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Two new norsesterterpene 1,2-dioxanes, mycaperoxides A (2) and B (3), have been isolated from a Thai sponge of the genus Mycale. Their relative structures were determined by X-ray and spectroscopic methods and their absolute configurations assigned by applying the Kusumi and Kakisawa modification of Mosher's method. Both compounds showed significant cytotoxicity and in vitro antiviral activity.

The discovery that the sesquiterpene peroxide yingzhaosu A (13) and 1,2,4-trioxane artemisinin (14) are active against chloroquine-resistant strains of Plasmodium falciparum, has opened a new era in the chemotherapy of malaria. In vitro and in vivo tests with synthetic structurally simpler trioxanes clearly demonstrate that much of the skeleton of 14 is redundant and that chirality is not required for activity. In addition, structure-activity relations and the search for the pharmacophore reveal that high antimalarial activity can be displayed by molecules which do not resemble the geometry of 13 and 14 at all. The possible mode of action of 13, 14, and synthetic peroxides is examined. They are believed to kill intraerythrocytic Plasmodium by interacting with the heme discarded by proteolysis of ingested hemoglobin. Complexation of heme with the peroxide bond followed by electron transfer generates an oxy radical that evolves to the ultimate parasiticidal agent. Experiments with ferrous reagents indicate that active peroxides including 14 and its congeners kill the parasite by alkylation with a sterically non-encumbered C-centered radical. However, another possibility is the involvement of a Fe(IV)=O species as the toxic agent. The review covers our own and other contributions to this timely topic and evaluates the different mechanisms proposed for the mode of action of peroxidic antimalarials.

The treatment of artemisinin (1) and ß-artemether (6) with Zn dissolving in AcOH for a few hours results in mono-deoxygenation giving deoxyartemisinin (5) and deoxy-ß-artemether (7), respectively, as the sole product. In contrast, submission of 1 to FeCl2 · 4 H2O in MeCN at room temperature for 15 min causes only isomerization, (3aS,4R,6aS,7R,10S,10aR)-octahydro-4,7-dimethyl-8-oxo-2H-10H-furo[3,2-i] benzopyran-10-yl acetate (8) and (3R)-3-hydroxydeoxyartemisinin (9) being produced in 78 and 17% yield, respectively. The action of FeCl2 · 4 H2O in MeCN on 6 is similar. Under the same conditions, 6 gives products analogous to 8 and 9 accompanied by an epimeric mixture of 2-[4-methyl-2-oxo-3-(3-oxobutyl)cyclohexyl]propanaldehyde in yields of 32, 23, and 16%, respectively. No epoxide is formed on repeating the last two experiments in the presence of cyclohexene. The deoxygenation of 1 and 6 by Zn is rationalized in terms of its oxophilic nature. The catalyzed isomerization of 1 and 6 by Fe2+ is attributed to the redox properties of the Fe2+/Fe3+ system

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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 ) .