Spiro- and dispiro-1,2-dioxolanes: contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides

J Med Chem. 2007 Nov 15;50(23):5840-7. doi: 10.1021/jm0707673. Epub 2007 Oct 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Dioxolanes / chemical synthesis*
  • Dioxolanes / chemistry
  • Dioxolanes / pharmacology
  • Drug Resistance
  • Ferrous Compounds / chemistry*
  • Malaria / drug therapy
  • Mice
  • Oxidation-Reduction
  • Peroxides / chemical synthesis*
  • Peroxides / chemistry
  • Peroxides / pharmacology
  • Plasmodium berghei
  • Plasmodium falciparum / drug effects
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Dioxolanes
  • Ferrous Compounds
  • Peroxides
  • Spiro Compounds