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As our research focus on anticancer drugs, two series of novel derivatives of Flexicaulin A (FA), an ent -kaurene diterpene, condensation with amino acid trifluoroacetate were synthesized, and their anti-proliferative activity against four human cancer cell lines (TE-1, MCF-7, A549 and MGC-803) were evaluated. Compared with FA, the anticancer activity and solubility of most derivatives were significantly improved. Among them, compound 6d had the best activity, and its IC 50 value against Esophageal cancer cells (TE-1) was up to 0.75 μM. Subsequent cellular mechanism studies showed that compound 6d could inhibit the proliferation of cancer cells, the formation of cell colonies, and increase the level of ROS on TE-1 cells. In addition, 6d could up-regulate the expressions of SAPK/JNK pathway-associated proteins (p-ASK1, p-MKK4 and p-JNK) and pro-apoptotic proteins (Bak, Bad and Noxa), remarkably increase the ratio of Bax to Bcl-2 and activate Cleaved Caspase-3/9/PARP. These results indicate that compound 6d induces apoptosis through the ROS/JNK/Bcl-2 pathway and holds promising potential as an anti-proliferative agent. The schematic diagram shown the possible pathway for 6d induced apoptosis on TE-1 cells. Image 1 • Two series of novel derivatives of Flexicaulin A were discovered as potential anti-proliferative agent. • Most of the derivatives showed improved solubility and enhanced anti-proliferative activity. • Compound 6d exerted the best anti-proliferative activity against TE-1 cells. • Compound 6d could inhibit the formation of cell colonies and increase the level of ROS on TE-1 cells. • Compound 6d could induce cell apoptosis of TE-1 cells through the ROS/JNK/Bcl-2 pathway. [ABSTRACT FROM AUTHOR]