title: Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity.
abstract: These data suggest that iron(II) reactivity for a set of homologous spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane peroxide heterocycles is a necessary, but insufficient, property of animalarial peroxides. Heme alkylation efficiency appears to give a more accurate prediction of antimalarial activity than FeSO(4)-mediated reaction rates, suggesting that antimalarial activity is not merely dependent on peroxide bond cleavage, but also on the ability of reactive intermediates to alkylate heme or other proximal targets.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schiaffo
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Jacques
authors.initials: J
authors.lastname: Chollet
authors.forename: Christian
authors.initials: C
authors.lastname: Scheurer
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Dussault
authors.forename: James K
authors.initials: JK
authors.lastname: Wood
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000478:Alkylation; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D005290:Ferric Compounds / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry*; D006418:Heme / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000737:chemistry*
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D005290:Ferric Compounds; D005296:Ferrous Compounds; D006571:Heterocyclic Compounds; D010545:Peroxides; C024823:ferric sulfate; D006418:Heme