Xu J, Kullgren B, Durbin P W, Raymond K N
Department of Chemistry, University of California, Berkeley 94720, USA.
J Med Chem. 1995 Jul 7;38(14):2606-14. doi: 10.1021/jm00014a013.
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.
报道了一类基于4-(取代氨基甲酰基)-3-羟基-2-吡啶酮的新型螯合剂。这些螯合剂在氮原子上有可选的末端取代基，并且羟基吡啶酮（HOPO）环通过酰胺键连接到分子主链上。甲基取代的配体衍生物（Me-3,2-HOPOs）的一个非常重要的特征是，与铁载体肠杆菌素及其类似物的儿茶酚酰胺配合物类似，这些HOPO衍生物在金属配合物中酰胺质子与酚盐的相邻氧之间形成强氢键；这增强了配合物的稳定性。这种刚性有助于解释在此生理条件下观察到的Me-3,2-HOPO配体对钚（IV）的高亲和力。与注射钚的对照组相比，所研究的所有13种化合物均显著增强了小鼠体内钚的排泄。所研究的8种配体促进钚排泄的能力明显高于等摩尔量的CaNa3-DTPA（目前临床使用的化合物）。5种注射给药和2种口服给药的Me-3,2-HOPO配体促进钚排泄的能力与等摩尔量的八齿3,4,3-LI(1,2-HOPO)相同或略高，3,4,3-LI(1,2-HOPO)是之前体内最有效的配体。令人惊讶的是，尽管钚需要八配位，但四齿和六齿的Me-3,2-HOPO配体与所研究的一种八齿配体基本一样有效。这些观察结果表明，即使是四齿的Me-3,2-HOPO配体也能与哺乳动物转铁蛋白竞争钚（IV）。对于三种最有前景的化合物，在高达1000 μmol/kg的最高给药剂量下未观察到急性毒性。一种化合物，六齿的TREN-(Me-3,2-HOPO)，无论是注射还是口服都特别有效，并且除了钚（IV）之外，还是几种锕系元素的出色体内螯合剂。所研究的这些化合物中有三种毒性低，制备相对简单且成本低廉。它们是很有前景的治疗药物。
