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

TL;DR

A new compound, E10, was found to strongly inhibit cancer cell growth and induce cell death through a specific pathway, suggesting its potential as a cancer drug.

Contribution

The study introduces E10, a novel isolongifolenone-based caprolactam derivative with potent anticancer activity.

Findings

Compound E10 showed strong anti-proliferation effects on MCF-7, HepG2, and A549 cancer cells.

E10 induces apoptosis via the p53/mTOR/autophagy pathway and reduces mitochondrial function.

E10's antitumor activity was confirmed in a zebrafish MCF-7 xenograft model.

Abstract

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 (E1–E19) 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 E10, containing an m-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, E10 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 E10 induced autophagy-associated cell apoptosis in MCF-7 cancer cells. Additionally, the antitumor activity of E10 was validated in a zebrafish MCF-7 xenograft model. The observation that E10 exhibits potent antitumor activity in both a three-dimensional (3D) cell culture model and the zebrafish xenograft model supports the development of E10 as a potential drug candidate for cancer therapy.

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