title: Spiro- and dispiro-1,2-dioxolanes: contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides.
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.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Darren
authors.initials: D
authors.lastname: Creek
authors.forename: Jacques
authors.initials: J
authors.lastname: Chollet
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Josefina Santo
authors.initials: JS
authors.lastname: Tomas
authors.forename: Christian
authors.initials: C
authors.lastname: Scheurer
authors.forename: Christopher
authors.initials: C
authors.lastname: Snyder
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D005296:Ferrous Compounds / Q000737:chemistry*; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010084:Oxidation-Reduction; D010545:Peroxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004148:Dioxolanes; D005296:Ferrous Compounds; D010545:Peroxides; D013141:Spiro Compounds