Anticancer Effects with Molecular Docking Confirmation of Newly Synthesized Isatin Sulfonamide Molecular Hybrid Derivatives against Hepatic Cancer Cell Lines

• Published in: Biomedicines 2022-03, Vol.10 (3), p.722
• Main Authors: Eldeeb, Mahmoud, Sanad, Eman F, Ragab, Ahmed, Ammar, Yousry A, Mahmoud, Khaled, Ali, Mamdouh M, Hamdy, Nadia M
• Format: Article
• Language: English
• Subjects: Angiogenesis; Apoptosis; Bcl-2 protein; Cell cycle; Chemicals; Cytotoxicity; Design; Doxorubicin; Drugs; Epidermal growth factor receptors; Fibroblast growth factor 2; Gene expression; Hepatocellular carcinoma; HepG2; Huh7; Hybridization; invasion; Invasiveness; isatin sulfonamides; Kinases; Laboratory animals; Liver cancer; Organic chemistry; Pharmaceuticals; Retina; Sulfonamides; Tumor cell lines; U-Plasminogen activator
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines10030722

The current study investigated the cytotoxic effect of ten sulfonamide-derived isatins, following molecular hybridization, based on the association principles, on hepatocellular carcinoma (HCC) HepG2 and Huh7 cell lines, compared for safety using human normal retina pigmented epithelial (RPE-1) cells. The ten compounds showed variable in vitro cytotoxicity on HepG2 and Huh7 cells, using the MTT assay. Four compounds (4/10) were highly cytotoxic to both HepG2 and HuH7. However, only 3 of these 4 were of the highest safety margin on RPE-1 cells in vitro and in the acute (14-day) oral toxicity study. These later, superior three compounds' structures are 3-hydroxy-3-(2-oxo-2-(p-tolyl)ethyl)-5-(piperidin-1-ylsulfonyl)indolin-2-one ( ), N-(4-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide ( ), and N-(3-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide ( ). The half-maximal inhibitory concentration (IC50) of the tested compounds ( , , and ) on HepG2 cells were approximately 16.8, 44.7, and 39.7 μM, respectively. The , , and compounds significantly decreased the angiogenic marker epithelial growth factor receptor (EGFR) level and that was further confirmed via molecular docking inside the EFGR active site (PDB: 1M17). The binding free energies ranged between -19.21 and -21.74 Kcal/mol compared to Erlotinib (-25.65 Kcal/mol). The most promising compounds, , , and , showed variable anticancer potential on "hallmarks of cancer", significant cytotoxicity, and apoptotic anti-angiogenic and anti-invasive effects, manifested as suppression of Bcl-2, urokinase plasminogen activation, and heparanase expression in HepG2-treated cells' lysate, compared to non-treated HepG2 cells. In conclusion, compound " " is highly comparable to doxorubicin regarding cell cycle arrest at G2/M, the pre-G0 phases and early and late apoptosis induction and is comparable to Erlotinib regarding binding to EGFR active site. Therefore, the current study could suggest that compound " " is, hopefully, the most safe and active synthesized isatin sulfonamide derivative for HCC management.