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New ligands based on hydroxypyridinonate (HOPO) and other bidentate ligands are explored as iron(III) sequestering agents. These are based on the N,N',N"-tris[(3-hydroxy-1-methyl- 2-oxo-1,2-didehydropyrid-4-yl)-carboxamidoethyl]amine (TREN-Me-3,2-HOPO) platform in which one Me-3,2-HOPO ligand group is substituted with either a 2-hydroxyisophthalamide (TREN-Me-3,2-HOPOIAM) or a 2,3-dihydroxyterephthalamide (TREN-Me-3,2-HOPOTAM) moiety. The ferric complexes have been prepared and structurally characterized by X-ray diffraction: Fe[TREN-Me-3,2-HOPOIAM] crystallizes in the monoclinic space group C2/c with cell parameters a = 18.1186(3) A, b = 17.5926(2) A, c = 25.0476(2) A, beta = 98.142(1) degrees, Z = 8. Fe[TREN-Me-3,2-HOPOTAM]- crystallizes in the monoclinic space group C2/c with cell parameters a = 31.7556(12) A, b = 14.0087(6) A, c = 22.1557(9) A, beta = 127.919(1) degrees, Z = 8. The aqueous coordination chemistry of these ligands with both the ferric and ferrous redox states of iron has been examined using spectroscopic and electrochemical methods, giving log formation constants of 26.89(3) (beta 110), 31.16(6) (beta 111) for the ferric TREN-Me-3,2-HOPOIAM complexes and 33.89(2) (beta 110), 38.45(2) (beta 111) for the ferric TREN-Me-3,2-HOPOTAM complexes. For the reduced (ferrous) complexes values of 10.03(9) (beta 110) and 13.7(2) (beta 110) were observed for the Fe[TREN-Me-3,2-HOPOIAM]- and Fe[TREN-Me-3,2-HOPOTAM]2- complexes, respectively. These data provide a complete description of metal-ligand speciation as a function of pH and of redox activity. The ligands described in this work are part of a new class of heteropodate ligands which exploit the various chelating properties of several binding units within a single tripodal ligand and allow for systematic variation of the properties for medical or other applications.

Chelating agents were tested for removal of simultaneously injected Pu-238 and Am-241 from the rat. The effectiveness of early single chelate injections of Pu-238 retention in tissues decreased in the order 3,4,3-LIHOPO > DFO-HOPO > DTPA > DTPA-DX, and for Am-241 in the order 3,4,3-LIHOPO > DTPA-DX > DTPA >> DFO-HOPO. DTPA-DX showed a special ability to remove Am-241 from the liver. Injected 3,4,3-LIHOPO decreased the contents of Pu-238 in bone and liver to 9 and 3%, respectively, of those in untreated controls. Corresponding values for Am-241 in bone and liver were 30 and 6%, respectively, which indicates that 3,4,3-LIHOPO (unlike DFO-HOPO) is not a plutonium-specific chelator. The effectiveness of prompt single oral treatment with 3,4,3-LIHOPO and DFO-HOPO in reducing retention of actinides was comparable with that of those chelators injected with 1 h delay and at one-third of the oral dose. When 3,4,3-LIHOPO was administered by continuous infusion, a superior effect was achieved with total chelate amounts only slightly exceeding that given as single injection. The retention of PU-238 and Am-241 in bones was reduced to < 5 and 10% of controls, respectively; the contents in the liver were < 2% of controls.