title: Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy.
abstract: In only two steps and in 70% overall yield, naturally occurring trioxane artemisinin (1) was converted on a gram scale into C-10-carba trioxane dimer 3. This new, very stable dimer was then transformed easily in one additional step into four different dimers 4-7. Alcohol and diol dimers 4 and 5 and ketone dimer 7 are 10 times more antimalarially potent in vitro than artemisinin (1), and alcohol and diol dimers 4 and 5 are strongly growth inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives 8aand 9 were easily prepared in one additional step from dimers 4 and 5. Carboxylic acid dimers 8a and 9 are thermally stable even at 60 degrees C for 24 h, are more orally efficacious as antimalarials in rodents than either artelinic acid or sodium artesunate, and are strongly inhibitory but not cytotoxic toward several human cancer cell lines.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218-2685, USA. ghp@jhu.edu
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
authors.forename: Ik-Hyeon
authors.initials: IH
authors.lastname: Paik
authors.forename: Surojit
authors.initials: S
authors.lastname: Sur
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McRiner
authors.forename: Kristina
authors.initials: K
authors.lastname: Borstnik
authors.forename: Suji
authors.initials: S
authors.lastname: Xie
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Shapiro
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011108:Polymers; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014867:Water
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D011108:Polymers; D014867:Water