Design, synthesis and molecular docking of novel substituted azepines as inhibitors of PI3K/Akt/TSC2/mTOR signaling pathway in colorectal carcinoma.

ABSTRACT

A series of novel substituted azepines (2-7) was synthesized using both traditional and ultrasonic techniques. The efficiency of the reaction rate and yield was improved by sonication technique. We identified the newly synthesized compounds based on their melting points, elemental analyses, and spectral data. Human cancers are regulated mainly by the phosphatidylinositol 3-kinase/protein kinases B (PI3K/Akt) pathway, and its abnormal activation is linked to carcinogenesis, and angiogenesis. Using in-silico studies, we evaluated the ability of all the novel substituted diazepines and oxazepines to prevent cancer growth and metastasis by targeting the PI3K/Akt signaling pathway. Based on our findings, compounds 4a and 7a were chosen for in-vitro testing as they ranked via molecular docking the highest binding energies of -10.9, -10.3, -10.6, and -10.4 kcal/mol respectively. Compounds 4a and 7a displayed significant cytotoxicity on Caco-2 colorectal cancer cells with IC50 values of 8.445 ± 2.26 and 33.04 ± 2.06 µM, respectively. Additionally, they considerably suppressed the PI3K/Akt proteins and generated reactive oxygen species (ROS), which increased p53 and Bax, decreased Bcl-2 levels, and arrested the cell cycle at sub-G0/G1 phase. We also observed a remarkable overexpression of the Tuberous Sclerosis Complex 2 (TSC2) gene, an inhibitor of the mammalian target of rapamycin (mTOR). These results showed that compounds 4a and 7a obeyed Lipinski's rule of five and might be potential cancer treatment scaffolds by preventing metastasis and proliferation via blocking the PI3K/Akt/TSC2/m-TOR signaling pathway. This supports our hypothesis that diazepine 4a and oxazepine 7a are promising drug candidates for colorectal cancer.