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SAR study of niclosamide derivatives in the human glioblastoma U-87 MG cells

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Abstract

Glioblastoma is a lethal malignant brain tumor, and the development of efficient chemotherapeutic agents remains an urgent need. Niclosamide, an anthelmintic drug, which has been used to treat tapeworm infections more than 50 years, has recently attracted renewed attention due to its evident anticancer activities. It has been shown that niclosamide induces cytotoxicity in human glioblastoma U-87 MG cells corresponding with increased protein ubiquitination, ER stress, and autophagy. Furthermore, niclosamide showed down regulation of multiple pro-survival signaling pathways including Wnt/β-catenin, PI3K/AKT, MAPK/ERK, and STAT3, which further caused reduction of U87-MG cell viability. However, the molecular mechanisms of niclosimide and its derivatives in cancer are not fully understood. In the present article, 12 niclosamide derivatives were synthesized by the replacement of substituents for the structure-activity relationship (SAR) study of the protein ubiquitination and related signaling pathways. Our approach is to identify which substituents of niclosamide play important roles in inducing cell apoptosis, inhibition of cell growth, and down regulation of cell survival signaling pathways. Our results indicate that phenol OH of niclosamide plays a significant role in the anti-glioblastoma activity, while missing Cl (5- or 2′-Cl) showed almost no such effect. 4′-N3 or CF3 has the similar activity to niclosamide (4′-NO2) whereas NH2 significantly decreased the cytotoxicity in U87 cells. These modified compounds can be tested to determine which are most effective on cancer treatment. These findings are important in the development of multi-functionalized niclosamide and drug design therapy in the future.

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Acknowledgements

The chemistry part in this manuscript is supported by College of Science SEED grant at The University of Texas Rio Grande Valley (UTRGV), and Welch Foundation departmental Grant (BX-0048). SM acknowledge the support of COS Writing-mentoring program. Valerie Tobias is also acknowledged for checking the references. Also, this work is supported by the Department of Molecular Science, School of Medicine at UTRGV and funding from the State of Texas Innovative Research and Development Program. The authors also appreciate Drs. J. G. Persons and J. Gutierrez for proofreading this manuscript.

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Authors and Affiliations

  1. Department of Chemistry, The University of Texas Rio Grande Valley, 1201 W University Drive, Edinburg, TX, 78539, USA

    Shizue Mito, Benjamin A. Garcia & Tess C. Ruiz

  2. Department of Molecular Science, School of Medicine, The University of Texas Rio Grande Valley, 5300 N L Street, McAllen, TX, 78504, USA

    Benxu Cheng, Daniela Gonzalez, Xin Yee Ooi, Francisco X. Elisarraras & Andrew Tsin

  3. Department of Health and Biomedical Sciences, The University of Texas Rio Grande Valley, One West University Boulevard, Brownsville, TX, 78520, USA

    Sue Anne Chew & Marco A. Arriaga

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  1. Shizue Mito
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Contributions

SM and BC conceptualized the study and supervised and provided support throughout the project. SM designed the modifications and interpreted the data. SM, BAG and TCR synthesized and characterized the compounds. BC, DG, XYO and FXE conducted the cell culture and Western blot analysis. AZ provided the support for biological assays. SC and MAA conducted MTT assays. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

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Correspondence to Shizue Mito.

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Mito, S., Cheng, B., Garcia, B.A. et al. SAR study of niclosamide derivatives in the human glioblastoma U-87 MG cells. Med Chem Res 31, 1313–1322 (2022). https://doi.org/10.1007/s00044-022-02907-w

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