Novel Isolongifolenone-Based Caprolactam Derivatives as Potential Anticancer Agents via the p53/mTOR/Autophagy Pathway

Isolongifolenone, a natural sesquiterpenoid widely used in food additives and perfume, demonstrates a range of biological activities. In this study, a series of isolongifolenone-based caprolactam derivatives (<b>E1</b>-<b>E19</b>) were designed, synthesized, and evaluated for their anticancer activities in vitro. Most of the synthesized compounds significantly inhibited the proliferation of cultured cancer cells. Compound <b>E10</b>, containing an <i>m</i>-trifluoromethyl group, demonstrated the strongest anti-proliferation activities against MCF-7 (IC₅₀ = 0.32 µM), HepG2 (IC₅₀ = 1.36 µM), and A549 (IC₅₀ = 1.39 µM) cells. Moreover, <b>E10</b> was shown to increase intracellular ROS, reduce mitochondrial function, and induce cancer cell apoptosis via the p53/mTOR/autophagy pathway. Together, these results indicate that compound <b>E10</b> induced autophagy-associated cell apoptosis in MCF-7 cancer cells. Additionally, the antitumor activity of <b>E10</b> was validated in a zebrafish MCF-7 xenograft model. The observation that <b>E10</b> exhibits potent antitumor activity in both a three-dimensional (3D) cell culture model and the zebrafish xenograft model supports the development of <b>E10</b> as a potential drug candidate for cancer therapy.