title: Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity.
abstract: 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.
authors.affiliation: Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218-2685, USA.
authors.forename: Ik-Hyeon
authors.initials: IH
authors.lastname: Paik
authors.forename: Suji
authors.initials: S
authors.lastname: Xie
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Shapiro
authors.forename: Tanzina
authors.initials: T
authors.lastname: Labonte
authors.forename: Amy A
authors.initials: AA
authors.lastname: Narducci Sarjeant
authors.forename: Astrid C
authors.initials: AC
authors.lastname: Baege
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D019281:Dimerization; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D012717:Sesquiterpenes / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D006571:Heterocyclic Compounds; D012717:Sesquiterpenes; C031327:artemisinin