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Design, synthesis, and in silico studies of novel di-(2-aryl hydrozonopropanal) arene derivatives as potent anticancer for targeting A2AR and LRP6 in HCT116 cell

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Abstract

Colorectal cancer (CRC) is a frequent malignancy with a poor prognosis and a high fatality rate, unlike other malignancies. Structural improvements have been developed to better comprehend the binding of small-molecule inhibitors, reducing the side effects of chemotherapy medications. A significant functional group extensively present in both pharmacological medicines and natural compounds is the nitrile group; consequently, novel treatment compounds are desperately needed. This study aimed to design and synthesize novel anticancer drug candidates and then examine their anticancer activity against human cancer cell lines. The anti-proliferation of human colon cancer cells (HCT116) was examined using the MMT assay and compared to the activity of doxorubicin as chemotherapy after characterizing novel derivatives of di (2-aryl hydrazonopropane) arene by elemental analyzer, FTIR, 1H, 13C NMR, and ESI-MS. Chemoinformatic tools predicted their targets, and then molecular docking was performed to predict the binding affinity of compounds to the main receptors expressed in colon cancer: the adenosine receptor (A2AR) and the low-density lipoprotein receptor-related protein (LRP6). To form the corresponding diaryl hydrazone coupling products from the di-(2-aryl hydrazonopropane) arene derivatives, equivalent amounts of enaminones were coupled with diazotized aniline derivatives. Compound 11b, containing a benzonitrile moiety, was the most potent against HCT116 cells (IC50 of 0.098 ± 0.03 μM) and had a greater binding affinity to both A2AR and LRP6 of −12.43 and −16.45 kcal/mol, respectively. Our results demonstrated that the dibenzonitrile moiety is a good part of compounds that are candidates as anticancer drugs against HCT116 cells.

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Acknowledgements

This work was funded by the University of Jeddah, Jeddah, Saudi Arabia, under grant No. (UJ-23-DR-57). The authors, therefore, thank the University of Jeddah for its technical and financial support.

United States patent

Patent No.: US10,981,872B1, Date of Patent: Apr. 20, 2021.

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Authors and Affiliations

  1. Department of Biology, College of Science, University of Jeddah, Jeddah, 21589, Saudi Arabia

    Tahani Bakhsh

  2. Department of Chemistry, College of Science, University of Jeddah, Jeddah, 21589, Saudi Arabia

    Tamer S. Saleh & Khadijah M. Al-Zaydi

  3. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    Dalal A. Al-Saedi

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  1. Tahani Bakhsh
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Bakhsh, T., Saleh, T.S., Al-Saedi, D.A. et al. Design, synthesis, and in silico studies of novel di-(2-aryl hydrozonopropanal) arene derivatives as potent anticancer for targeting A2AR and LRP6 in HCT116 cell. Med Chem Res 33, 66–76 (2024). https://doi.org/10.1007/s00044-023-03164-1

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