Loyevsky M, Lytton S D, Mester B, Libman J, Shanzer A, Cabantchik Z I
Department of Biological Chemistry, Hebrew University of Jerusalem, Israel.
J Clin Invest. 1993 Jan;91(1):218-24. doi: 10.1172/JCI116174.
We designed the N-methylanthranilic-desferrioxamine (MA-DFO) as a fluorescent iron (III) chelator with improved membrane permeation properties. Upon binding of iron (III), MA-DFO fluorescence is quenched, thus allowing traceability of drug-iron (III) interactions. MA-DFO is well tolerated by mammalian cells in culture. Its antimalarial activity is pronounced: IC50 values on in vitro (24-h) growth of Plasmodium falciparum were 3 +/- 1 microM for MA-DFO compared with 30 +/- 8 for DFO. The onset of growth inhibition of rings or trophozoites occurs 2-4 h after exposure to 13 microM MA-DFO. This effect is commensurate with MA-DFO permeation into infected cells. In a 24-h exposure to MA-DFO or DFO, trophozoites take up either compound to approximately 10% of the external concentration, rings to 5%, and noninfected cells to < 1%. Red cells encapsulated with millimolar concentrations of DFO or MA-DFO fully support parasite invasion and growth. We conclude that extracellular MA-DFO and DFO gain selective access into parasites by bypassing the host. The rate-limiting step is permeation through the parasite membrane, which MA-DFO accomplishes faster than DFO, in accordance with its higher hydrophobicity. These views are consistent with the proposed duct, which apparently provides parasitized cells with a window to the external medium.
我们设计了N-甲基邻氨基苯甲酸-去铁胺（MA-DFO）作为一种具有改善膜渗透特性的荧光铁（III）螯合剂。与铁（III）结合后，MA-DFO的荧光被淬灭，从而能够追踪药物与铁（III）的相互作用。MA-DFO在培养的哺乳动物细胞中耐受性良好。其抗疟活性显著：对于MA-DFO，恶性疟原虫体外（24小时）生长的IC50值为3±1微摩尔，而DFO为30±8微摩尔。在暴露于13微摩尔MA-DFO后2-4小时，环状体或滋养体的生长抑制开始。这种效应与MA-DFO渗透到受感染细胞中相一致。在24小时暴露于MA-DFO或DFO的情况下，滋养体摄取两种化合物的量约为外部浓度的10%，环状体为5%，未感染细胞为<1%。用毫摩尔浓度的DFO或MA-DFO包裹的红细胞完全支持寄生虫的入侵和生长。我们得出结论，细胞外的MA-DFO和DFO通过绕过宿主选择性地进入寄生虫。限速步骤是通过寄生虫膜的渗透，MA-DFO比DFO完成得更快，这与其更高的疏水性一致。这些观点与所提出的管道一致，该管道显然为被寄生的细胞提供了一个通向外部介质的窗口。
