Synthesis, Biological Screening, and Binding Mode Analysis of Some N-Substituted Tetrahydroquinoline Analogs As Apoptosis Inducers and Anticancer Agents

One of the most common malignancies in the world is lung cancer. Lung cancer involves mutations in many different genes, however, EGFR, KRAS, PTEN, and PIK3CA involvement is more frequent. The lack of effective drugs and drug resistance are major issues and obstacles associated with the current treatment of lung cancer. Seven novel tetrahydroquinoline analogs were synthesized and screened against a range of cancer cell lines in this study. Among these, 17f (IC50=0.082µM) was shown to be the most potent when compared to the standard drug 5-Flurouracil (5FU) (IC50=0.28µM). Moreover, flow cytometry analysis was carried out to ascertain the nature of programmed cell death. This provides conclusive evidence of late apoptosis in all synthesized compounds when contrasted with the standard drug (5FU) and control. After comparing all of the outputs, additional binding mode analysis was carried out to determine the potential mechanism of its anticancer activity. Molecular docking and MD simulation studies were carried out, and the results show that all of the synthesized compounds 17-a-f (17f docking score -10.5 Kcal/mol) have a better binding affinity towards mTOR (PDB id: 4JT6) than both the standard drug 5FU and the co-crystal ligand X6K (docking score: -7.6 Kcal/mol). Despite the aforementioned information, strong hit compounds from this series may eventually be developed to become lead mTOR inhibitors for the treatment of lung cancer.