Abstract
Cyclobentinib was designed and synthesized as a novel anti-CML agent, its in vitro activity against K562 cells was evaluated by MTT assay. CB1107 showed remarkable cytotoxicity against K562 cell line with an IC50 of 0.037 ± 0.028 μmol/L, and thus it was 17-fold more potent than the reference drug Imatinib. Inducing cell apoptosis and affecting cell cycling of this compound in K562 cells were estimated by using flow cytometry and Acridine Orange/Ethidium Bromide (AO/EB) staining. The results showed that CB1107 was capable of arresting cell cycle at G0/G1 phase as well as inducing cell apoptosis significantly. Molecular mechanism of CB1107 was detected by the protein expression of Bcr-AblP210 using western blotting analysis. Downregulation of expression of Bcr-AblP210 was obviously revealed in the treatment of this tetralin amide compound. Of note, the results of these investigations suggested that CB1107 is more potent than the reference drug Imatinib against K562 cells. Additionally, in vivo results indicated that CB1107 significantly decreased tumor growth in K562 tumor-bearing Non-obese Diabetic/Severe Combined Immunodeficiency (NOD/SCID) mice. Histopathological investigation revealed that CB1107 without notable toxicity in a given dose range. These findings collectively demonstrate CB1107 is a promising candidate as a novel anti-CML agent.
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Acknowledgements
This work was supported by the Department of Science and Technology of Shenyang Government (F16-182-9-00) and Innovation Team Project from the Education Department of Liaoning province (no.: LT2015011).
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Zhou, Z., Wang, Y., Li, J. et al. Design, synthesis, and biological evaluation of Cyclobentinib (CB1107) as a potential anti-CML agent. Med Chem Res 27, 1863–1875 (2018). https://doi.org/10.1007/s00044-018-2198-5
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DOI: https://doi.org/10.1007/s00044-018-2198-5