title: Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonol-derived hybrid molecules against Plasmodium falciparum and multidrug-resistant human leukemia cells.
abstract: Malaria and cancer cause the death of millions of people every year. To combat these two diseases, it is important that new pharmaceutically active compounds have the ability to overcome multidrug resistance in cancer and Plasmodium falciparum strains. In search of effective anti-cancer and anti-malaria hybrids that possess improved properties compared to their parent compounds, a series of novel 1,2,4-trioxane-based hybrids incorporating egonol and/or ferrocene fragments were synthesized and tested in vitro against P. falciparum strains, CCRF-CEM cells and the multidrug-resistant P-glycoprotein-over-expressing CEM/ADR5000 cells. The most active compounds against P. falciparum strains were artesunic acid homodimers 12 and 13 (IC50 of 0.32 and 0.30 nM, respectively), whereas novel hybrids 7 (1,2,4-trioxane-ferrocene-egonol), 9 (1,2,4-trioxane-ferrocene) and 11 (artesunic acid-egonol) showed a remarkable cytotoxicity toward CCRF-CEM cells (IC50 of 0.07, 0.25 and 0.18 μM, respectively). A cooperative and synergistic effect of the three moieties 1,2,4-trioxane, ferrocene and egonol in hybrid molecule 7 is significant and is obviously stronger than in hybrids 9 (1,2,4-trioxane-ferrocene) and 11 (artesunic acid-egonol), which comprises of only two of the three considered parent compounds. Interestingly, hybrid 9 containing a 1,2,4-trioxane and a ferrocene fragment has shown to be the most effective among the studied hybrids against the tested multidrug-resistant leukemia CEM/ADR5000 cells (IC50 of 0.57 μM) and possesses a degree of cross-resistance of 2.34.
authors.affiliation: Institute of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reiter
authors.affiliation: Institute of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany.
authors.forename: Aysun
authors.initials: A
authors.lastname: Capcı Karagöz
authors.affiliation: Institute of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Fröhlich
authors.affiliation: Institute of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Klein
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Maen
authors.initials: M
authors.lastname: Zeino
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Viertel
authors.affiliation: Institute of Tropical Medicine, University of Tübingen, Wilhelmstraße 27, 72074 Tübingen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Held
authors.affiliation: Institute of Tropical Medicine, University of Tübingen, Wilhelmstraße 27, 72074 Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
authors.affiliation: Chemistry Department, Faculty of Science, Ege University, Bornova, Izmir 35100, Turkey.
authors.forename: Safiye
authors.initials: S
authors.lastname: Emirdağ Öztürk
authors.affiliation: Chemistry Department, Faculty of Science, Ege University, Bornova, Izmir 35100, Turkey.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Anıl
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.affiliation: Institute of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany. Electronic address: svetlana.tsogoeva@fau.de.
authors.forename: Svetlana B
authors.initials: SB
authors.lastname: Tsogoeva
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019070:Cell Lineage; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D000075163:Metallocenes; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D000970:Antineoplastic Agents; D001572:Benzofurans; D005296:Ferrous Compounds; D006571:Heterocyclic Compounds; D000075163:Metallocenes; C004998:ferrocene
keywords: Artemisinin; Cancer; Egonol; Ferrocene; Hybrid; Malaria