Ferric ion sequestering agents. 11. Synthesis and kinetics of iron removal from transferrin of catechoyl derivatives of desferrioxamine B.
Ferric ion sequestering agents. 11. Synthesis and kinetics of iron removal from transferrin of catechoyl derivatives of desferrioxamine B.
复制标题
三价铁离子螯合剂。
DOI：
10.1021/jm00357a022
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发表时间：
1983
影响因子：
7.3
通讯作者：
Raymond,KN
中科院分区：
文献类型：
--
作者：
Rodgers,SJ;Raymond,KN
目前用于治疗跨融合铁超载的首选药物是Desferal，这是三羟氨酸铁载体去铁胺B的甲磺酸盐酸盐。虽然Desferal已被证明在服用多年时可诱导/3地中海贫血患者铁排泄增加和降低肝脏铁含量，5其缺点包括缺乏口服活动和体内滞留时间短，这就需要通过繁琐而昂贵的缓慢皮下或静脉输注的方法来给药。为了改善去铁胺B的临床性质，Bickel等人报道了去铁胺B的临床应用。制备了一些将酰基连接到去铁胺B的末端氨基上的衍生物6 78910这些衍生物中没有一个具有任何额外的螯合能力，显然不会增加药物在体内的除铁性能。评估铁络合剂可能的医疗效果的一个常用标准是它从哺乳动物铁转运蛋白转铁蛋白中除铁的能力。邻苯二酚类铁载体和合成类似物在热力学和动力学上都能够去除转铁蛋白结合的铁。7，8相反，Desferal虽然在热力学上有能力，但在体内和体外清除转铁蛋白铁的动力学速度很慢，9，10这一特性可能是所有羟基磷酸盐铁载体的共同属性。为了使转铁蛋白结合的铁能够动力学地进行络合，我们在去铁胺B的末端氨基上连接了单儿茶酚基团。
The current drug of choice for the treatment of trans-fusional iron overload is Desferal, the mesylate saltof the trihydroxamate siderophore desferrioxamine B. While Desferal has been shownto induce increased iron excretion and reduce liver iron in/3-thalassemic patients when ad-ministered over a period of years, 5 its drawbacks include a lack of oral activity and a short body retention time, which necessitates its administration by the cumbersome and expensive methods of slow subcutaneous or intrave-neous infusion. In an attempt to improve theclinical properties of desferrioxamine B, Bickel etal. prepared a number of derivatives in which acyl groups were attached to the terminal amino group of desferrioxamine B. 6 78910None of these derivatives had any extra chelating abilities and apparently did not increase the drug’s iron-removing properties in vivo.A frequently used criterion for evaluating the possible medical efficacy of an iron-chelating agent is its ability to remove iron from transferrin, the mammalian iron trans-port protein. Catechol-based siderophores and synthetic analogues are both thermodynamically and kinetically capable of removing transferrin bound iron. 7, 8 In contrast, Desferal, although thermodynamically capable, is kinetically slow in removing transferrin iron both in vivo and in vitro, 9, 10 a property that may be common to all hy-droxamate siderophores. In an attempt to make transferrin-bound iron kinetically available for chelation, we have attached single catechol groups to the terminal amino group of desferrioxamine B. The synthesis and kinetics