title: Manadoperoxides, a new class of potent antitrypanosomal agents of marine origin.
abstract: Chemical investigation of the marine sponge Plakortis cfr. lita afforded a library of endoperoxyketal polyketides, manadoperoxides B-K (3-5 and 7-13) and peroxyplakoric esters B(3) (6) and C (14). Eight of these metabolites are new compounds and some contain an unprecedented chlorine-bearing THF-type ring in the side chain. The library of endoperoxide derivatives was evaluated for in vitro activity against Trypanosoma brucei rhodesiense and Leishmania donovani. Some compounds, such as manadoperoxide B, exhibited ultrapotent trypanocidal activity (IC(50) = 3 ng mL(-1)) without cytotoxicity. Detailed examination of the antitrypanosomal activity data and comparison with those available in the literature for related dioxane derivatives enabled us to draw a series of structure-activity relationships. Interestingly, it appears that minor structural changes, such as a shift of the methyl group around the dioxane ring, can dramatically affect the antitrypanosomal activity. This information can be valuable to guide the design of optimized antitrypanosomal agents based on the dioxane scaffold.
authors.affiliation: Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chianese
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.forename: Fernando
authors.initials: F
authors.lastname: Scala
authors.forename: Roberta
authors.initials: R
authors.lastname: Teta
authors.forename: Barbara
authors.initials: B
authors.lastname: Calcinai
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bavestrello
authors.forename: Henny A
authors.initials: HA
authors.lastname: Dien
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Deniz
authors.initials: D
authors.lastname: Tasdemir
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
mesh_terms: D000818:Animals; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D010545:Peroxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047229:Plakortis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D010545:Peroxides; D014344:Trypanocidal Agents