title: New agents for in vivo chelation of uranium(VI): efficacy and toxicity in mice of multidentate catecholate and hydroxypyridinonate ligands.
abstract: Soluble uranyl ion [UO2(2+), U(VI)] is a kidney poison. Uranyl ion accumulates in bone, and the high specific activity uranium isotopes induce bone cancer. Although sought since the 1940's, no multidentate ligand was identified, until now, that efficiently and stably binds U(VI) at physiological pH, promotes its excretion, and reduces deposits in kidneys and bone. Ten multidentate ligands patterned after natural siderophores and composed of sulfocatechol [CAM(S)], carboxy-catechol [CAM(C)], or hydroxypyridinone [Me-3,2-HOPO] metal-binding units have been tested for in vivo chelation of U(VI). Ligands were injected intraperitoneally (i.p.) into mice 3 min after intravenous (i.v.) injection of 233U or (232+235)U as UO2Cl2 [ligand-to-metal molar ratio 75 to 92]. Regardless of backbone structure, denticity, or binding unit, all 10 ligands significantly reduced kidney U(VI) compared with controls or with mice given CaNa3-DTPA, and four CAM(S) or CAM(C) ligands also significantly reduced skeleton U(VI). Several ligands removed U(VI) from kidneys, when injected at 1 or 24 h. Injected at molar ratios > or = 300, 5-LIO(Me-3,2-HOPO) and TREN-(Me-3,2-HOPO) reduced kidney U(VI) to about 10% of control. Given orally to fasted mice at molar ratios > or = 300, those ligands significantly reduced kidney U(VI). In mice injected i.v. with 0.42 micromol kg(-1) of 235U and given 100 micromol kg(-1) of one of those Me-3,2-HOPO ligands i.p. daily for 10 d starting at 1 h after the U(VI)) loss of kidney U(VI) was greatly accelerated, and the kidneys of treated mice showed no microscopic evidence of renal injury. Crystals of uranyl chelates with linear tetradentate ligands containing bidentate Me-3,2-HOPO groups demonstrate a 1:1 structure. Considering low toxicity, effectiveness, and reasonable cost, the structurally simple linear tetradentate ligands based on the 5-LI backbone (diaminopentane) offer the most promising approach to a clinically acceptable therapeutic agent for U(VI). Work is in progress to identify the most suitable CAM or HOPO binding unit(s).
authors.affiliation: Chemical Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, CA 94720, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Durbin
authors.forename: B
authors.initials: B
authors.lastname: Kullgren
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: K N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D000284:Administration, Oral; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D015195:Drug Design; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D007700:Kinetics; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D014018:Tissue Distribution; D014501:Uranium / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D002396:Catechols; D002614:Chelating Agents; D008024:Ligands; D011728:Pyridones; D014501:Uranium