Iron(II)-Induced Degradation of Antimalarial β-Sulfonyl Endoperoxides. Evidence for the Generation of Potentially Cytotoxic Carbocations
- 13 September 2001
- journal article
- Published by American Chemical Society (ACS) in The Journal of Organic Chemistry
- Vol. 66 (20) , 6531-6540
- https://doi.org/10.1021/jo001265z
Abstract
Reactions of antimalarial β-sulfonyl endoperoxides 9 and 10, which, like yingzhaosu A (2), derive from the 2,3-dioxabicyclo[3.3.1]nonane system 3, with iron(II) salts were studied. Product analysis of the iron(II)-induced degradations provided evidence for the intermediacy of carbon-centered cyclohexyl radicals 20 and 31 and their possible oxidation to the corresponding carbocations 21 and 32. It is conceivable that the antimalarial activity of β-sulfonyl endoperoxides of type 5 may derive from alkylation of vital intraparasitic biomolecules by free radicals and/or carbocations, generated within the malaria parasite through a similar iron(II)-induced degradation process.Keywords
This publication has 23 references indexed in Scilit:
- Ferryl–oxo heme intermediate in the antimalarial mode of action of artemisininFEBS Letters, 2000
- Alkylating Properties of Antimalarial Artemisinin Derivatives and Synthetic Trioxanes when Activated by a Reduced Heme ModelChemistry – A European Journal, 1998
- Synthesis and in vitro antimalarial activity of sulfone endoperoxidesBioorganic & Medicinal Chemistry Letters, 1998
- Is alkylation the main mechanism of action of the antimalarial drug artemisinin?Chemical Society Reviews, 1998
- Artemisinin mediated alteration of haemin to a δ-meso oxidation product: relevance to mechanism of actionJournal of the Chemical Society, Perkin Transactions 1, 1998
- Characterization of the First Covalent Adduct between Artemisinin and a Heme ModelJournal of the American Chemical Society, 1997
- Evidence for the Importance of High-Valent FeO and of a Diketone in the Molecular Mechanism of Action of Antimalarial Trioxane Analogs of ArtemisininJournal of the American Chemical Society, 1996
- Evidence for Fe(IV):O in the Molecular Mechanism of Action of the Trioxane Antimalarial ArtemisininJournal of the American Chemical Society, 1995
- Reaction of antimalarial endoperoxides with specific parasite proteinsAntimicrobial Agents and Chemotherapy, 1994
- Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial actionMolecular and Biochemical Parasitology, 1991