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

• Published in: Medicinal chemistry research Vol. 33; no. 1; pp. 66 - 76
• Main Authors: Bakhsh, Tahani, Saleh, Tamer S., Al-Saedi, Dalal A., Al-Zaydi, Khadijah M.
• Format: Journal Article
• Language: English
• Published: New York Springer US 2024; Springer Nature B.V
• Subjects: Adenosine; Affinity; Aniline; Anticancer properties; Antineoplastic drugs; Antitumor activity; Antitumor agents; Aromatic compounds; Benzonitrile; Binding; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Cell proliferation; Chemotherapy; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Doxorubicin; Drug development; Functional groups; Hydrazones; Inorganic Chemistry; Malignancy; Medicinal Chemistry; Molecular docking; NMR; Nuclear magnetic resonance; Original Research Article; Pharmacology/Toxicology; Receptor density; Receptors; Side effects; Tumor cell lines; Di(2-aryl-hydrazonopropanal) arene; Diazotized aniline; HCT116 cell; Enaminones; A2AR; LRP6
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-023-03164-1

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 (IC 50 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.