Novel magnolol–sulforaphane hybrids as potent antitumor agents: synthesis and biological characterization

The natural product-based hybrid strategy is a promising approach for innovative drug discovery. Leveraging the privileged architecture of sulforaphane-a prominent anticancer natural product-we engineered a novel library of magnolol-sulforaphane molecular hybrids for antitumor evaluation through a concise synthetic strategy for the pharmacophore of sulforaphane (SFN), culminating in the identification of CTNPC8 as a promising anticancer compound. Notably, CTNPC8 not only displays exceptional broad-spectrum anticancer activity with potency surpassing both parent compounds and cisplatin, but also exhibits potent <i>in vitro</i> efficacy against the challenging nasopharyngeal carcinoma (NPC) cell model. Mechanistic studies in nasopharyngeal carcinoma models reveal that CTNPC8 triggers mitochondrial-mediated apoptosis through regulating ROS generation and induces G₂/M phase arrest. Transcriptomic profiling coupled with validation experiments reveals that CTNPC8 exerts its anti-NPC activity primarily by modulating the Akt/mTOR pathway. The present study provided a valuable strategy for discovering new antitumor agents through hybrid molecular design, nominating CTNPC8 as a promising hit compound for anti-NPC research.