Molenda J J, Jones M M, Cecil K M, Basinger M A
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Chem Res Toxicol. 1994 Nov-Dec;7(6):815-22. doi: 10.1021/tx00042a015.
Current attempts to remove iron from individuals suffering from iron overload have encountered difficulty due to the toxicity of the administered chelating agent. In a search for iron chelators of potentially reduced toxicity, nine monoanionic compounds have been examined. To determine the chemical features which govern their ability to induce the excretion of iron, the compounds were administered to female Sprague-Dawley rats. All carboxylate derivatives were tested for biliary excretion following iv injection, as well as for urinary excretion following iv or po injection. Sulfonate derivatives were tested for biliary and urinary excretion as well, but only one representative compound was tested po. The biological activity of the new pyridinones was compared to that of 1,2-dimethyl-3-hydroxypyrid-4-one, L1, which served as the standard. While none of the chelators was able to surpass L1 in both urinary and biliary iron excretion, all of the chelators at least equaled L1 in one of these two areas following iv administration. Two derivatives surpassed the standard in mobilizing iron into the bile, and all others were statistically equivalent. In terms of urinary excretion, two compounds were equivalent to L1 after iv administration, although none of the compounds equaled L1 when administered orally. The structure of (1,4-dihydro-3-hydroxy-2-methyl-4-oxo-1- pyridyl)methanecarboxylic acid was determined by X-ray diffraction, as this compound showed higher activity than previously reported by other investigators. We speculate that these chelators utilize organ-specific, monoanionic transport systems in the liver and kidneys to mobilize iron and that their toxicity may be substantially less than that of their neutral analogs.
目前，试图从铁过载患者体内去除铁的尝试因所使用的螯合剂具有毒性而遇到困难。为了寻找潜在毒性较低的铁螯合剂，已对九种单阴离子化合物进行了研究。为了确定决定其诱导铁排泄能力的化学特征，将这些化合物施用于雌性斯普拉格 - 道利大鼠。所有羧酸盐衍生物在静脉注射后进行胆汁排泄测试，以及在静脉注射或口服后进行尿液排泄测试。磺酸盐衍生物也进行胆汁和尿液排泄测试，但仅对一种代表性化合物进行口服测试。将新吡啶酮的生物活性与用作标准的1,2 - 二甲基 - 3 - 羟基吡啶 - 4 - 酮（L1）进行比较。虽然没有一种螯合剂在尿铁和胆汁铁排泄方面能够超过L1，但所有螯合剂在静脉给药后在这两个方面中的至少一个方面至少与L1相当。两种衍生物在将铁转运到胆汁方面超过了标准，其他所有衍生物在统计学上相当。就尿液排泄而言，两种化合物在静脉给药后与L1相当，尽管没有一种化合物在口服给药时与L1相当。通过X射线衍射确定了（1,4 - 二氢 - 3 - 羟基 - 2 - 甲基 - 4 - 氧代 - 1 - 吡啶基）甲羧酸的结构，因为该化合物显示出比其他研究者先前报道的更高的活性。我们推测这些螯合剂利用肝脏和肾脏中器官特异性的单阴离子转运系统来转运铁，并且它们的毒性可能远低于其中性类似物。
