Investigating the antimalarial action of 1,2,4-trioxolanes with fluorescent chemical probes.
The 1,2,4-trioxolanes are a new class of synthetic peroxidic antimalarials currently in human clinical trials. The well-known reactivity of the 1,2,4-trioxolane ring toward inorganic ferrous iron and ferrous iron heme is proposed to play a role in the antimalarial action of this class of compounds. We have designed structurally relevant fluorescent chemical probes to study the subcellular localization of 1,2,4-trioxolanes in cultured  Plasmodium falciparum  parasites. Microscopy experiments revealed that a probe fluorescently labeled on the adamantane ring accumulated specifically in digestive vacuole-associated neutral lipid bodies within the parasite while an isosteric, but nonperoxidic, congener did not. Probes fluorescently labeled on the cyclohexane ring showed no distinct localization pattern. In their subcellular localization and peroxidative effects, 1,2,4-trioxolane probes behave much like artemisinin-based probes studied previously. Our results are consistent with a role for adamantane-derived carbon-centered radicals in the antimalarial action of 1,2,4-trioxolanes, as hypothesized previously on the basis of chemical reactivity studies.
Department of Biological Sciences, Old Dominion University, Norfolk, Virginia, United States.
Carmony L
CL
Hartwig
Erica M W
EM
Lauterwasser
Sumit S
SS
Mahajan
Jonathan M
JM
Hoke
Roland A
RA
Cooper
Adam R
AR
Renslo
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001190:Arylsulfonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
D000962:Antimalarials; D001190:Arylsulfonates; D005456:Fluorescent Dyes; D009281:Naphthalenes; D010545:Peroxides; D000218:Adamantane