SYNTHESIS, STRUCTURE, AND ANTIMALARIAL ACTIVITY OF SOME ENANTIOMERICALLY PURE, CIS-FUSED CYCLOPENTENO-1,2,4-TRIOXANES

Two pairs of enantiomerically 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 to the allylic hydroperoxides, reduction to the corresponding alcohols, a...

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Published inHelvetica chimica acta Vol. 78; no. 3; pp. 647 - 662
Main Authors JEFFORD, CW, KOHMOTO, S, JAGGI, D, TIMARI, G, ROSSIER, JC, RUDAZ, M, BARBUZZI, O, GERARD, D, BURGER, U, KAMALAPRIJA, P, MAREDA, J, BERNARDINELLI, G, MANZANARES, CANFIELD, CJ, FLECK, SL, ROBINSON, BL, PETERS, W
Format Journal Article
LanguageEnglish
Published BASEL NEUE SCHWEIZ CHEM GESELLSCHAFT 10.05.1995
Subjects
Chemistry
Chemistry, Multidisciplinary
Physical Sciences
Science & Technology
DRUG
CHLOROQUINE-RESISTANT PARASITES
HEME
RODENT MALARIA
INVITRO
PARAMETERS
ARTEMISININ QINGHAOSU
PLASMODIUM-BERGHEI
1,2,4-TRIOXANES
CHEMOTHERAPY
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Summary:Two pairs of enantiomerically 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 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 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 sigma* orbital, and scission to the acetal radical which then irreversibly isomerizes to a C-centered radical, the ultimate lethal agent (Scheme 5).
ISSN:0018-019X
DOI:10.1002/hlca.19950780312