocatechol [CAM(S)], carboxycatechol [CAM(C)], methylterephthalamide (MeTAM), 1,2-hydroxypyridinone (1,2-HOPO), or 3,2-hydroxypyridinone (Me-3,2-HOPO)--were each attached to two linear backbones (4-LI and 5-LI or 5-LIO). Those ten tetradentate ligands and octadentate 3,4,3-LI(1,2-HOPO), an effective actinide chelator, were evaluated in mice for in vivo chelation of 233U(VI) (injection at 3 min, 1 h, or 24 h or oral administration at 3 min after intravenous injection of 233UO2Cl2) and for acute toxicity (100 micromol kg(-1) injected daily for 10 d). The combined efficacy and toxicity screening identified 5-LIO(Me-3,2-HOPO) and 5-LICAM(S) as the most effective low-toxicity agents. They chelate circulating U(VI) efficiently at ligand:uranium molar ratios > or = 20, remove useful amounts of newly deposited U(VI) from kidney and bone at molar ratios > or = 100, and reduce kidney U(VI) levels significantly when given orally at molar ratios > or = 100. 5-LIO(Me-3,2-HOPO) has greater affinity for kidney U(VI) while 5-LICAM(S) has greater affinity for bone U(VI), and a 1:1 mixture (total molar ratio = 91) reduced kidney and bone U(VI) to 15 and 58% of control, respectively--more than an equimolar amount of either ligand alone.

The Influence of Linker Geometry in Bis(3‐hydroxy‐N‐methyl‐pyridin‐2‐one) Ligands on Solution Phase Uranyl Affinity

“…This high affinity is consistent with the relatively relaxed geometry observed in the UO 2 (4Li-Me-3,2-HOPO)(DMSO) crystal structure as well as with the superior ability for 4Li-Me-3,2-HOPO to chelate actinides in vivo. [31,36] Of the rigidly-linked ligands L 6 H 2 -L 8 H 2 , L 6 H 2 is the most acidic, and yet displays the poorest uranyl affinity at all pH. This may be due to the inability to form monomeric uranyl complexes.…”

“…Examples of biologically relevant investigations include that of Czerwinski and co-workers that addresses uranyl speciation with the naturally-occuring siderophore desferrioxamine (DFO) [29] as well as those by Durbin and co-workers that examine the in vivo decorporating ability of polybidentate catecholamides and their structural analogs towards the uranyl and transuranic cations. [30][31][32][33] These latter studies revealed that 4-or 5-carbon linear linkers provided optimal decorporating ability to poly-bidentate ligands, but the detailed thermodynamic rationale for this result is relatively unexplored.…”

Uranyl sequestration: synthesis and structural characterization of uranyl complexes with a tetradentate methylterephthalamide ligand

“…Several of these ligands are orally active decorporation agents and effective in reducing UO 2 2+ in both kidneys and skeleton (removal efficiency in the sequence MeTAM > CAM(S) > CAM(C) > Me-3,2-HOPO > 1,2-HOPO). 9,[12][13][14] Of the ligands evaluated, the 5LiO-(Me-3,2-HOPO) and 5Li-CAM(S) ligands were identified as low or non-toxic ligands with high efficiency.…”

“…Given these issues, the strong binding affinity of MeTAM makes this class of ligands attractive for nuclear waste remediation. Due to the low-toxicity and improved solubility of the 5LiO backbone as shown by previous studies with the 5LiO-(Me-3,2-HOPO) ligand, 14 we prepared the MeTAM analog 5LiO-(MeTAM) (LH 4 , Scheme 2) to study the structures of its uranyl complexes. Herein, we describe the synthesis and characterization of the uranyl complexes with L. Xray crystallography has revealed that [ 4 8-has a helical structure, in which the ligands adopt a bridging coordination mode with two TAM units in each L coordinated to two uranyl ions.…”

Synthesis and Thermodynamic Evaluation of Mixed Hexadentate Linear Iron Chelators Containing Hydroxypyridinone and Terephthalamide Units1

“…The high affinity for ferric ion of these linear ligands is strongly reflected in their efficacy at removing iron in vivo, as reported elsewhere. 15 …”