Specific Sequestering Agents for the Actinides. a6. Synthesis and Initial Biological Testing of Polydentate Oxohydroxypyridinecarboxylate Ligands

Article abstract of DOI:10.1021/jm00396a005

Chemical and biological similarities of plutonium (IV) and iron (III) suggested that octadentate ligands containing hydroxamate or catecholate functional groups, which are found in microbial iron chelating agents (siderophores), would be effective and relatively selective complexing agents for actinide(IV) ions.However, their usefulness for in vivo chelation of actinide(IV) is limited, because catechol and hydroxamate are such weak acids that the potential for octadentate binding of actinide(IV) cannot be achieved at physiological pH.The structurally similar monoprotic and more acidic 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) group was, therefore, incorporated into multidentate ligands.Treatment of 1,2-dihydro-1-hydroxy-2-oxopyridine-6-carboxylic acid (5) with phosgene in THF solution gives the active ester poly<1,2-dihydro-1,2-dioxopyridine-6-carboxylate>, which upon treatment with excess anhydrous dimethylamine gave a 60percent yield of N,N-dimethyl-1,2-dihydro-1-hydroxy-2-oxopyridine-6-carboxamide (6).A similarly reactive intermediate was prepared from 5 and and equimolar amount of phosgene in N,N-dimethylacetamide.Combined in situ with 1,3-propanediamine, benzylamine, spermine, spermidine, 1,3,5-tris(aminomethyl)benzene, or desferrioxamine B and excess triethylamine, the latter intermediate gave the corresponding amides in isolated yields ranging from 16percent to 60percent.The free ligands, their Zn(II) complexes, and their ferric complexes of 3,4,3-LIHOPO were administered to mice <30 μmol/kg intraperitoneally 1 h after Pu(IV)-238 citrate, kill at 24 h>.Net Pu removal , expressed as percent of injected Pu, was as follows: Na salt and Zn(II) complexes, respectively, of 3-LIHOPO (54,56), 3,4-LIHOPO (58,60), 3,4,3-LIHOPO (73,76); Na salts of MEHOPO (46), DFO-HOPO (78); Fe(III) complex of 3,4,3-LIHOPO (79).DFO-HOPO and 3,4,3-LIHOPO and its Zn(II) and Fe(III) complexes promoted significantly more Pu excretion than CaNa3-DTPA (61percent of injected Pu).Preliminary findings on the acute toxicity of the poly(HOPO) ligands and HOPO monomers are presented in an appendix.The biological data indicate strongly that the aqueous solubility and relatively high acidity of the octadentate HOPO ligands 3,4,3-LIHOPO and DFO-HOPO allow them to form complete eight-coordinate complexes with Pu(IV) ion.