Four 5-carbon-linked trioxane dimer orthoesters (6a-6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally.
Keywordsantimalarial chemotherapy; trioxane dimer orthoesters; single oral dose ACT cure Many standard antimalarial drugs like chloroquine are no longer effective due to widespread resistance. 1 A new non-alkaloid class of antimalarial artemisinin trioxanes 2-9 , based on ancient Chinese folk medicine, is now recommended by the World Health Organization (WHO) and is being adopted widely [10][11][12][13][14][15][16] ; artemisinin combination therapy (ACT) features the very rapid clearance of most of the parasites by the trioxane drug followed by the prolonged antimalarial action of the partner drug. Typically, fixed dose combinations are used 17 , with the most popular example being a curative 6 dose regimen of a 1:6 fixed combination of artemether (total 320 mg) and lumefantrine (total 1920 mg). Often, however, patient compliance with a repeated-dose regimen is problematic. Therefore, a single dose cure of malaria-infected humans is highly desirable. Toward this goal, we have developed some trioxane monomers 18 and dimers 19 able to cure malaria-infected mice using only a single low oral dose combined with mefloquine. We recently reported a new series of 5-Supplementary data Supplementary data (experimental details and spectroscopic data for 5 and 6a-d) associated with this article can be found in the online version.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2012 May 1.
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript carbon-linked trioxane dimers 4 which, combined with mefloquine, cure malaria-infected mice 20 . We report here a new series of 5-carbon-linked trioxane dimer orthoesters 6a-d.C-10 Acetoxy artemisinin 2b, prepared in nearly quantitative yield by reducing and then acetylating artemisinin ((1 → 2a → 2b) 21 , reacted with silylated 5-carbon-linker 3 to form 10β,10β-dimer allylic alcohol 4 as the major product in 65% yield (Figure 1) 20 . Scale up is not expected to be problematic. Dithexylborane hydroboration of bis-allylic...
An enantioselective total synthesis of (+)-jasplakinolide is described. The synthesis of the polyketide template utilized a diastereoselective syn-aldol, ortho-ester Claisen rearrangement followed by efficient conversion to a cyanide. The beta-amino acid unit was constructed in a highly diastereoselective manner utilizing nucleophilic addition to a chiral sulfinimine. Yamaguchi macrocyclization and removal of the protecting group provided a convenient access to (+)-jasplakinolide.
Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure.
Synthesis and biological evaluation of jasplakinolide analogs are described. The synthesis of analogs utilized a diastereoselective syn-aldol reaction and an orthoester Claisen rearrangement as key steps. All synthetic analogs were evaluated for their ability to disrupt the actin cytoskeleton. Compounds 2, 3, and 4 essentially displayed similar activity to jasplakinolide.
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