Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer
Authors: Regine Schneider-Stock
Tony Fr√∂hlich
Chirine El-Baba
Hala Gali-Muhtasib
Julienne K Muenzner
Svetlana B Tsogoeva
Sandra Mederer
Elisabeth Hofmeister
Maamoun Fatfat
Christoph Reiter
Benardina Ndreshkjana
Journal: ChemMedChem (2017)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: anticancer activity; artemisinin; artesunic acid; natural product hybrids; thymoquinone.
Affiliations: Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich Alexander University of Erlangen-N√ºrnberg, Henkestr.‚Ä?2, 91054, Erlangen, Germany., Experimental Tumor Pathology, Institute of Pathology, Friedrich Alexander University of Erlangen-N√ºrnberg, Universit√§tsstr.‚Ä?2, 91054, Erlangen, Germany., Department of Biology, Department of Anatomy, Cell Biology and Physiological Science, American University of Beirut, Beirut, Lebanon.

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 IC50 value of 2.4 Œºm (HCT116) and 2.8 Œºm (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 &gt;100 Œºm). 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 Œ≥-H2AX were observed. Both effects seem to be involved in the molecular mechanism of action for hybrid 7 a in colorectal cancer cells. 

Retracted: No

PubPeer comments:
 Figure 4A. * Red box: The center H2AZ panel has six lanes, while only five were expected.  , 
 Penultimate author. https: retractionwatch.com 2016 12 29 cancer-researcher-germany-loses-multiple-papers-misconduct-finding 4 retractions to date. http: retractiondatabase.org RetractionSearch.aspx#?auth%3dSchneider-Stock%252c%2bRegine , 
 #1Thank you for pointing this out to us. The sixth lane in central H2AX (not H2AZ) panel is actually redundant, as it pertains to compound 7b, which also ran, but was cut off in other lanes because 7b was not the focus here, while first five lanes correspond to column headings in figure 4A. Please see for original membranes used for Figure 4A:  , 
 Corrigendum, May 2021, found here: https: chemistry-europe.onlinelibrary.wiley.com doi 10.1002 cmdc.202100088  *Because of author oversight at the proof correction stage, Figureu20054A contains an error. In the row for H2AX, in the middle panel (7a, Control, TQ, Art, Combi), a sixth lane band appears, when there should be only five. This sixth band is redundant and pertains to another sample lane that was not used in the manuscript. It only appears because the original blot was cropped incorrectly, thus including an extra band. The correct Figureu20054A is shown below (with the corrected panel boxed in green). This correction does not affect the original conclusions presented for that figure and the article as a whole.* I thank the authors and journal for quickly addressing this error. ,