Spiro- and dispiro-1,2-dioxolanes: contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides
| Autor: | Sergio Wittlin, Josefina Santo Tomas, Jonathan L. Vennerstrom, Jacques Chollet, Xiaofang Wang, Darren J. Creek, Yuxiang Dong, Christopher Snyder, Susan A. Charman, Christian Scheurer |
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| Rok vydání: | 2007 |
| Předmět: |
Organic peroxide
Stereochemistry Plasmodium berghei Radical Plasmodium falciparum Drug Resistance Medicinal chemistry Chemical synthesis Ion chemistry.chemical_compound Antimalarials Mice Structure-Activity Relationship Transition metal Drug Discovery Structure–activity relationship Animals Spiro Compounds Ferrous Compounds Ozonolysis Geminal Dioxolanes Malaria Peroxides chemistry Molecular Medicine Oxidation-Reduction |
| Zdroj: | Journal of medicinal chemistry. 50(23) |
| ISSN: | 0022-2623 |
| Popis: | Fourteen spiro- and dispiro-1,2-dioxolanes were synthesized by peroxycarbenium ion annulations with alkenes in yields ranging from 30% to 94%. Peroxycarbenium ion precursors included triethylsilyldiperoxyketals and -acetals derived from geminal dihydroperoxides and from a new method employing triethylsilylperoxyketals and -acetals derived from ozonolysis of alkenes. The 1,2-dioxolanes were either inactive or orders of magnitude less potent than the corresponding 1,2,4-trioxolanes or artemisinin against P. falciparum in vitro and P. berghei in vivo. In reactions with iron(II), the predominant reaction course for 1,2-dioxolane 3a was two-electron reduction. In contrast, the corresponding 1,2,4-trioxolane 1 and the 1,2,4-trioxane artemisinin undergo primarily one-electron iron(II)-mediated reductions. The key structural element in the latter peroxides appears to be an oxygen atom attached to one or both of the peroxide-bearing carbon atoms that permits rapid beta-scission reactions (or H shifts) to form primary or secondary carbon-centered radicals rather than further reduction of the initially formed Fe(III) complexed oxy radicals. |
| Databáze: | OpenAIRE |
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