Synthesis,Structure, and Antimalarial Activity of Some Enantiomerically Pure,cis-fused cyclopenteno-1,2,4-trioxanes |
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Authors: | Charles W Jefford Shigeo Kohmoto Danielle Jaggi Gza Timri Jean-Claude Rossier Manyck Rudaz Olivier Barbuzzi David Grard Ulrich Burger Philippe Kamalaprija Jiri Mareda Grald Bernardinelli Ignacio Manzanares Craig J Canfield Suzanne L Feck Brain L Robinson Wallace Peters |
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Institution: | 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 |
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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 σ* 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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