title: Highly potent artemisinin-derived dimers and trimers: Synthesis and evaluation of their antimalarial, antileukemia and antiviral activities.
abstract: New pharmaceutically active compounds can be obtained by modification of existing drugs to access more effective agents in the wake of drug resistance amongst others. To achieve this goal the concept of hybridization was established during the last decade. We employed this concept by coupling two artemisinin-derived precursors to obtain dimers or trimers with increased in vitro activity against Plasmodiumfalciparum 3D7 strain, leukemia cells (CCRF-CEM and multidrug-resistant subline CEM/ADR5000) and human cytomegalovirus (HCMV). Dimer 4 (IC50 of 2.6 nM) possess superior antimalarial activity compared with its parent compound artesunic acid(3) (IC50 of 9.0 nM). Dimer5 and trimers6 and 7 display superior potency against both leukemia cell lines (IC50 up to 0.002 μM for CCRF-CEM and IC50 up to 0.20 μM for CEM/ADR5000) and are even more active than clinically used doxorubicin (IC50 1.61 μM for CEM/ADR5000). With respect to anti-HCMV activity, trimer6 is the most efficient hybrid (IC50 0.04 μM) outperforming ganciclovir (IC50 2.6 μM), dihydroartemisinin(IC50 >10 μM) and artesunic acid (IC50 3.8 μM).
authors.affiliation: Department of Chemistry and Pharmacy, Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), University of Erlangen-Nuremberg, Henkestraße 42, 91054 Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reiter
authors.affiliation: Department of Chemistry and Pharmacy, Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), University of Erlangen-Nuremberg, Henkestraße 42, 91054 Erlangen, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Fröhlich
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gruber
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Schlossgarten 4, 91054 Erlangen, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Hutterer
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Schlossgarten 4, 91054 Erlangen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
authors.affiliation: Institute of Medical Biotechnology, University of Erlangen-Nuremberg, Paul-Gordon-Straße 3, 91052 Erlangen, Germany; Erlangen Graduate School of Advanced Optical Technologies (SAOT), Paul-Gordon-Straße 6, 91058 Erlangen, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Voigtländer
authors.affiliation: Institute of Medical Biotechnology, University of Erlangen-Nuremberg, Paul-Gordon-Straße 3, 91052 Erlangen, Germany; Erlangen Graduate School of Advanced Optical Technologies (SAOT), Paul-Gordon-Straße 6, 91058 Erlangen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Friedrich
authors.affiliation: Institute of Medical Biotechnology, University of Erlangen-Nuremberg, Paul-Gordon-Straße 3, 91052 Erlangen, Germany; Erlangen Graduate School of Advanced Optical Technologies (SAOT), Paul-Gordon-Straße 6, 91058 Erlangen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kappes
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.affiliation: Department of Chemistry and Pharmacy, Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), 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 / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015394:Molecular Structure
chemical_list: D000962:Antimalarials; D000972:Antineoplastic Agents, Phytogenic; D000998:Antiviral Agents; D037621:Artemisinins; C031327:artemisinin
keywords: Anticancer activity; Antimalarial activity; Antiviral activity; Artemisinin-derived dimers; Artemisinin-derived hybrids; Artemisinin-derived trimers