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Design and synthesis of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential Werner-dependent antiproliferative agents

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Abstract

To discover new Werner (WRN) helicase inhibitors, a series of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives were designed and synthesized through a structural optimization strategy, and the anticancer activities of 25 new target compounds against PC3, K562, and HeLa cell lines were evaluated by the MTT assay. Some of these compounds exhibited excellent inhibitory activity against three different cancer cell lines. Compounds 6a, 8i, and 13a showed better antiproliferative activity against K562 cells, with IC50 values of 3871.5, 613.6 and 134.7 nM, respectively, than did paclitaxel (35.6 nM), doxorubicin (2689.0 nM), and NSC 617145 (20.3 nM). To further verify whether the antiproliferative activity of these compounds is dependent on WRN, PC3 cells overexpressing WRN (PC3-WRN) were constructed to further study their antiproliferative potency in vitro, and the inhibition ratio and IC20 values showed that compounds 6a, 8i, and 13a were more sensitive to PC3-WRN than were the control group cells (PC3-NC). The IC20 ratios of compounds 6a, 8i, and 13a to PC3-NC and PC3-WRN were 94.3, 153.4 and 505.5, respectively. According to the docking results, the compounds 6a, 8i, and 13a overlapped well with the binding pocket of 6YHR. Further study demonstrated that among the tested compounds, 13a was the most sensitive to PC3-WRN. In summary, our research identified a series of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential WRN-dependent anticancer agents.

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Funding

This work was supported by the National Natural Science Foundations of China (82260675), the Department of Science and Technology of Guizhou Province (No. QKHPTRC[2016]5678, No. QKHZYD[2022]4015), and the Natural Science Foundation of Guizhou Province (No. QKHJC-ZK[2021]YB07, No. QKHJC-ZK[2022]ZD031). The Science and Technology Planning Project of Guizhou Province (No. QKHZC [2023]YB241, No. QKHZC [2020]4Y161), the Guizhou Province “Hundred” Level Innovative Talent Training Project (No. QKHPTRC-GCC [2022]034-1), and the Natural Science Foundation of Guizhou Medical University (No. 21NSFCP42, No. 22NSFCP24) were used.

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  1. Huimin Li and Jia Yu have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China

    Huimin Li, Jia Yu, Gang Yu, Sha Cheng, Hui Wu, Jiaomei Wei, Chang You, Kun Liu, Menghan Wang, Xueling Meng, Guangcan Xu, Heng Luo & Bixue Xu

  2. Natural Products Research Center of Guizhou Province, Guiyang, 550014, China

    Huimin Li, Jia Yu, Gang Yu, Sha Cheng, Hui Wu, Jiaomei Wei, Chang You, Kun Liu, Menghan Wang, Xueling Meng, Guangcan Xu, Heng Luo & Bixue Xu

  3. School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China

    Huimin Li

  4. College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China

    Chang You & Menghan Wang

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Correspondence to Guangcan Xu, Heng Luo or Bixue Xu.

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Li, H., Yu, J., Yu, G. et al. Design and synthesis of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential Werner-dependent antiproliferative agents. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10844-6

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