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Synthesis, Structure, and Antimalarial Activity of Some Enantiomerically Pure, cis-fused cyclopenteno-1,2,4-trioxanes

Kohmoto, Shigeo
Jaggi, Danielle
Rossier, Jean-Claude
Rudaz, Manyck
Barbuzzi, Olivier
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Published in Helvetica chimica acta. 1995, vol. 78, no. 3, p. 647-662
Abstract Two pairs of enantiomerically pure cis-fused cyclopenteno-1,2,4-trioxanes (7, ent-7 and 8, ent-8) are prepared (Schemes 1-3). Their identities are established by dye-sensitized photo-oxygenation of ent-7 and 8, ent-8 to the allylichydroperxides, reduction to the corresponding alcohols, and conversion to the (1S)-camphanates (Scheme 4), the structures of which are determined by X-ray analysis. The dynamic properties of ent-7 are investigated by NMR spectroscopy and PM3 calculations. Evidence for an easily accessible twist-boat conformation is obtained. The in vitro and in vivo antimalarial activities of 7, ent-7,8, and ent-8 as well as those of the racemic mixtures are evaluated against Plasmodium falciparum, P. berghei, and P. yoelii. No correlation is observed between configuration and activity. Racemates and pure enantiomers have commensurate activities. The mode of action on the intraerythrocytic parasite is rationalized in terms of close docking by the twist-boat conformer of the trioxane on the surface of a molecule of heme, single-electron transfer to the O--O d* orbital, and scission to the acetal radical which then irreversibly isomerizes to a C-centered radical, the ultimate lethal agent (Scheme 5).
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JEFFORD, Charles et al. Synthesis, Structure, and Antimalarial Activity of Some Enantiomerically Pure, cis-fused cyclopenteno-1,2,4-trioxanes. In: Helvetica chimica acta, 1995, vol. 78, n° 3, p. 647-662. doi: 10.1002/hlca.19950780312 https://archive-ouverte.unige.ch/unige:6231

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Deposited on : 2010-04-20

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