The biomimetic iron-mediated degradation of arteflene (Ro-42-1611),an endoperoxide antimalarial: Implications for the mechanism of antimalarial activity

Kinetics of iron-mediated artemisinin degradation: Effect of solvent composition and iron salt

“…4,25,29 The literature contains a number of reports of the reaction of iron or haem with artemisinin or related endoperoxides. 5,14,15,26,27,30,31 However, the use of significantly different reaction conditions, such as solvent composition, iron salt form, reagent concentration, and temperature, has resulted in conflicting reports of the preferential degradation pathway and relative reactivity of artemisinin and its analogs. Furthermore, attempts to correlate iron reactivity with antimalarial activity may also be unreliable due to the effect of reaction conditions that all differ significantly from the biological situation.…”

Safety assessment of peroxide antimalarials: clinical and chemical perspectives

“…More recently, we have proposed a mechanism of action for arteflene based on similar mechanistic studies using Fe(II) salts [ 53]. Arteflene, on reaction with FeCl 2 .4H 2 O, yielded two products, the two‐electron reduction diol product and the enone, a surrogate marker for the formation of the cyclohexyl radical ( Figure 5).…”

“…However, this ability depends upon the regeneration of iron (II), which may be prevented by binding of Fe(III) to a carrier protein [ 49]. Iron complexed to haem also catalyses the bioactivation of peroxide antimalarials [ 53], and this activity appears to be preserved in haemothiolate enzymes [ 55]. In contrast, cytochrome P450 enzymes can effect the hydroxylation of either artemisinin or arteflene at a site close (<2 A°) to the peroxide bridge without necessarily activating the peroxide bridge [ 54].…”

Design and Synthesis of Endoperoxide Antimalarial Prodrug Models

“…Biomimetic Fe II ‐induced degradation reactions of arteflene ( 7 ) provided some clues on the mode of action of these endoperoxides 22. 23 Thus, on being subjected to ferrous‐mediated fragmentation in water/MeCN, arteflene ( 7 ) gave the stable enone 10 and the transient carbon‐centered cyclohexyl radical 11 (Scheme ) 22.…”

“…Biomimetic Fe II ‐induced degradation reactions of arteflene ( 7 ) provided some clues on the mode of action of these endoperoxides 22. 23 Thus, on being subjected to ferrous‐mediated fragmentation in water/MeCN, arteflene ( 7 ) gave the stable enone 10 and the transient carbon‐centered cyclohexyl radical 11 (Scheme ) 22. This latter species was directly detected by EPR23 and trapped with TEMPO (2,2,6,6‐tetramethylpiperidinyloxy) in a degradation induced by Mn II –tetraphenylporphyrin (TPP) 24.…”