Design, synthesis, and biological evaluation of novel dihydropyrimidinone imines as potent anticancer agents targeting AKT to induce cell cycle arrest and apoptosis in breast Cancer cells.
TL;DR
Findings indicate that compound 10 exerts efficient antineoplastic impact associated with the downregulation of the RAS/PI3K/AKT/GSK-3β pathway proteins.
Abstract
Breast cancer is a primary contributor to cancer-related mortality, particularly among females worldwide, and the number of new cases is rising annually. For a very long period, breast carcinoma was treated with chemotherapy; however, its efficacy is often limited by drug resistance and severe side effects. Accordingly, the development of safer and more effective bioactive compounds capable of halting breast neoplastic cells' proliferation and metastasis remains a critical priority. In the present study, a series of novel dihydropyrimidinone (DHPM) imines (5-14) was synthesized and characterized via different spectroscopic techniques, including NMR, mass spectroscopy, FT-IR, and elemental analysis. The binding interactions of DHPMs with the AKT protein, along with their pharmacokinetic profiles, were evaluated through in silico analysis. Subsequent in vitro studies demonstrated that compound 10 exhibited substantial toxicity on MCF-7 cells with minimal toxicity towards normal fibroblasts. Flow cytometry revealed G0/G1 cell cycle arrest and apoptosis induction by compound 10 in MCF-7 cells. This was accompanied by the downregulation of RAS, PI3K, AKT, and GSK-3β protein levels, along with upregulation of p21 and Bax and suppression of c-Myc and Bcl-2 gene expression. Moreover, compound 10 suppressed colony formation and the wound healing assay confirmed its ability to constrain cell migration. Collectively, these findings indicate that compound 10 exerts efficient antineoplastic impact associated with the downregulation of the RAS/PI3K/AKT/GSK-3β pathway proteins.