Novel urea- and piperazine-functionalized alepterolic acid derivatives: synthesis, anticancer activity, and mechanism...

Lung cancer remains the leading cause of both cancer incidence and mortality worldwide, rendering it a primary focus in oncology research. This pressing global health challenge has created an urgent demand for novel therapeutic agents with high efficacy and low toxicity. Owing to their distinctive chemical structures and wide range of biological activities, natural products have become essential resources in the development of medicines. Alepterolic acid is a natural diterpenoid from the plant Aleuritopteris argentea (Gmél.) Fée, a fern used in folk medicine in China. In this study, a total of 31 derivatives were gained by the incorporation of urea and piperazine groups into alepterolic acid. Among them, the inhibition rate of 21 compounds against A549 cells exceeded 50% at 10 μM. Specifically, the IC₅₀ values of compounds 15o and 15u against A549 cells were 1.8 ± 0.3 and 1.5 ± 0.2 μM, respectively. Moreover, it was found that the proliferation and migration of A549 cells were inhibited remarkably by both compounds 15o and 15u as the cell cycle was arrested at the G1 phase. At the molecular level, compounds 15o and 15u exhibited the ability to induce cleavage and activation of caspase-3 and caspase-9, promote PARP-1 cleavage, downregulate Bcl-2 expression, and upregulate Bax protein levels. The docking simulation results suggested that compounds 15o and 15u could stably bind to caspase-3, Bax, Bcl-2, caspase-9, and PARP-1. The physicochemical property/ADMET evaluation demonstrated that the physicochemical characteristics of compound 15o were indicative of an enhanced bioavailability. To sum up, urea- and piperazine-functionalized alepterolic acid derivatives possess significant anti-cancer activities and are worthy of further research.