Shanzer A, Libman J, Lytton S D, Glickstein H, Cabantchik Z I
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6585-9. doi: 10.1073/pnas.88.15.6585.
We describe here a family of biomimetic iron carriers that display high binding efficiency for ferric ions and favorable permeation properties across erythrocytic membranes. These carriers inhibit in vitro growth of Plasmodium falciparum by scavenging intracellular iron. The chemical features were realized by reproducing the iron-binding cavities of natural iron carriers (siderophores) and by systematic substitutions of their hydrophilic envelopes for more hydrophobic ones. In contrast to natural carriers, which participate in receptor-mediated iron uptake in cells and act as growth promoters, our synthetic carriers were designed to penetrate cellular membranes by diffusion, scavenge intracellular iron, and thereby act as growth inhibitors. Based on these properties we designate the compounds reversed siderophores and refer to the specific analogs of the natural ferrichrome as synthetic ferrichromes. The antimalarial activity of the synthetic ferrichromes correlated with their lipophilicity, and this antimalarial activity was averted when the chelators were applied as iron (III) complexes. The sites of synthetic ferrichrome action reside in the intraerythrocytic parasite and not in serum or on normal erythrocyte components. The agents were effective against all stages of parasite growth and against a variety of multidrug-resistant strains of P. falciparum. The most potent agent of this synthetic ferrichrome series, SF1-ileu, was not toxic to mammalian cells in culture and was 15-fold more potent and 20-fold faster acting than desferrioxamine. Taken in toto, these agents constitute a series of promising candidates for future use in malaria chemotherapy.
我们在此描述了一类仿生铁载体，它们对铁离子具有高结合效率，并对红细胞膜具有良好的渗透特性。这些载体通过清除细胞内铁来抑制恶性疟原虫的体外生长。其化学特性是通过重现天然铁载体（铁载体）的铁结合腔，并将其亲水性包膜系统地替换为更疏水的包膜来实现的。与参与细胞中受体介导的铁摄取并作为生长促进剂的天然载体不同，我们的合成载体被设计为通过扩散穿透细胞膜，清除细胞内铁，从而作为生长抑制剂。基于这些特性，我们将这些化合物称为反向铁载体，并将天然高铁色素的特定类似物称为合成高铁色素。合成高铁色素的抗疟活性与其亲脂性相关，当螯合剂以铁（III）配合物的形式应用时，这种抗疟活性就会消失。合成高铁色素的作用位点位于红细胞内的寄生虫中，而不是血清中或正常红细胞成分上。这些药物对寄生虫生长的各个阶段以及多种耐多药恶性疟原虫菌株均有效。该合成高铁色素系列中最有效的药物SF1-ileu对培养中的哺乳动物细胞无毒，其效力比去铁胺高15倍，作用速度快20倍。总体而言，这些药物构成了未来用于疟疾化疗的一系列有前景的候选药物。
