Design, Synthesis, and Evaluation of Novel Cephalotaxine-Cinnamic Acid Derivatives Against Hepatocellular Carcinoma.

Cephalotaxine (1) is a parent compound within the cephalotaxine alkaloids class mainly derived from Cephalotaxus plants. In this study, by coupling 1 with cinnamic acid, 17 novel cephalotaxine-cinnamic acid derivatives (S1-S17) were designed and synthesized to enhance their anti-tumor efficacy. Among them, S10 showed the strongest cytotoxic activity against Huh7 cells, with the IC50 values of 9.3 and 5.9 μM after 24 h and 48 h, respectively, which were 21 and 32 times more potent than those of 1. In addition, compared with those against AML-12 cells, the proliferation inhibition rates of S10 against Huh7 cells were 5.0-fold lower, indicating a certain therapeutic window. Network pharmacology screening results indicate that S10 may exert regulatory effects closely related to cell migration and apoptosis through pathways such as PI3K/AKT. Molecular docking showed that S10 could effectively bind to the key targets PI3K and AKT. And the Western blot experiment results confirm that S10 could downregulate the expression of p-PI3K and p-AKT at the protein level while keeping total PI3K and AKT unchanged. Notably, S10 may regulate liver cancer cells by inhibiting the PI3K/AKT signaling pathway. Mechanistically, S10 induces S cycle arrest, reduces mitochondrial membrane potential, induces apoptosis, and inhibits migration and invasion. Overall, we reported S10 as a promising lead compound for the treatment of liver cancer.