Specific Sequestering Agents for the Actinides. 28. Synthesis and Initial Evaluation of Multidentate 4-Carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone Ligands for in Vivo Plutonium(IV) Chelation

Abstract

A new family of chelating agents based on 4-(substituted-carbamoyl)-3-hydroxy-2-pyridinones is reported. These have optional terminal substituents on the nitrogens, and the hydroxypyridonate (HOPO) rings are attached to molecular backbones through amide linkages. A very important feature of the methyl-substituted ligand derivatives (Me-3,2-HOPOs) is that, similarly to the catechoylamide complexes of the siderophore enterobactin and its analogs, these HOPO derivatives form strong hydrogen bonds between the amide proton and the adjacent oxygen of the phenolate in the metal complex; this enhances the stability of the complex. This rigidity helps to explain the great affinity of the Me-3,2-HOPO ligands for plutonium(IV), as observed here under physiological conditions. All 13 compounds studied significantly enhanced Pu excretion from mice compared with Pu-injected controls. Eight of the ligands studied promoted significantly more Pu excretion than an equal molar amount of CaNa3-DTPA (the compound in present clinical use). Five injected and two orally administered Me-3,2-HOPO ligands promoted as much or slightly more Pu excretion than an equal molar amount of the octadentate 3,4,3-LI(1,2-HOPO), the previously most effective in vivo ligand. Surprisingly, although plutonium has an eight-coordination requirement, tetra- and hexadentate Me-3,2-HOPO ligands were essentially as effective as the one octadentate ligand studied. These observations suggest that even the tetradentate Me-3,2-HOPO ligands compete with mammalian transferrin for Pu(IV). For the three most promising compounds, there is no acute toxicity seen up to the highest dose administered, which was 1000 mumol/kg. One compound, the hexadentate TREN-(Me-3,2-HOPO), is particularly effective, either injected or orally, and an exceptionally good in vivo chelator of several actinides in addition to Pu(IV). Three of these compounds studied have low toxicity and are relatively simple and inexpensive to prepare. They are promising therapeutic agents.

Advanced Extraction Methods for Actinide/Lanthanide Separations

“…32,33 The attachment of the CMPS moieties was facilitated using synthetic methodology developed for preparation of the hydroxypyridinones. 39 Since all steps of these syntheses are high yielded, multi-gram quantities of ligands were produced with little synthetic effort…”

The Hexadentate Hydroxypyridinonate TREN‐(Me‐3,2‐HOPO) is a More Orally Active Iron Chelator Than Its Bidentate Analogue

“…Among those developed, the bidentate hydroxypyridinones, 3-hydroxy-4-(1H)-pyridinones (3,4-HOPOs), developed by Hider et al 5 have proven efficacy as Fe chelators. The 4-carboxy-3-hydroxy-1-methyl-2-(1H)-pyridinones (Me-3,2-HOPOs) developed in the laboratory of Dr. Kenneth Raymond 6 have potential efficacy as Fe chelators. When ionized, these HOPO isomers are isoelectronic with catechol, the bidentate functional group of hexadentate enterobactin, a powerful naturally produced Fe chelator.…”

“…7 10 and can be produced at a reasonable cost. 6,8,[10][11][12] Preclinical studies of the bidentate CP20 suggested a potency comparable to DFO when the 1:3 metal/chelator stoichiometry required to form the preferred hexacoordinated ferric complex was considered. 11 Clinical investigations of in vivo Fe chelation have been initiated with CP20, but bone marrow cytotoxicity, presumably associated with the large amounts of CP20 needed for effective Fe removal from the human, is a serious concern.…”

“…22 A hexadentate HOPO chelator is expected to have the following advantages over both DFO and bidentate chelators in vivo: more powerful metal complexation at low chelator concentration, complete and stable metal binding, and favorable reaction kinetics at physiologic pH. 6,23,24 A potential disadvantage of multidentate HOPO chelators is poor gastrointestinal (GI) absorption caused by hydrophilicity and high molecular weight. However, hydrophilicity does not correlate well with bioavailability or the efficacy of the bidentate 3,4-HOPOs.…”

“…Absorption of a small fraction of highly effective multidentate HOPO chelators markedly augments metal excretion; this effect is dose dependent. 6,[26][27][28] The aims of this study were to test the hypothesis that increasing the denticity of an HOPO chelator from 2 to 6 increases its in vivo Fe chelation efficacy. This hypothesis was based on the expected advantages of matching the number of donor atoms of the chelator to the coordination requirement of the metal.…”