title: Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer.
abstract: Colorectal cancer causes 0.5 million deaths each year. To combat this type of cancer the development of new specific drug candidates is urgently needed. In the present work seven novel thymoquinone-artemisinin hybrids with different linkers were synthesized and tested for their in vitro anticancer activity against a panel of various tumor cell lines. The thymoquinone-artesunic acid hybrid 7 a, in which both subunits are connected via an ester bond, was found to be the most active compound and selectively decreased the viability of colorectal cancer cells with an IC50value of 2.4 μm (HCT116) and 2.8 μm (HT29). Remarkably, hybrid 7 a was up to 20-fold more active than its parent compounds (thymoquinone and artesunic acid), while not affecting nonmalignant colon epithelial HCEC cells (IC50>100 μm). Moreover, the activity of hybrid 7 a was superior to that of various 1:1 mixtures of thymoquinone and artesunic acid. Furthermore, hybrid 7 a was even more potent against both colon cancer cell lines than the clinically used drug 5-fluorouracil. These results are another excellent proof of the hybridization concept and confirm that the type and length of the linker play a crucial role for the biological activity of a hybrid drug. Besides an increase in reactive oxygen species (ROS), elevated levels of the DNA-damage marker γ-H2AX were observed. Both effects seem to be involved in the molecular mechanism of action for hybrid 7 a in colorectal cancer cells.
authors.affiliation: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Fröhlich
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany.
authors.forename: Benardina
authors.initials: B
authors.lastname: Ndreshkjana
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany.
authors.forename: Julienne K
authors.initials: JK
authors.lastname: Muenzner
authors.affiliation: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reiter
authors.affiliation: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hofmeister
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mederer
authors.affiliation: Department of Biology, Department of Anatomy, Cell Biology and Physiological Science, American University of Beirut, Beirut, Lebanon.
authors.forename: Maamoun
authors.initials: M
authors.lastname: Fatfat
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany.
authors.forename: Chirine
authors.identifier: 0000-0002-9015-5115
authors.initials: C
authors.lastname: El-Baba
authors.affiliation: Department of Biology, Department of Anatomy, Cell Biology and Physiological Science, American University of Beirut, Beirut, Lebanon.
authors.forename: Hala
authors.identifier: 0000-0001-6840-3015
authors.initials: H
authors.lastname: Gali-Muhtasib
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-Nürnberg, Universitätsstr. 22, 91054, Erlangen, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.affiliation: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-Nürnberg, Henkestr. 42, 91054, Erlangen, Germany.
authors.forename: Svetlana B
authors.identifier: 0000-0003-4845-0951
authors.initials: SB
authors.lastname: Tsogoeva
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D037621:Artemisinins / Q000737:chemistry*; D016227:Benzoquinones / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D016227:Benzoquinones; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; C031327:artemisinin; C003466:thymoquinone
keywords: anticancer activity; artemisinin; artesunic acid; natural product hybrids; thymoquinone