Reiter Christoph, Fröhlich Tony, Gruber Lisa, Hutterer Corina, Marschall Manfred, Voigtländer Cornelia, Friedrich Oliver, Kappes Barbara, Efferth Thomas, Tsogoeva Svetlana B
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.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
Bioorg Med Chem. 2015 Sep 1;23(17):5452-8. doi: 10.1016/j.bmc.2015.07.048. Epub 2015 Jul 29.
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).
通过对现有药物进行修饰，可以获得新的具有药学活性的化合物，以便在出现耐药性等情况时获得更有效的药物。为了实现这一目标，在过去十年中建立了杂化的概念。我们运用这一概念，将两种青蒿素衍生的前体进行偶联，以获得对恶性疟原虫3D7株、白血病细胞（CCRF-CEM和多药耐药亚系CEM/ADR5000）和人巨细胞病毒（HCMV）具有增强体外活性的二聚体或三聚体。二聚体4（IC50为2.6 nM）与其母体化合物青蒿琥酯（3）（IC50为9.0 nM）相比，具有更强的抗疟活性。二聚体5以及三聚体6和7对两种白血病细胞系均显示出更强的效力（CCRF-CEM的IC50高达0.002 μM，CEM/ADR5000的IC50高达0.20 μM），甚至比临床使用的阿霉素更具活性（CEM/ADR5000的IC50为1.61 μM）。在抗HCMV活性方面，三聚体6是最有效的杂化物（IC50为0.04 μM），优于更昔洛韦（IC50为2.6 μM）、双氢青蒿素（IC50>10 μM）和青蒿琥酯（IC50为3.8 μM）。
