Kazmierski W M, Wolberg G, Wilson J G, Smith S R, Williams D S, Thorp H H, Molina L
Division of Organic Chemistry, Burroughs Wellcome, Research Triangle Park, NC 27709, USA.
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9138-41. doi: 10.1073/pnas.93.17.9138.
The hydroxamic acid siderophore ferrioxamine B [FeIII(HDFB)+] and the iron complex of diethylenetri-aminepentaacetic acid [FeIII(DTPA)2-] protected mice against death by septic shock induced by Corynebacterium parvum + lipopolysaccharide. Although FeIII(DTPA)2- was somewhat more effective than FeIII(HDFB)+, the iron-free ligand H4DFB+ was significantly more effective than DTPA. The hydroxamic acid chelator has a much higher iron affinity than the amine carboxylate, allowing for more efficient formation of the FeIII(HDFB)+ complex upon administration of the iron-free ligand. Electrochemical studies show that FeIII(DTPA)2- binds NO stoichiometrically upon reduction to iron(II) at biologically relevant potentials to form a stable NO adduct. In contrast, FeIII(HDFB)+ is a stable and efficient electrocatalyst for the reduction of NO to N2O at biologically relevant potentials. These results suggest that the mechanism of protection against death by septic shock involves NO scavenging and that particularly effective drugs that operate a low dosages may be designed based on the principle of redox catalysis. These complexes constitute a new family of drugs that rely on the special ability of transition metals to activate small molecules. In addition, the wealth of information available on siderophore chemistry and biology provides an intellectual platform for further development.
异羟肟酸铁载体去铁胺B [FeIII(HDFB)+] 和二乙烯三胺五乙酸铁络合物 [FeIII(DTPA)2-] 可保护小鼠免受微小棒状杆菌+脂多糖诱导的脓毒性休克致死。尽管FeIII(DTPA)2- 比FeIII(HDFB)+ 稍有效，但无铁配体H4DFB+ 比DTPA显著更有效。异羟肟酸螯合剂比胺羧酸盐具有更高的铁亲和力，在给予无铁配体后能更有效地形成FeIII(HDFB)+ 络合物。电化学研究表明，在生物相关电位下，FeIII(DTPA)2- 还原为铁(II) 时按化学计量结合NO以形成稳定的NO加合物。相比之下，FeIII(HDFB)+ 在生物相关电位下是将NO还原为N2O的稳定且高效的电催化剂。这些结果表明，预防脓毒性休克致死的机制涉及NO清除，并且基于氧化还原催化原理可能设计出在低剂量下起作用的特别有效的药物。这些络合物构成了一类新的药物，它们依赖于过渡金属激活小分子的特殊能力。此外，关于铁载体化学和生物学的丰富信息为进一步开发提供了一个知识平台。
