title: 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.
authors.affiliation: Chemical Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA. pwdurbin-heavey@LBL.gov
authors.forename: P W
authors.initials: PW
authors.lastname: Durbin
authors.forename: B
authors.initials: B
authors.lastname: Kullgren
authors.forename: S N
authors.initials: SN
authors.lastname: Ebbe
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: K N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D000818:Animals; D002396:Catechols / Q000633:toxicity; D002614:Chelating Agents / Q000737:chemistry / Q000633:toxicity; D008024:Ligands; D051379:Mice; D011728:Pyridones / Q000633:toxicity; D014501:Uranium
chemical_list: D002396:Catechols; D002614:Chelating Agents; D008024:Ligands; D011728:Pyridones; D014501:Uranium