Hybrid drugs with a twist: The coupling of iron(II)‐promoted trioxolane ring scission with a β‐elimination reaction enables the targeted delivery of multiple drug activities to the malaria parasite. A prototypical fragmenting hybrid (shown) comprises an iron(II)‐reactive 1,2,4‐trioxolane ring (red) joined via a masked retro‐Michael linker (blue) to a partner drug—in this case a protease inhibitor (green). Successful delivery of the protease inhibitor to intra‐erythrocytic Plasmodium falciparum parasites is demonstrated using a chemical–biological approach.
A concise asymmetric approach to the indeno-tetrahydropyridine core of the unusual alkaloid haouamine B allowed for an investigation of a biomimetic oxidative phenol coupling as a proposed biosynthetic step, and ultimately provided access to the published structure of the natural product. As a consequence of our synthetic studies, the structure of haouamine B has been revised.
The 1,2,4-trioxolanes are a new class of synthetic peroxidic antimalarials currently in human clinical trials. The well known reactivity of the 1,2,4-trioxolane ring towards inorganic ferrous iron and ferrous iron heme is proposed to play a role in the antimalarial action of this class of compounds. We have designed structurally relevant fluorescent chemical probes to study the sub-cellular localization of 1,2,4-trioxolanes in cultured Plasmodium falciparum parasites. Microscopy experiments revealed that a probe fluorescently labeled on the adamantane ring accumulated specifically in digestive vacuole-associated neutral lipid bodies within the parasite while an isosteric, but non-peroxidic congener did not. Probes fluorescently labeled on the cyclohexane ring showed no distinct localization pattern. In their sub-cellular localization and peroxidative effects, 1,2,4-trioxolane probes behave much like artemisinin-based probes studied previously. Our results are consistent with a role for adamantane-derived carbon-centered radicals in the antimalarial action of 1,2,4-trioxolanes, as hypothesized previously on the basis of chemical reactivity studies.
The antimalarial agents artemisinin and arterolane act via initial reduction of a peroxide bond in a process likely mediated by ferrous iron sources in the parasite. Here, we report the synthesis and antiplasmodial activity of arterolane-like 1,2,4-trioxolanes specifically designed to release a tethered drug species within the malaria parasite. Compared to our earlier drug delivery scaffolds, these new arterolane-inspired systems are of significantly reduced molecular weight and possess superior metabolic stability. We also demonstrate the use of the aminonucleoside antibiotic puromycin as a chemo/biomarker to validate successful drug release in live P. falciparum parasites.
The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe II ) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe II -sensitive "trigger," making drug release contingent on Fe II -promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe II -dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe II -targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron.iron-mediated delivery | targeted prodrugs | dipeptidyl peptidase | combination therapy
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