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

✍ Scribed by Charles W. Jefford; Shigeo Kohmoto; Danielle Jaggi; Géza Timári; Jean-Claude Rossier; Manyck Rudaz; Olivier Barbuzzi; David Gérard; Ulrich Burger; Philippe Kamalaprija; Jiri Mareda; Gérald Bernardinelli; Ignacio Manzanares; Craig J. Canfield; Suzanne L. Feck; Brain L. Robinson; Wallace Peters

Publisher
John Wiley and Sons
Year
1995
Tongue
German
Weight
891 KB
Volume
78
Category
Article
ISSN
0018-019X

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✦ Synopsis

Two pairs of enantiomerically pure cis-fused cyclopenteno-l,2,4-trioxanes (7, en!-7 and 8, ent-8) are prepared (Schemes 1-3). Their identities are established by dye-sensitized photo-oxygenation of ent-7 and 8 to the allylic hydroperoxides, reduction to the corresponding alcohols, and conversion to the (1s)-camphanoates (Scheme 4 ) , the structures of which are determined by X-ray analysis. The dynamic properties of em-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 faleiparum, 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 0-0 u* 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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