Anti-Cancer Potential of Dehydrozingerone's Phenoxy-Acetamide Derivatives: Discovery of a Potent Lead with Dual Anti-Proliferative and Anti-Metastatic Activities

Herein, we report the design and synthesis of twenty-eight novel phenoxy-acetamide derivatives of dehydrozingerone (DHZ), aimed at exploring their potential as anticancer agents. The newly synthesized compounds were characterized using NMR, mass spectrometry, and HPLC. The in vitro anticancer activity was evaluated against MCF-7, HCT-116, and A549 cancer cell lines, where compounds 2, 4, 9, 14, 26, and 27 exhibited the highest potency, with IC₅₀ values ranging from 3.52 to 9.93 μM. These promising molecules were further tested against PC3 and Panc1 cell lines, demonstrating strong anticancer effects. Selectivity index analysis revealed that compound 14 demonstrated the highest selectivity for PC3, while compound 2 consistently exhibited notable selectivity across multiple cancer cell lines, highlighting their potential for targeted therapy. Clonogenic assays confirmed that compound 2 significantly reduced the long-term proliferative capacity of HCT-116 and MCF-7 cells in a dose-dependent manner. Mechanistic studies revealed that compound 2 induced cell cycle arrest by modulating Cyclin D1, leading to altered BAX/Bcl-2 and PARP levels, caspase cascade activation, and apoptotic cell death. Additionally, compound 2 regulated epithelial-mesenchymal transition (EMT), as evidenced by downregulation of Snail and upregulation of E-cadherin and occludin in a dose-dependent manner. Furthermore, molecular docking and ADMET predictions support compound 2 as a promising lead for anticancer drug discovery.