Degradation arteflene

Although arteflene 5 is not a 1,2,4-trioxane, its mechanism of action is believed to be very similar to trioxanes dne to the presence of the peroxide bond. Indeed, when radioactive C-arteflene was incnbated with P. falciparum, several alkylated parasitic proteins were identified . The O Neill gronp carried out the first iron(II) degradation studies of arteflene using iron(II) chloride in aqneons acetonitrile they isolated enone 63a (in tandem with radical 63b) and diol 64a (Scheme 19A). The degradation with heme (generated from hemin chloride by A-acetylcysteine) was observed to be slower, but afforded the same products although in different ratio. 

Meunier and coworkers investigated the degradation of arteflene using manganese(II) TPP as a heme model. They were able to spin-trap the secondary C-centred radical with the piperidyl radical (TEMPO) and the adduct 64c was fully characterized following acetylation of the crude reaction mixture (Scheme 20). An arteflene-heme adduct was not observed and the authors suggest that this is attributable to steric hindrance factors. However, this could be further evidence that endoperoxide antimalarials do not target heme. 

Based on the potent activity of arteflene and yingzhaosu A, Bachi and coworkers developed a very efficient synthesis of bicyclic /3-sulphonyl endoperoxides (65a and 65b) (described in more detail later). In order to gain insight into the potential mechanism of action of analogues in this class, Bachi and coworkers investigated the iron(II)-induced as used previously by degradation of 65a and 65b. The conditions used were based on those used previously by Posner and coworkers and Avery and coworkers. ... 

In effect, antimalarial trojan horse drugs of this type should deliver a double blow to the parasite by exploiting the presence of high concentrations of ferrous ion present in the parasite food vacuole as the trigger for protease inhibitor release. In model studies with prototype 81d, in the presence of ferrous ions, these systems readily degrade to produce the desired chalcone (82b, R = H, in 45% yield from 81d), in tandem with secondary carbon-centred radical 82a (Scheme 29). Furthermore, analogues 81d-f have superior in vitro antimalarial activity to that of arteflene (<25 nM in vitro versus Plasmodium falciparum, arteflene >50 nM). The other product obtained is the diol (82c), a product of two-electron reduction of the endoperoxide bridge. 

The EPR spin-trapping techniques were used to obtain evidence for the formation of a radical intermediate in the biomimetic Fe(n)-induced degradation of arteflene 194 in the presence of sodium 3,5-dibromo-4-nitrosobenzene-sulfonate (DBNBS) and 5,5-dimethyl-l-pyrroline /V-oxide (DMPO) <2000JOC1578>. 

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