In only four chemical steps from naturally occurring artemisinin (1), trioxane dimers 6 and 7 were prepared on a multigram scale in overall 32-44% yields. In mice, both isonicotinate N-oxide dimer 6 and isobutyric acid dimer 7 were considerably more antimalarially efficacious than clinically used sodium artesunate (2) via both oral and intravenous administration. In the transgenic adenocarcinoma of mouse prostate model, some of the trioxane dimers had potent anticancer activity.
In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.
We disclose here for the first time the curative activity of a new generation of trioxane dimers, designed logically and prepared easily from the natural trioxane artemisinin in only four or five chemical steps that would be easily accomplished also on a manufacturing scale. Four of these trioxane dimers cure malaria-infected mice after only a single subcutaneous dose, and two other dimers cure after three oral doses.
Chemical insights into artemisinin's biological mechanism of action have allowed rational design of some new trioxane and endoperoxide antimalarial drug candidates that are efficacious and safe. This review summarizes recent achievements in this area of peroxide drug development for malaria chemotherapy.
A streamlined five-step chemical synthesis of rationally designed, simplified 3-aryltrioxane 8a is described. A noteworthy feature of this synthetic scheme is use of air rather than expensive molecular oxygen as the source of the pharmacologically critical peroxide unit in trioxane 8a. This simplified acetal trioxane carboxylic acid 8a is thermally stable, and it is hydrolytically stable in water even at 40 degrees C and pH 7.4 for at least 7 days. Preclinical evaluation of this water-soluble synthetic trioxane 8a in rodents shows it to have at least as good a therapeutic index (efficacy/toxicity) as that of water-soluble semisynthetic trioxane artelinic acid (5).
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