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Synthesis and biological evaluation of new thiazolyl-urea derivatives as potential dual C-RAF/FLT3 inhibitors

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Abstract

Based on a structure-activity relationship of compounds such as Sorafenib and Quizartinib, a series of thiazol-urea derivatives containing hydrophilic side moiety were designed and synthesized, aiming to improve the druggability of target compounds. Among them, compound 6h exhibited the best anti-hepatocellular carcinoma activity, especially against HepG2 cells with an IC50 of 5.62 μM. In addition, compound 6h was able to suppress the formation of HepG2 colonies. Mechanism studies revealed that compound 6h effectively inhibited C-RAF/FLT3 kinases. Furthermore, compound 6h was able to inhibit the rapid proliferation, and exerted marked migration inhibitory effects on HepG2 cells. Moreover, compound 6h induced cell cycle arrest in G2/M phase and led to cell apoptosis. Besides, ADMET properties prediction showed that compound 6h had more aqueous solubility than Sorafenib. Collectively, these results suggested that compound 6h represents a novel C-RAF/FLT3 inhibitor deserving further investigation.

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Acknowledgements

We gratefully acknowledge the financial support from the Natural Science Foundation of Liaoning Province (2019-ZD-0693 and 2021-MS-336).

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Authors and Affiliations

  1. College of Chemistry and Environmental Engineering, Liaoning University of Technology, No. 169, Shiying Street, Guta District, **zhou, Liaoning, 121001, China

    Zhi-Hua Zhang

  2. College of Pharmacy, **zhou Medical University, No. 40, Section 3, Songpo Road, Linghe District, **zhou, Liaoning, 121001, China

    Bi-Fan Zeng, Zhe-Xue Song, Ying-Yu Yang, Kai-yun Zhang, Xue Du, Lin-lin Zhang & Dong Cai

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Correspondence to Dong Cai.

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Zhang, ZH., Zeng, BF., Song, ZX. et al. Synthesis and biological evaluation of new thiazolyl-urea derivatives as potential dual C-RAF/FLT3 inhibitors. Med Chem Res 31, 1862–1874 (2022). https://doi.org/10.1007/s00044-022-02971-2

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